Breast Cancer

Key clinical point: In the real-world setting, adding pertuzumab to trastuzumab+chemotherapy improved overall survival (OS) in a large cohort of patients with metastatic breast cancer (BC).

Major finding: Median OS was higher with pertuzumab+trastuzumab+chemotherapy (40.2 months; 95% CI 35.6-47.8 months) vs. trastuzumab+chemotherapy (25.3 months; 95% CI 22.8-27.6 months), with pertuzumab associated with significantly reduced mortality (hazard ratio 0.66; 95% CI 0.57-0.79). The 1-year cumulative incidence of a direct hospital visit was lower in the pertuzumab+trastuzumab+chemotherapy vs. trastuzumab+chemotherapy group (P < .001).

Study details: Findings are from a population-based retrospective study including 1,158 patients with metastatic BC who received first-line treatment with pertuzumab+trastuzumab+chemotherapy (n = 579) or trastuzumab+chemotherapy (n = 579).

Disclosures: This study was supported by the Canadian Institutes of Health Research. Dr. Liu declared being an employee of ICES, which is funded by the Ontario Ministry of Health and Long-Term Care.

Source: Dai WF et al. Comparative effectiveness and safety of pertuzumab and trastuzumab plus chemotherapy vs trastuzumab plus chemotherapy for treatment of metastatic breast cancer. JAMA Netw Open. 2022;5(2):e2145460 (Feb 28). Doi: 10.1001/jamanetworkopen.2021.45460

Key clinical point: In the real-world setting, adding pertuzumab to trastuzumab+chemotherapy improved overall survival (OS) in a large cohort of patients with metastatic breast cancer (BC).

Major finding: Median OS was higher with pertuzumab+trastuzumab+chemotherapy (40.2 months; 95% CI 35.6-47.8 months) vs. trastuzumab+chemotherapy (25.3 months; 95% CI 22.8-27.6 months), with pertuzumab associated with significantly reduced mortality (hazard ratio 0.66; 95% CI 0.57-0.79). The 1-year cumulative incidence of a direct hospital visit was lower in the pertuzumab+trastuzumab+chemotherapy vs. trastuzumab+chemotherapy group (P < .001).

Study details: Findings are from a population-based retrospective study including 1,158 patients with metastatic BC who received first-line treatment with pertuzumab+trastuzumab+chemotherapy (n = 579) or trastuzumab+chemotherapy (n = 579).

Disclosures: This study was supported by the Canadian Institutes of Health Research. Dr. Liu declared being an employee of ICES, which is funded by the Ontario Ministry of Health and Long-Term Care.

Source: Dai WF et al. Comparative effectiveness and safety of pertuzumab and trastuzumab plus chemotherapy vs trastuzumab plus chemotherapy for treatment of metastatic breast cancer. JAMA Netw Open. 2022;5(2):e2145460 (Feb 28). Doi: 10.1001/jamanetworkopen.2021.45460

Key clinical point: In the real-world setting, adding pertuzumab to trastuzumab+chemotherapy improved overall survival (OS) in a large cohort of patients with metastatic breast cancer (BC).

Major finding: Median OS was higher with pertuzumab+trastuzumab+chemotherapy (40.2 months; 95% CI 35.6-47.8 months) vs. trastuzumab+chemotherapy (25.3 months; 95% CI 22.8-27.6 months), with pertuzumab associated with significantly reduced mortality (hazard ratio 0.66; 95% CI 0.57-0.79). The 1-year cumulative incidence of a direct hospital visit was lower in the pertuzumab+trastuzumab+chemotherapy vs. trastuzumab+chemotherapy group (P < .001).

Study details: Findings are from a population-based retrospective study including 1,158 patients with metastatic BC who received first-line treatment with pertuzumab+trastuzumab+chemotherapy (n = 579) or trastuzumab+chemotherapy (n = 579).

Disclosures: This study was supported by the Canadian Institutes of Health Research. Dr. Liu declared being an employee of ICES, which is funded by the Ontario Ministry of Health and Long-Term Care.

Source: Dai WF et al. Comparative effectiveness and safety of pertuzumab and trastuzumab plus chemotherapy vs trastuzumab plus chemotherapy for treatment of metastatic breast cancer. JAMA Netw Open. 2022;5(2):e2145460 (Feb 28). Doi: 10.1001/jamanetworkopen.2021.45460

Key clinical point: HD201, a trastuzumab biosimilar, and reference trastuzumab display equivalence in terms of efficacy (along with a similar safety profile) in patients with human epidermal growth factor receptor 2 (ERBB2)-positive early breast cancer (BC) treated in the neoadjuvant setting.

Major finding: At the time of surgery, the rate of total pathological complete response with HD201 vs. referent trastuzumab was 45% vs. 48.7%, respectively, with the difference between the groups within the predefined equivalence margin (−3.8%; 95% CI −12.8% to 5.4%). Treatment-emergent adverse events of special interest for trastuzumab were reported by 88% and 84.5% of patients receiving HD201 and trastuzumab, respectively.

Study details: Findings are from the phase 3 TROIKA study including 502 women with ERBB2-positive early BC who were randomly assigned to receive HD201 or trastuzumab in a neoadjuvant setting along with chemotherapy.

Disclosures: This study was funded by Prestige BioPharma Ltd. Some of the authors declared serving as unpaid advisors or receiving personal fees and grants from several sources, including Prestige BioPharma Ltd. Three authors declared being employees of DICE Ltd.

Source: Pivot X et al. Efficacy of HD201 vs referent trastuzumab in patients with ERBB2-positive breast cancer treated in the neoadjuvant setting: A multicenter phase 3 randomized clinical trial. JAMA Oncol. 2022 (Mar 3). Doi: 10.1001/jamaoncol.2021.8171

Key clinical point: HD201, a trastuzumab biosimilar, and reference trastuzumab display equivalence in terms of efficacy (along with a similar safety profile) in patients with human epidermal growth factor receptor 2 (ERBB2)-positive early breast cancer (BC) treated in the neoadjuvant setting.

Major finding: At the time of surgery, the rate of total pathological complete response with HD201 vs. referent trastuzumab was 45% vs. 48.7%, respectively, with the difference between the groups within the predefined equivalence margin (−3.8%; 95% CI −12.8% to 5.4%). Treatment-emergent adverse events of special interest for trastuzumab were reported by 88% and 84.5% of patients receiving HD201 and trastuzumab, respectively.

Study details: Findings are from the phase 3 TROIKA study including 502 women with ERBB2-positive early BC who were randomly assigned to receive HD201 or trastuzumab in a neoadjuvant setting along with chemotherapy.

Disclosures: This study was funded by Prestige BioPharma Ltd. Some of the authors declared serving as unpaid advisors or receiving personal fees and grants from several sources, including Prestige BioPharma Ltd. Three authors declared being employees of DICE Ltd.

Source: Pivot X et al. Efficacy of HD201 vs referent trastuzumab in patients with ERBB2-positive breast cancer treated in the neoadjuvant setting: A multicenter phase 3 randomized clinical trial. JAMA Oncol. 2022 (Mar 3). Doi: 10.1001/jamaoncol.2021.8171

Key clinical point: HD201, a trastuzumab biosimilar, and reference trastuzumab display equivalence in terms of efficacy (along with a similar safety profile) in patients with human epidermal growth factor receptor 2 (ERBB2)-positive early breast cancer (BC) treated in the neoadjuvant setting.

Major finding: At the time of surgery, the rate of total pathological complete response with HD201 vs. referent trastuzumab was 45% vs. 48.7%, respectively, with the difference between the groups within the predefined equivalence margin (−3.8%; 95% CI −12.8% to 5.4%). Treatment-emergent adverse events of special interest for trastuzumab were reported by 88% and 84.5% of patients receiving HD201 and trastuzumab, respectively.

Study details: Findings are from the phase 3 TROIKA study including 502 women with ERBB2-positive early BC who were randomly assigned to receive HD201 or trastuzumab in a neoadjuvant setting along with chemotherapy.

Disclosures: This study was funded by Prestige BioPharma Ltd. Some of the authors declared serving as unpaid advisors or receiving personal fees and grants from several sources, including Prestige BioPharma Ltd. Three authors declared being employees of DICE Ltd.

Source: Pivot X et al. Efficacy of HD201 vs referent trastuzumab in patients with ERBB2-positive breast cancer treated in the neoadjuvant setting: A multicenter phase 3 randomized clinical trial. JAMA Oncol. 2022 (Mar 3). Doi: 10.1001/jamaoncol.2021.8171

Key clinical point: Patients with metastatic breast cancer (BC) with a lobular subtype may have worse outcomes compared with those with a ductal subtype.

Major finding: Invasive lobular carcinoma (ILC) vs. invasive ductal carcinoma (IDC) subtype was significantly associated with worse survival (hazard ratio [HR] 1.31; P < .0001) and progression-free survival (HR 1.15; P < .0001).

Study details: Findings are from a retrospective analysis of 13,111 patients with metastatic BC with ILC (13.8%) or IDC (86.2%) subtype from the UNICANCER Epidemiological Strategy and Medico Economics (ESME)-metastatic BC cohort.

Disclosures: ESME is supported by Roche, Pfizer, and other pharmaceutical companies. The authors declared no conflicts of interest.

Source: Dalenc F et al. Impact of lobular versus ductal histology on overall survival in metastatic breast cancer: a French retrospective multicentre cohort study. Eur J Cancer. 2022;164:70-79 (Feb 14). Doi: 10.1016/j.ejca.2021.12.031

Key clinical point: Patients with metastatic breast cancer (BC) with a lobular subtype may have worse outcomes compared with those with a ductal subtype.

Major finding: Invasive lobular carcinoma (ILC) vs. invasive ductal carcinoma (IDC) subtype was significantly associated with worse survival (hazard ratio [HR] 1.31; P < .0001) and progression-free survival (HR 1.15; P < .0001).

Study details: Findings are from a retrospective analysis of 13,111 patients with metastatic BC with ILC (13.8%) or IDC (86.2%) subtype from the UNICANCER Epidemiological Strategy and Medico Economics (ESME)-metastatic BC cohort.

Disclosures: ESME is supported by Roche, Pfizer, and other pharmaceutical companies. The authors declared no conflicts of interest.

Source: Dalenc F et al. Impact of lobular versus ductal histology on overall survival in metastatic breast cancer: a French retrospective multicentre cohort study. Eur J Cancer. 2022;164:70-79 (Feb 14). Doi: 10.1016/j.ejca.2021.12.031

Key clinical point: Patients with metastatic breast cancer (BC) with a lobular subtype may have worse outcomes compared with those with a ductal subtype.

Major finding: Invasive lobular carcinoma (ILC) vs. invasive ductal carcinoma (IDC) subtype was significantly associated with worse survival (hazard ratio [HR] 1.31; P < .0001) and progression-free survival (HR 1.15; P < .0001).

Study details: Findings are from a retrospective analysis of 13,111 patients with metastatic BC with ILC (13.8%) or IDC (86.2%) subtype from the UNICANCER Epidemiological Strategy and Medico Economics (ESME)-metastatic BC cohort.

Disclosures: ESME is supported by Roche, Pfizer, and other pharmaceutical companies. The authors declared no conflicts of interest.

Source: Dalenc F et al. Impact of lobular versus ductal histology on overall survival in metastatic breast cancer: a French retrospective multicentre cohort study. Eur J Cancer. 2022;164:70-79 (Feb 14). Doi: 10.1016/j.ejca.2021.12.031

Key clinical point: The addition of atezolizumab to chemotherapy with nanoparticle albumin-bound nab-paclitaxel and carboplatin failed to improve pathological complete response (pCR) rates compared with chemotherapy alone in early high-risk, locally advanced, triple-negative breast cancer (TNBC).

Major finding: The rate of pCR was not significantly different between atezolizumab and non-atezolizumab treatment arms (48.6% vs. 44.4%; odds ratio 1.18; P = .48). Serious adverse events and any grade liver transaminase abnormalities were higher in the atezolizumab vs. non-atezolizumab treatment arm (P = .001).

Study details: Findings are from the NeoTRIP study including 280 women with early high-risk, locally advanced TNBC who were randomly assigned to receive neoadjuvant carboplatin and nab-paclitaxel with or without atezolizumab.

Disclosures: This study was supported by Fondazione Michelangelo. The authors declared serving on advisory boards or receiving consulting fees, honoraria, grants, support for attending meetings, and other nonfinancial support from several sources.

Source: Gianni L et al. Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study. Ann Oncol. 2022 (Feb 16). Doi: 10.1016/j.annonc.2022.02.004

Key clinical point: The addition of atezolizumab to chemotherapy with nanoparticle albumin-bound nab-paclitaxel and carboplatin failed to improve pathological complete response (pCR) rates compared with chemotherapy alone in early high-risk, locally advanced, triple-negative breast cancer (TNBC).

Major finding: The rate of pCR was not significantly different between atezolizumab and non-atezolizumab treatment arms (48.6% vs. 44.4%; odds ratio 1.18; P = .48). Serious adverse events and any grade liver transaminase abnormalities were higher in the atezolizumab vs. non-atezolizumab treatment arm (P = .001).

Study details: Findings are from the NeoTRIP study including 280 women with early high-risk, locally advanced TNBC who were randomly assigned to receive neoadjuvant carboplatin and nab-paclitaxel with or without atezolizumab.

Disclosures: This study was supported by Fondazione Michelangelo. The authors declared serving on advisory boards or receiving consulting fees, honoraria, grants, support for attending meetings, and other nonfinancial support from several sources.

Source: Gianni L et al. Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study. Ann Oncol. 2022 (Feb 16). Doi: 10.1016/j.annonc.2022.02.004

Key clinical point: The addition of atezolizumab to chemotherapy with nanoparticle albumin-bound nab-paclitaxel and carboplatin failed to improve pathological complete response (pCR) rates compared with chemotherapy alone in early high-risk, locally advanced, triple-negative breast cancer (TNBC).

Major finding: The rate of pCR was not significantly different between atezolizumab and non-atezolizumab treatment arms (48.6% vs. 44.4%; odds ratio 1.18; P = .48). Serious adverse events and any grade liver transaminase abnormalities were higher in the atezolizumab vs. non-atezolizumab treatment arm (P = .001).

Study details: Findings are from the NeoTRIP study including 280 women with early high-risk, locally advanced TNBC who were randomly assigned to receive neoadjuvant carboplatin and nab-paclitaxel with or without atezolizumab.

Disclosures: This study was supported by Fondazione Michelangelo. The authors declared serving on advisory boards or receiving consulting fees, honoraria, grants, support for attending meetings, and other nonfinancial support from several sources.

Source: Gianni L et al. Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study. Ann Oncol. 2022 (Feb 16). Doi: 10.1016/j.annonc.2022.02.004

Key clinical point: Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab postsurgery significantly prolonged event-free survival (EFS) compared with neoadjuvant chemotherapy alone in patients with early triple-negative breast cancer (TNBC).

Major finding: At 36 months, estimated EFS significantly improved in the pembrolizumab-chemotherapy vs. placebo-chemotherapy group (84.5% vs. 76.8%; hazard ratio for event or death, 0.63; P < .001). No new adverse events were reported.

Study details: Findings are from an interim analysis of the phase 3 KEYNOTE-522 study including 1,174 patients with early, previously untreated stage II/III TNBC who were randomly assigned to receive neoadjuvant therapy with pembrolizumab or placebo. In the adjuvant phase, patients received pembrolizumab or placebo after definitive surgery and radiotherapy, if indicated.

Disclosures: This study was supported by Merck Sharp and Dohme. The authors declared serving as consultants, advisory board members, or receiving research grants, contracts, and honoraria from several sources, including Merck/Merck Sharp and Dohme. Four authors declared being employees and stock/stock option owners of Merck/Merck Sharp and Dohme.

Source: Schmid P et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567 (Feb 10). Doi: 10.1056/NEJMoa2112651

Key clinical point: Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab postsurgery significantly prolonged event-free survival (EFS) compared with neoadjuvant chemotherapy alone in patients with early triple-negative breast cancer (TNBC).

Major finding: At 36 months, estimated EFS significantly improved in the pembrolizumab-chemotherapy vs. placebo-chemotherapy group (84.5% vs. 76.8%; hazard ratio for event or death, 0.63; P < .001). No new adverse events were reported.

Study details: Findings are from an interim analysis of the phase 3 KEYNOTE-522 study including 1,174 patients with early, previously untreated stage II/III TNBC who were randomly assigned to receive neoadjuvant therapy with pembrolizumab or placebo. In the adjuvant phase, patients received pembrolizumab or placebo after definitive surgery and radiotherapy, if indicated.

Disclosures: This study was supported by Merck Sharp and Dohme. The authors declared serving as consultants, advisory board members, or receiving research grants, contracts, and honoraria from several sources, including Merck/Merck Sharp and Dohme. Four authors declared being employees and stock/stock option owners of Merck/Merck Sharp and Dohme.

Source: Schmid P et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567 (Feb 10). Doi: 10.1056/NEJMoa2112651

Key clinical point: Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab postsurgery significantly prolonged event-free survival (EFS) compared with neoadjuvant chemotherapy alone in patients with early triple-negative breast cancer (TNBC).

Major finding: At 36 months, estimated EFS significantly improved in the pembrolizumab-chemotherapy vs. placebo-chemotherapy group (84.5% vs. 76.8%; hazard ratio for event or death, 0.63; P < .001). No new adverse events were reported.

Study details: Findings are from an interim analysis of the phase 3 KEYNOTE-522 study including 1,174 patients with early, previously untreated stage II/III TNBC who were randomly assigned to receive neoadjuvant therapy with pembrolizumab or placebo. In the adjuvant phase, patients received pembrolizumab or placebo after definitive surgery and radiotherapy, if indicated.

Disclosures: This study was supported by Merck Sharp and Dohme. The authors declared serving as consultants, advisory board members, or receiving research grants, contracts, and honoraria from several sources, including Merck/Merck Sharp and Dohme. Four authors declared being employees and stock/stock option owners of Merck/Merck Sharp and Dohme.

Source: Schmid P et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567 (Feb 10). Doi: 10.1056/NEJMoa2112651

Doctors’ opinions about whether to treat women with osteoporosis with hormone therapy vary. Guidelines by medical societies including those of the American College of Physicians, on the other hand, generally do not recommend it as a first line therapy for the disease, at least in part due to the risks associated with taking it.

This type of hormone therapy (HT) can be given as estrogen or a combination of hormones including estrogen. The physicians interviewed for this piece who prescribe HT for osteoporosis suggest the benefits outweigh the downsides to its use for some of their patients. But such doctors may be a minority group, suggests Michael R. McClung, MD, founding director of the Oregon Osteoporosis Center, Portland.

According to Dr. McClung, HT is now rarely prescribed as treatment – as opposed to prevention – for osteoporosis in the absence of additional benefits such as reducing vasomotor symptoms.

Researchers’ findings on HT use in women with osteoporosis are complex. While HT is approved for menopausal prevention of osteoporosis, it is not indicated as a treatment for the disease by the Food and Drug Administration. See the prescribing information for Premarin tablets, which contain a mixture of estrogen hormones, for an example of the FDA’s indications and usage for the type of HT addressed in this article.
 

Women’s Health Initiative findings

The Women’s Health Initiative (WHI) hormone therapy trials showed that HT reduces the incidence of all osteoporosis-related fractures in postmenopausal women, even those at low risk of fracture, but osteoporosis-related fractures was not a study endpoint. These trials also revealed that HT was associated with increased risks of cardiovascular and cerebrovascular events, an increased risk of breast cancer, and other adverse health outcomes.

The release of the interim results of the WHI trials in 2002 led to a fair amount of fear and confusion about the use of HT after menopause. After the WHI findings were published, estrogen use dropped dramatically, but for everything, including for vasomotor symptoms and the prevention and treatment of osteoporosis.

Prior to the WHI study, it was very common for hormone therapy to be prescribed as women neared or entered menopause, said Risa Kagan MD, clinical professor of obstetrics, gynecology, and reproductive sciences, University of California, San Francisco.

“When a woman turned 50, that was one of the first things we did – was to put her on hormone therapy. All that changed with the WHI, but now we are coming full circle,” noted Dr. Kagan, who currently prescribes HT as first line treatment for osteoporosis to some women.
 

Hormone therapy’s complex history

HT’s ability to reduce bone loss in postmenopausal women is well-documented in many papers, including one published March 8, 2018, in Osteoporosis International, by Dr. Kagan and colleagues. This reduced bone loss has been shown to significantly reduce fractures in patients with low bone mass and osteoporosis.

While a growing number of therapies are now available to treat osteoporosis, HT was traditionally viewed as a standard method of preventing fractures in this population. It was also widely used to prevent other types of symptoms associated with the menopause, such as hot flashes, night sweats, and sleep disturbances, and multiple observational studies had demonstrated that its use appeared to reduce the incidence of cardiovascular disease (CVD) in symptomatic menopausal women who initiated HT in early menopause.

Even though the WHI studies were the largest randomized trials ever performed in postmenopausal women, they had notable limitations, according to Dr. Kagan.

“The women were older – the average age was 63 years,” she said. “And they only investigated one route and one dose of estrogen.”

Since then, many different formulations and routes of administration with more favorable safety profiles than what was used in the WHI have become available.

It’s both scientifically and clinically unsound to extrapolate the unfavorable risk-benefit profile of HT seen in the WHI trials to all women regardless of age, HT dosage or formulation, or the length of time they’re on it, she added.
 

Today’s use of HT in women with osteoporosis

Re-analyses and follow-up studies from the WHI trials, along with data from other studies, have suggested that the benefit-risk profiles of HT are affected by a variety of factors. These include the timing of use in relation to menopause and chronological age and the type of hormone regimen.

“Clinically, many advocate for [hormone therapy] use, especially in the newer younger postmenopausal women to prevent bone loss, but also in younger women who are diagnosed with osteoporosis and then as they get older transition to more bone specific agents,” noted Dr. Kagan.

“Some advocate preserving bone mass and preventing osteoporosis and even treating the younger newly postmenopausal women who have no contraindications with hormone therapy initially, and then gradually transitioning them to a bone specific agent as they get older and at risk for fracture.

“If a woman is already fractured and/or has very low bone density with no other obvious secondary metabolic reason, we also often advocate anabolic agents for 1-2 years then consider estrogen for maintenance – again, if [there is] no contraindication to using HT,” she added.

Thus, an individualized approach is recommended to determine a woman’s risk-benefit ratio of HT use based on the absolute risk of adverse effects, Dr. Kagan noted.

“Transdermal and low/ultra-low doses of HT, have a favorable risk profile, and are effective in preserving bone mineral density and bone quality in many women,” she said.

According to Dr. McClung, HT “is most often used for treatment in women in whom hormone therapy was begun for hot flashes and then, when osteoporosis was found later, was simply continued.

“Society guidelines are cautious about recommending hormone therapy for osteoporosis treatment since estrogen is not approved for treatment, despite the clear fracture protection benefit observed in the WHI study,” he said. “Since [women in the WHI trials] were not recruited as having osteoporosis, those results do not meet the FDA requirement for treatment approval, namely the reduction in fracture risk in patients with osteoporosis. However, knowing what we know about the salutary skeletal effects of estrogen, many of us do use them in our patients with osteoporosis – although not prescribed for that purpose.”
 

Additional scenarios when doctors may advise HT

“I often recommend – and I think colleagues do as well – that women with recent menopause and menopausal symptoms who also have low bone mineral density or even scores showing osteoporosis see their gynecologist to discuss HT for a few years, perhaps until age 60 if no contraindications, and if it is well tolerated,” said Ethel S. Siris, MD, professor of medicine at Columbia University Medical Center in New York.

“Once they stop it we can then give one of our other bone drugs, but it delays the need to start them since on adequate estrogen the bone density should remain stable while they take it,” added Dr. Siris, an endocrinologist and internist, and director of the Toni Stabile Osteoporosis Center in New York. “They may need a bisphosphonate or another bone drug to further protect them from bone loss and future fracture [after stopping HT].”

Victor L. Roberts, MD, founder of Endocrine Associates of Florida, Lake Mary, pointed out that women now have many options for treatment of osteoporosis.

“If a woman is in early menopause and is having other symptoms, then estrogen is warranted,” he said. “If she has osteoporosis, then it’s a bonus.”

“We have better agents that are bone specific,” for a patient who presents with osteoporosis and no other symptoms, he said.

“If a woman is intolerant of alendronate or other similar drugs, or chooses not to have an injectable, then estrogen or a SERM [selective estrogen receptor modulator] would be an option.”

Dr. Roberts added that HT would be more of a niche drug.

“It has a role and documented benefit and works,” he said. “There is good scientific data for the use of estrogen.”

Dr. Kagan is a consultant for Pfizer, Therapeutics MD, Amgen, on the Medical and Scientific Advisory Board of American Bone Health. The other  experts interviewed for this piece reported no conflicts.

Doctors’ opinions about whether to treat women with osteoporosis with hormone therapy vary. Guidelines by medical societies including those of the American College of Physicians, on the other hand, generally do not recommend it as a first line therapy for the disease, at least in part due to the risks associated with taking it.

This type of hormone therapy (HT) can be given as estrogen or a combination of hormones including estrogen. The physicians interviewed for this piece who prescribe HT for osteoporosis suggest the benefits outweigh the downsides to its use for some of their patients. But such doctors may be a minority group, suggests Michael R. McClung, MD, founding director of the Oregon Osteoporosis Center, Portland.

According to Dr. McClung, HT is now rarely prescribed as treatment – as opposed to prevention – for osteoporosis in the absence of additional benefits such as reducing vasomotor symptoms.

Researchers’ findings on HT use in women with osteoporosis are complex. While HT is approved for menopausal prevention of osteoporosis, it is not indicated as a treatment for the disease by the Food and Drug Administration. See the prescribing information for Premarin tablets, which contain a mixture of estrogen hormones, for an example of the FDA’s indications and usage for the type of HT addressed in this article.
 

Women’s Health Initiative findings

The Women’s Health Initiative (WHI) hormone therapy trials showed that HT reduces the incidence of all osteoporosis-related fractures in postmenopausal women, even those at low risk of fracture, but osteoporosis-related fractures was not a study endpoint. These trials also revealed that HT was associated with increased risks of cardiovascular and cerebrovascular events, an increased risk of breast cancer, and other adverse health outcomes.

The release of the interim results of the WHI trials in 2002 led to a fair amount of fear and confusion about the use of HT after menopause. After the WHI findings were published, estrogen use dropped dramatically, but for everything, including for vasomotor symptoms and the prevention and treatment of osteoporosis.

Prior to the WHI study, it was very common for hormone therapy to be prescribed as women neared or entered menopause, said Risa Kagan MD, clinical professor of obstetrics, gynecology, and reproductive sciences, University of California, San Francisco.

“When a woman turned 50, that was one of the first things we did – was to put her on hormone therapy. All that changed with the WHI, but now we are coming full circle,” noted Dr. Kagan, who currently prescribes HT as first line treatment for osteoporosis to some women.
 

Hormone therapy’s complex history

HT’s ability to reduce bone loss in postmenopausal women is well-documented in many papers, including one published March 8, 2018, in Osteoporosis International, by Dr. Kagan and colleagues. This reduced bone loss has been shown to significantly reduce fractures in patients with low bone mass and osteoporosis.

While a growing number of therapies are now available to treat osteoporosis, HT was traditionally viewed as a standard method of preventing fractures in this population. It was also widely used to prevent other types of symptoms associated with the menopause, such as hot flashes, night sweats, and sleep disturbances, and multiple observational studies had demonstrated that its use appeared to reduce the incidence of cardiovascular disease (CVD) in symptomatic menopausal women who initiated HT in early menopause.

Even though the WHI studies were the largest randomized trials ever performed in postmenopausal women, they had notable limitations, according to Dr. Kagan.

“The women were older – the average age was 63 years,” she said. “And they only investigated one route and one dose of estrogen.”

Since then, many different formulations and routes of administration with more favorable safety profiles than what was used in the WHI have become available.

It’s both scientifically and clinically unsound to extrapolate the unfavorable risk-benefit profile of HT seen in the WHI trials to all women regardless of age, HT dosage or formulation, or the length of time they’re on it, she added.
 

Today’s use of HT in women with osteoporosis

Re-analyses and follow-up studies from the WHI trials, along with data from other studies, have suggested that the benefit-risk profiles of HT are affected by a variety of factors. These include the timing of use in relation to menopause and chronological age and the type of hormone regimen.

“Clinically, many advocate for [hormone therapy] use, especially in the newer younger postmenopausal women to prevent bone loss, but also in younger women who are diagnosed with osteoporosis and then as they get older transition to more bone specific agents,” noted Dr. Kagan.

“Some advocate preserving bone mass and preventing osteoporosis and even treating the younger newly postmenopausal women who have no contraindications with hormone therapy initially, and then gradually transitioning them to a bone specific agent as they get older and at risk for fracture.

“If a woman is already fractured and/or has very low bone density with no other obvious secondary metabolic reason, we also often advocate anabolic agents for 1-2 years then consider estrogen for maintenance – again, if [there is] no contraindication to using HT,” she added.

Thus, an individualized approach is recommended to determine a woman’s risk-benefit ratio of HT use based on the absolute risk of adverse effects, Dr. Kagan noted.

“Transdermal and low/ultra-low doses of HT, have a favorable risk profile, and are effective in preserving bone mineral density and bone quality in many women,” she said.

According to Dr. McClung, HT “is most often used for treatment in women in whom hormone therapy was begun for hot flashes and then, when osteoporosis was found later, was simply continued.

“Society guidelines are cautious about recommending hormone therapy for osteoporosis treatment since estrogen is not approved for treatment, despite the clear fracture protection benefit observed in the WHI study,” he said. “Since [women in the WHI trials] were not recruited as having osteoporosis, those results do not meet the FDA requirement for treatment approval, namely the reduction in fracture risk in patients with osteoporosis. However, knowing what we know about the salutary skeletal effects of estrogen, many of us do use them in our patients with osteoporosis – although not prescribed for that purpose.”
 

Additional scenarios when doctors may advise HT

“I often recommend – and I think colleagues do as well – that women with recent menopause and menopausal symptoms who also have low bone mineral density or even scores showing osteoporosis see their gynecologist to discuss HT for a few years, perhaps until age 60 if no contraindications, and if it is well tolerated,” said Ethel S. Siris, MD, professor of medicine at Columbia University Medical Center in New York.

“Once they stop it we can then give one of our other bone drugs, but it delays the need to start them since on adequate estrogen the bone density should remain stable while they take it,” added Dr. Siris, an endocrinologist and internist, and director of the Toni Stabile Osteoporosis Center in New York. “They may need a bisphosphonate or another bone drug to further protect them from bone loss and future fracture [after stopping HT].”

Victor L. Roberts, MD, founder of Endocrine Associates of Florida, Lake Mary, pointed out that women now have many options for treatment of osteoporosis.

“If a woman is in early menopause and is having other symptoms, then estrogen is warranted,” he said. “If she has osteoporosis, then it’s a bonus.”

“We have better agents that are bone specific,” for a patient who presents with osteoporosis and no other symptoms, he said.

“If a woman is intolerant of alendronate or other similar drugs, or chooses not to have an injectable, then estrogen or a SERM [selective estrogen receptor modulator] would be an option.”

Dr. Roberts added that HT would be more of a niche drug.

“It has a role and documented benefit and works,” he said. “There is good scientific data for the use of estrogen.”

Dr. Kagan is a consultant for Pfizer, Therapeutics MD, Amgen, on the Medical and Scientific Advisory Board of American Bone Health. The other  experts interviewed for this piece reported no conflicts.

Doctors’ opinions about whether to treat women with osteoporosis with hormone therapy vary. Guidelines by medical societies including those of the American College of Physicians, on the other hand, generally do not recommend it as a first line therapy for the disease, at least in part due to the risks associated with taking it.

This type of hormone therapy (HT) can be given as estrogen or a combination of hormones including estrogen. The physicians interviewed for this piece who prescribe HT for osteoporosis suggest the benefits outweigh the downsides to its use for some of their patients. But such doctors may be a minority group, suggests Michael R. McClung, MD, founding director of the Oregon Osteoporosis Center, Portland.

According to Dr. McClung, HT is now rarely prescribed as treatment – as opposed to prevention – for osteoporosis in the absence of additional benefits such as reducing vasomotor symptoms.

Researchers’ findings on HT use in women with osteoporosis are complex. While HT is approved for menopausal prevention of osteoporosis, it is not indicated as a treatment for the disease by the Food and Drug Administration. See the prescribing information for Premarin tablets, which contain a mixture of estrogen hormones, for an example of the FDA’s indications and usage for the type of HT addressed in this article.
 

Women’s Health Initiative findings

The Women’s Health Initiative (WHI) hormone therapy trials showed that HT reduces the incidence of all osteoporosis-related fractures in postmenopausal women, even those at low risk of fracture, but osteoporosis-related fractures was not a study endpoint. These trials also revealed that HT was associated with increased risks of cardiovascular and cerebrovascular events, an increased risk of breast cancer, and other adverse health outcomes.

The release of the interim results of the WHI trials in 2002 led to a fair amount of fear and confusion about the use of HT after menopause. After the WHI findings were published, estrogen use dropped dramatically, but for everything, including for vasomotor symptoms and the prevention and treatment of osteoporosis.

Prior to the WHI study, it was very common for hormone therapy to be prescribed as women neared or entered menopause, said Risa Kagan MD, clinical professor of obstetrics, gynecology, and reproductive sciences, University of California, San Francisco.

“When a woman turned 50, that was one of the first things we did – was to put her on hormone therapy. All that changed with the WHI, but now we are coming full circle,” noted Dr. Kagan, who currently prescribes HT as first line treatment for osteoporosis to some women.
 

Hormone therapy’s complex history

HT’s ability to reduce bone loss in postmenopausal women is well-documented in many papers, including one published March 8, 2018, in Osteoporosis International, by Dr. Kagan and colleagues. This reduced bone loss has been shown to significantly reduce fractures in patients with low bone mass and osteoporosis.

While a growing number of therapies are now available to treat osteoporosis, HT was traditionally viewed as a standard method of preventing fractures in this population. It was also widely used to prevent other types of symptoms associated with the menopause, such as hot flashes, night sweats, and sleep disturbances, and multiple observational studies had demonstrated that its use appeared to reduce the incidence of cardiovascular disease (CVD) in symptomatic menopausal women who initiated HT in early menopause.

Even though the WHI studies were the largest randomized trials ever performed in postmenopausal women, they had notable limitations, according to Dr. Kagan.

“The women were older – the average age was 63 years,” she said. “And they only investigated one route and one dose of estrogen.”

Since then, many different formulations and routes of administration with more favorable safety profiles than what was used in the WHI have become available.

It’s both scientifically and clinically unsound to extrapolate the unfavorable risk-benefit profile of HT seen in the WHI trials to all women regardless of age, HT dosage or formulation, or the length of time they’re on it, she added.
 

Today’s use of HT in women with osteoporosis

Re-analyses and follow-up studies from the WHI trials, along with data from other studies, have suggested that the benefit-risk profiles of HT are affected by a variety of factors. These include the timing of use in relation to menopause and chronological age and the type of hormone regimen.

“Clinically, many advocate for [hormone therapy] use, especially in the newer younger postmenopausal women to prevent bone loss, but also in younger women who are diagnosed with osteoporosis and then as they get older transition to more bone specific agents,” noted Dr. Kagan.

“Some advocate preserving bone mass and preventing osteoporosis and even treating the younger newly postmenopausal women who have no contraindications with hormone therapy initially, and then gradually transitioning them to a bone specific agent as they get older and at risk for fracture.

“If a woman is already fractured and/or has very low bone density with no other obvious secondary metabolic reason, we also often advocate anabolic agents for 1-2 years then consider estrogen for maintenance – again, if [there is] no contraindication to using HT,” she added.

Thus, an individualized approach is recommended to determine a woman’s risk-benefit ratio of HT use based on the absolute risk of adverse effects, Dr. Kagan noted.

“Transdermal and low/ultra-low doses of HT, have a favorable risk profile, and are effective in preserving bone mineral density and bone quality in many women,” she said.

According to Dr. McClung, HT “is most often used for treatment in women in whom hormone therapy was begun for hot flashes and then, when osteoporosis was found later, was simply continued.

“Society guidelines are cautious about recommending hormone therapy for osteoporosis treatment since estrogen is not approved for treatment, despite the clear fracture protection benefit observed in the WHI study,” he said. “Since [women in the WHI trials] were not recruited as having osteoporosis, those results do not meet the FDA requirement for treatment approval, namely the reduction in fracture risk in patients with osteoporosis. However, knowing what we know about the salutary skeletal effects of estrogen, many of us do use them in our patients with osteoporosis – although not prescribed for that purpose.”
 

Additional scenarios when doctors may advise HT

“I often recommend – and I think colleagues do as well – that women with recent menopause and menopausal symptoms who also have low bone mineral density or even scores showing osteoporosis see their gynecologist to discuss HT for a few years, perhaps until age 60 if no contraindications, and if it is well tolerated,” said Ethel S. Siris, MD, professor of medicine at Columbia University Medical Center in New York.

“Once they stop it we can then give one of our other bone drugs, but it delays the need to start them since on adequate estrogen the bone density should remain stable while they take it,” added Dr. Siris, an endocrinologist and internist, and director of the Toni Stabile Osteoporosis Center in New York. “They may need a bisphosphonate or another bone drug to further protect them from bone loss and future fracture [after stopping HT].”

Victor L. Roberts, MD, founder of Endocrine Associates of Florida, Lake Mary, pointed out that women now have many options for treatment of osteoporosis.

“If a woman is in early menopause and is having other symptoms, then estrogen is warranted,” he said. “If she has osteoporosis, then it’s a bonus.”

“We have better agents that are bone specific,” for a patient who presents with osteoporosis and no other symptoms, he said.

“If a woman is intolerant of alendronate or other similar drugs, or chooses not to have an injectable, then estrogen or a SERM [selective estrogen receptor modulator] would be an option.”

Dr. Roberts added that HT would be more of a niche drug.

“It has a role and documented benefit and works,” he said. “There is good scientific data for the use of estrogen.”

Dr. Kagan is a consultant for Pfizer, Therapeutics MD, Amgen, on the Medical and Scientific Advisory Board of American Bone Health. The other  experts interviewed for this piece reported no conflicts.

The PARP inhibitor olaparib (Lynparza) is now approved by the U.S. Food and Drug Administration for use in early-stage breast cancer and later-stage disease. Specifically, the new approval is for the adjuvant treatment of adult patients with high-risk early-stage HER2-negative, BRCA-mutated breast cancer who have completed chemotherapy and local treatment.

The FDA also approved BRACAnalysis CDx (Myriad Genetics), a companion diagnostic test to identify patients who may benefit from olaparib.

The latest approval was based on phase 3 OlympiA trial results, which showed a 42% improvement in invasive and distant disease-free survival with olaparib in comparison with placebo. Data from OlympiaA and other clinical studies also confirm BRACAnalysis CDx as “an effective test for patients deciding on their best treatment options,” Myriad Genetics noted in a press release.

The OlympiA results, as reported by this news organization, were presented during the plenary session of the American Society of Clinical Oncology 2021 annual meeting and were published in the New England Journal of Medicine.

Those findings prompted an ASCO “rapid recommendation” updating of ASCO’s 2020 guidelines for the management of hereditary breast cancer.

The latest results from OlympiA show that olaparib reduced the risk of death by 32% (hazard ratio, 0.68) in comparison with placebo, according to a company press release announcing the approval. Overall survival data are slated for presentation at a European Society for Medical Oncology Virtual Plenary session on March 16, 2022.

A version of this article first appeared on Medscape.com.

The PARP inhibitor olaparib (Lynparza) is now approved by the U.S. Food and Drug Administration for use in early-stage breast cancer and later-stage disease. Specifically, the new approval is for the adjuvant treatment of adult patients with high-risk early-stage HER2-negative, BRCA-mutated breast cancer who have completed chemotherapy and local treatment.

The FDA also approved BRACAnalysis CDx (Myriad Genetics), a companion diagnostic test to identify patients who may benefit from olaparib.

The latest approval was based on phase 3 OlympiA trial results, which showed a 42% improvement in invasive and distant disease-free survival with olaparib in comparison with placebo. Data from OlympiaA and other clinical studies also confirm BRACAnalysis CDx as “an effective test for patients deciding on their best treatment options,” Myriad Genetics noted in a press release.

The OlympiA results, as reported by this news organization, were presented during the plenary session of the American Society of Clinical Oncology 2021 annual meeting and were published in the New England Journal of Medicine.

Those findings prompted an ASCO “rapid recommendation” updating of ASCO’s 2020 guidelines for the management of hereditary breast cancer.

The latest results from OlympiA show that olaparib reduced the risk of death by 32% (hazard ratio, 0.68) in comparison with placebo, according to a company press release announcing the approval. Overall survival data are slated for presentation at a European Society for Medical Oncology Virtual Plenary session on March 16, 2022.

A version of this article first appeared on Medscape.com.

The PARP inhibitor olaparib (Lynparza) is now approved by the U.S. Food and Drug Administration for use in early-stage breast cancer and later-stage disease. Specifically, the new approval is for the adjuvant treatment of adult patients with high-risk early-stage HER2-negative, BRCA-mutated breast cancer who have completed chemotherapy and local treatment.

The FDA also approved BRACAnalysis CDx (Myriad Genetics), a companion diagnostic test to identify patients who may benefit from olaparib.

The latest approval was based on phase 3 OlympiA trial results, which showed a 42% improvement in invasive and distant disease-free survival with olaparib in comparison with placebo. Data from OlympiaA and other clinical studies also confirm BRACAnalysis CDx as “an effective test for patients deciding on their best treatment options,” Myriad Genetics noted in a press release.

The OlympiA results, as reported by this news organization, were presented during the plenary session of the American Society of Clinical Oncology 2021 annual meeting and were published in the New England Journal of Medicine.

Those findings prompted an ASCO “rapid recommendation” updating of ASCO’s 2020 guidelines for the management of hereditary breast cancer.

The latest results from OlympiA show that olaparib reduced the risk of death by 32% (hazard ratio, 0.68) in comparison with placebo, according to a company press release announcing the approval. Overall survival data are slated for presentation at a European Society for Medical Oncology Virtual Plenary session on March 16, 2022.

A version of this article first appeared on Medscape.com.

We have been interested in the quiz series focused on breast cancer screening for women with dense breasts presented in OBG Management by DenseBreast-Info.org. However, we have concerns with the answer as presented in the December 2021 issue, “Average-risk women with dense breasts—What breast screening is appropriate?” (OBG Manag. 2021;33(12):18-19. doi: 10.12788/obgm.0155.) The main question asks about appropriate imaging beyond mammography/tomosynthesis for women with extremely dense breasts and no other risk factors for breast cancer. The authors recommend magnetic resonance imaging (MRI), ultrasonography, or contrast-enhanced mammography (if MRI is not an option). This advice, however, does not follow current guidelines from the American College of Obstetricians and Gynecologists (ACOG) and other professional organizations. We can certainly understand that an advocacy group would want ObGyns to be proactive about adjunctive imaging in average-risk women with heterogeneously dense or extremely dense breasts. However, at this point in time, there are no clear data to support a recommendation for adding universal MRI in this population, for many reasons that we will discuss herein.

The concerns with breast cancer in particular

Breast cancer is not cervical cancer. It isn’t one disease. It is a multitude of diseases that happen to show up in the breast. Some are relatively slow-growing—the kinds of cancers that lend themselves to screening and to early intervention. But other cancers are rapidly-growing; they show up no matter how often or what modality we use for screening. Our goal should be to find an approach to screening that can diagnose breast cancer at a stage where we can intervene and positively impact breast cancer specific and overall mortality.

Screening guidelines vary

The variety of screening guidelines published by different professional organizations reflect differing assumptions and sets of values related to the early diagnosis and treatment of breast cancer. (For a comprehensive table of current screening guidelines, see https://www.cdc.gov/cancer/breast/pdf/breast-cancer-screening-guidelines-508.pdf.)

ACOG’s approach—to offer screening at age 40 but to begin by at least age 50 and, through shared decision making with the patient, screen every 1 or 2 years—is focused on capturing as many cases as we can identify, while minimizing the harms of false-positives.¹ The perspective of the US Preventive Services Task Force (USPSTF) recommendations (to screen every 2 years beginning at age 50) is at the population level, a cost-effective approach that will have the greatest benefit while minimizing harms in the population at large.² The American Society of Breast Surgeons recommends screening to begin by age 40.³ Like the breast surgeons, radiologists dedicated to breast imaging are focused on an individual rather than a population level. They strive to identify each and every instance of possible cancer, and therefore recommend annual screening beginning at age 40.⁴ However, with more aggressive screening in average-risk women many cases of ductal carcinoma in situ (DCIS) are identified—a lesion that, if not detected, may not impact the woman’s health during her lifetime—representing what some might call “overdiagnosis.” Yet there may be some instances in which the DCIS might affect an individual woman’s health. Unfortunately, we can’t prospectively distinguish between the first and the second types of cases.

Continue to: Research on breast cancer screening varies by design...

Research on breast cancer screening varies by design

There has not been a randomized clinical trial conducted on screening mammography since the days of the analog mammogram. The research that has been conducted is difficult to compare due to variations in screening ages and intervals, technology sensitivity, and patient adherence with recommended screening. Treatments for breast cancer also have changed dramatically over time, so the findings of older studies may no longer be relevant to current breast cancer screening. The kind of analysis that needs to be done is an interrupted time series, where you can look at the trajectory of breast cancer survival and whether screening mammography shifts that survival in any way.

One specific study from Australia measured the impact of newer available breast cancer treatments, including tamoxifen for women with receptor-positive tumors and newer chemotherapy strategies.⁵ The authors analyzed screening mammography trends in one large province where women aged 50 to 69 were offered biennial screening. Trends from the 1990s showed that more women were being screened over time. Simultaneously, however, advances in therapy were entering clinical practice. The researchers pointed to a substantial decline in mortality from breast cancer from the early 1980s until 2013. But their conclusion was that none of the decline in mortality for breast cancer could be attributed to screening mammography when they looked at time trends; from their perspective all of the important decline in breast cancer mortality resulted from better treatment. They concluded that government programs should not support screening mammography.⁵

That is a recommendation that we do not support. However, we do recognize the conundrum that mammography is less sensitive among those who have dense breasts. In order to have congruent professional guidelines, we support research funding to determine which types, starting ages, and intervals of screening would be best in various patient populations. The USPSTF cites data from studies performed in the 1980s based on outdated technology; more recent (and relevant) randomized clinical trials have not been performed, and yet this information is critical to provide sufficient evidence to develop appropriate guidelines.

Our recommendations for gathering new data

The kind of data we would find most valuable would assess how different screening strategies impact overall mortality and breast cancer-specific mortality. It would require decades of follow-up—which of course means that screening technology will change over that time. A surrogate for evaluating overall survival is to look at interval cancers, which are all breast cancers diagnosed following negative mammograms and prior to the next screening. These cancers may or may not be biologically active, again focusing us on the need to look at overall survival of the patient. In addition, reducing breast cancer mortality may not reduce overall mortality, because the treatment for breast cancer may cause heart disease, or osteoporosis, or something else that impacts overall survival. These are important considerations for women and physicians who are making choices on treatment. What matters to a patient are 2 overlapping questions:

• Do I have a life-threatening condition or do I not?
• Has screening identified a condition that might lead to treatment that’s unnecessary?

The problem is that with breast cancer we can’t tell the difference. We do not understand the biological potential of a lesion when we evaluate an image on MRI, or computed tomography (CT), or mammography.

A re-look at presented data

A trial conducted by Bakker and colleagues⁶ was discussed by the authors of the DenseBreast-info.org quiz in which they recommended breast MRI for all women with extremely dense breasts (but no other risk factors for breast cancer) detected on screening mammograms.⁷ The Bakker study was large and conducted in the Netherlands. The primary outcome of the trial was to compare the incidence of interval breast cancers of women aged 50 to 75 randomly assigned to MRI versus those assigned to continued screening mammography every 2 years. Importantly, among the more than 8,000 women who were assigned to MRI, 59%, or fewer than two-thirds, chose to actually undergo MRI.

Among women randomized to MRI, 20 interval cancers were found—4 were diagnosed in those who actually had MRIs, and 16 were diagnosed among women who were randomized to MRI but didn’t undergo the study. Among women assigned to screening mammography only, 161 interval cancers were diagnosed among more than 32,000 women screened. The primary outcome findings were 2.5 interval cancers per 1,000 screenings among women randomly assigned to MRI, and 5 interval cancers per 1,000 screenings among those randomly assigned to mammography only.⁶

Because the trial included women aged 50 and older, we can’t apply these results to younger women, who often undergo screening mammography in the United States. In addition, the majority of the population in the Netherlands are of Western European ethnicity, a less-diverse population of women than in the United States. Furthermore, among the tumors that were detected in the MRI group, a larger proportion were DCIS, early-stage tumors, well differentiated, and hormone receptor-positive. This observation supports that many of the MRI-detected tumors were cases of overdiagnosis, or the detection of tumors destined not to cause clinical problems for the patient during her lifetime, or for which earlier diagnosis would impact survival.

We also know that treatment of these small ER-positive tumors carries risks for patients, as we may treat them by depriving a patient of estrogen for the rest of her life, with potential consequences of sexual dysfunction, osteoporosis, and perhaps cardiovascular disease depending on her age at the time of that diagnosis. Weighing the risks and benefits of not only treatment but also use of more sensitive screening techniques such as MRI is extremely important. Although Bakker and colleagues’ study results are interesting, we do not feel they support routinely recommending MRI for women found to have extremely dense breasts with mammography.

Overdiagnosis: A difficult concept

One reason overdiagnosis is so challenging to understand is that it can’t be directly measured, which makes comprehending it that much more problematic for clinicians and our patients.

One way to help grasp the overall issue is to compare screening mammography with cervical and colon cancer screening.

We are well aware that cervical cancer screening has reduced the incidence of mortality from invasive cervical cancer.⁸ We can argue very validly that the biggest success in any cancer screening program in history and globally has been cervical cancer screening. Our specialty, in particular, should feel proud about this. Screening colonoscopy also has repeatedly been found to reduce colon cancer mortality.⁹ For breast cancer, decades of media messaging have emphasized the benefits of screening mammograms; however, in contrast with cervical cancer screening and colonoscopy, screening mammography has not reduced the incidence of breast cancer presenting with metastatic or advanced disease. Danish authors pointed out in 2017 that screening mammography has not achieved the hoped for or the promised reduction in breast cancer mortality.¹⁰

A report published in the March 2022, issue of Annals of Internal Medicine used modeling techniques to estimate the incidence of overdiagnosis and concluded that, among women aged 50-74 years receiving biennial screening mammograms (consistent with USPSTF recommendations), more than 15% of screen-detected breast cancers would represent cases of overdiagnosis. Of note, the study authors found that, among screen-detected cancers, the proportion representing overdiagnosis among women in their 60s (16.7%) and early 70s (23.6%) was higher than among women in their 50s-60s (11.5%-11.6%).¹¹

The former Chief Medical and Scientific Officer for the American Cancer Society Otis Brawley, MD, has stated that, at the same time that breast cancer screening should not be abandoned, “We must acknowledge that overdiagnosis is common. The benefits of screening have been overstated, and some patients considered as ‘cured’ from breast cancer have, in fact, been harmed by unneeded treatment.”¹²

“Everybody loves early detection,” said Donald Berry, PhD, from MD Anderson Cancer Center, “but it comes with harms.” He points out that mortality rates have improved for breast cancer, but he attributes it to improved treatment. “The harms [of screening] we know, but the benefits of screening are very uncertain.”¹³

Continue to: Limitations of breast MRI...

Limitations of breast MRI

Overall, MRI is a diagnostic and monitoring test. It is costlier than mammography, and because it is not recommended in guidelines as a screening modality for most women, it is not typically covered by insurance. Abbreviated (rapid) MRI is a non-standardized imaging strategy being used at a few health centers. It has a shorter protocol overall than MRI, so it takes less time than current MRI and is less expensive, but there are few data on sensitivity and specificity. It is yet to be determined which populations could benefit from this newer technology.

As mentioned, 41% of women in the Bakker et al trial who were randomly assigned to breast MRI chose not to proceed with that exam even though it would have been at no cost to them.⁶ Anecdotally, some patients who have undergone MRI say they would forgo it a second time as a screening modality because it was a very unpleasant, stressful experience. It’s not a perfect test, although it is more sensitive than mammography.

Other options for following up dense-breast screening. Besides MRI and abbreviated MRI, the following modalities can be used to evaluate women found to have dense breasts with screening mammograms: CT mammography with contrast, molecular breast imaging, and ultrasonography.

Screening and treatment advances

3D mammography. In the US, the great majority of screening mammography now is performed with tomosynthesis, or what our patients sometimes call 3D mammography. In fact, it is approaching standard of care. Women whose screening mammography includes tomosynthesis are less likely to experience a so-called callback for additional imaging with diagnostic mammography or breast ultrasonography.¹⁴

Liquid biopsy. A potential major advancement for making decisions about when to treat cancers in general involves determining the biological behavior of a tumor, based on analysis of either circulating tumor DNA or proteins in the blood. As more experience with this new technology accumulates, the role of liquid biopsies for breast cancer will expand.¹⁵ Liquid biopsies for screening remain investigational for now, but they hold tremendous potential.

Noninvasive proteomics. With the development of noninvasive proteomic biomarkers obtained from blood, saliva, or nipple aspiration fluid, there exists the possibility of not just evaluating an image of a tumor seen on a mammogram, but actually studying the biological characteristics of that lesion.¹⁶ The cost of this technology is far less in terms of resources than MRI or molecular-based imaging, and actually reveals the flaws with using image-based screening. With proteomics, we can tell whether or not a lump is generating proteins that are going to make that disease biologically meaningful, and treatment decisions can be based on that information. This idea has the potential to disrupt our current breast cancer screening paradigm.

Advocacy’s role in mandating legislation

Many advocacy groups lobby on Capitol Hill for legislation related to health care, but we don’t feel that is the best way to make scientific decisions, and it’s not the way to do medicine. Passionate people, who truly believe that their outcome would have been different had something else been done, have every right to advocate, and should. However, without longer-term data focusing on breast cancer and overall mortality, rather than surrogate outcomes like interval cancers, it is not clear that routinely recommending supplemental MRI will improve survival for women with extremely dense breasts. Unfortunately, overall, earlier diagnosis of highly aggressive breast cancer tumors does not result in better outcomes for patients. ●

We have been interested in the quiz series focused on breast cancer screening for women with dense breasts presented in OBG Management by DenseBreast-Info.org. However, we have concerns with the answer as presented in the December 2021 issue, “Average-risk women with dense breasts—What breast screening is appropriate?” (OBG Manag. 2021;33(12):18-19. doi: 10.12788/obgm.0155.) The main question asks about appropriate imaging beyond mammography/tomosynthesis for women with extremely dense breasts and no other risk factors for breast cancer. The authors recommend magnetic resonance imaging (MRI), ultrasonography, or contrast-enhanced mammography (if MRI is not an option). This advice, however, does not follow current guidelines from the American College of Obstetricians and Gynecologists (ACOG) and other professional organizations. We can certainly understand that an advocacy group would want ObGyns to be proactive about adjunctive imaging in average-risk women with heterogeneously dense or extremely dense breasts. However, at this point in time, there are no clear data to support a recommendation for adding universal MRI in this population, for many reasons that we will discuss herein.

The concerns with breast cancer in particular

Breast cancer is not cervical cancer. It isn’t one disease. It is a multitude of diseases that happen to show up in the breast. Some are relatively slow-growing—the kinds of cancers that lend themselves to screening and to early intervention. But other cancers are rapidly-growing; they show up no matter how often or what modality we use for screening. Our goal should be to find an approach to screening that can diagnose breast cancer at a stage where we can intervene and positively impact breast cancer specific and overall mortality.

Screening guidelines vary

The variety of screening guidelines published by different professional organizations reflect differing assumptions and sets of values related to the early diagnosis and treatment of breast cancer. (For a comprehensive table of current screening guidelines, see https://www.cdc.gov/cancer/breast/pdf/breast-cancer-screening-guidelines-508.pdf.)

ACOG’s approach—to offer screening at age 40 but to begin by at least age 50 and, through shared decision making with the patient, screen every 1 or 2 years—is focused on capturing as many cases as we can identify, while minimizing the harms of false-positives.¹ The perspective of the US Preventive Services Task Force (USPSTF) recommendations (to screen every 2 years beginning at age 50) is at the population level, a cost-effective approach that will have the greatest benefit while minimizing harms in the population at large.² The American Society of Breast Surgeons recommends screening to begin by age 40.³ Like the breast surgeons, radiologists dedicated to breast imaging are focused on an individual rather than a population level. They strive to identify each and every instance of possible cancer, and therefore recommend annual screening beginning at age 40.⁴ However, with more aggressive screening in average-risk women many cases of ductal carcinoma in situ (DCIS) are identified—a lesion that, if not detected, may not impact the woman’s health during her lifetime—representing what some might call “overdiagnosis.” Yet there may be some instances in which the DCIS might affect an individual woman’s health. Unfortunately, we can’t prospectively distinguish between the first and the second types of cases.

Continue to: Research on breast cancer screening varies by design...

Research on breast cancer screening varies by design

There has not been a randomized clinical trial conducted on screening mammography since the days of the analog mammogram. The research that has been conducted is difficult to compare due to variations in screening ages and intervals, technology sensitivity, and patient adherence with recommended screening. Treatments for breast cancer also have changed dramatically over time, so the findings of older studies may no longer be relevant to current breast cancer screening. The kind of analysis that needs to be done is an interrupted time series, where you can look at the trajectory of breast cancer survival and whether screening mammography shifts that survival in any way.

One specific study from Australia measured the impact of newer available breast cancer treatments, including tamoxifen for women with receptor-positive tumors and newer chemotherapy strategies.⁵ The authors analyzed screening mammography trends in one large province where women aged 50 to 69 were offered biennial screening. Trends from the 1990s showed that more women were being screened over time. Simultaneously, however, advances in therapy were entering clinical practice. The researchers pointed to a substantial decline in mortality from breast cancer from the early 1980s until 2013. But their conclusion was that none of the decline in mortality for breast cancer could be attributed to screening mammography when they looked at time trends; from their perspective all of the important decline in breast cancer mortality resulted from better treatment. They concluded that government programs should not support screening mammography.⁵

That is a recommendation that we do not support. However, we do recognize the conundrum that mammography is less sensitive among those who have dense breasts. In order to have congruent professional guidelines, we support research funding to determine which types, starting ages, and intervals of screening would be best in various patient populations. The USPSTF cites data from studies performed in the 1980s based on outdated technology; more recent (and relevant) randomized clinical trials have not been performed, and yet this information is critical to provide sufficient evidence to develop appropriate guidelines.

Our recommendations for gathering new data

The kind of data we would find most valuable would assess how different screening strategies impact overall mortality and breast cancer-specific mortality. It would require decades of follow-up—which of course means that screening technology will change over that time. A surrogate for evaluating overall survival is to look at interval cancers, which are all breast cancers diagnosed following negative mammograms and prior to the next screening. These cancers may or may not be biologically active, again focusing us on the need to look at overall survival of the patient. In addition, reducing breast cancer mortality may not reduce overall mortality, because the treatment for breast cancer may cause heart disease, or osteoporosis, or something else that impacts overall survival. These are important considerations for women and physicians who are making choices on treatment. What matters to a patient are 2 overlapping questions:

• Do I have a life-threatening condition or do I not?
• Has screening identified a condition that might lead to treatment that’s unnecessary?

The problem is that with breast cancer we can’t tell the difference. We do not understand the biological potential of a lesion when we evaluate an image on MRI, or computed tomography (CT), or mammography.

A re-look at presented data

A trial conducted by Bakker and colleagues⁶ was discussed by the authors of the DenseBreast-info.org quiz in which they recommended breast MRI for all women with extremely dense breasts (but no other risk factors for breast cancer) detected on screening mammograms.⁷ The Bakker study was large and conducted in the Netherlands. The primary outcome of the trial was to compare the incidence of interval breast cancers of women aged 50 to 75 randomly assigned to MRI versus those assigned to continued screening mammography every 2 years. Importantly, among the more than 8,000 women who were assigned to MRI, 59%, or fewer than two-thirds, chose to actually undergo MRI.

Among women randomized to MRI, 20 interval cancers were found—4 were diagnosed in those who actually had MRIs, and 16 were diagnosed among women who were randomized to MRI but didn’t undergo the study. Among women assigned to screening mammography only, 161 interval cancers were diagnosed among more than 32,000 women screened. The primary outcome findings were 2.5 interval cancers per 1,000 screenings among women randomly assigned to MRI, and 5 interval cancers per 1,000 screenings among those randomly assigned to mammography only.⁶

Because the trial included women aged 50 and older, we can’t apply these results to younger women, who often undergo screening mammography in the United States. In addition, the majority of the population in the Netherlands are of Western European ethnicity, a less-diverse population of women than in the United States. Furthermore, among the tumors that were detected in the MRI group, a larger proportion were DCIS, early-stage tumors, well differentiated, and hormone receptor-positive. This observation supports that many of the MRI-detected tumors were cases of overdiagnosis, or the detection of tumors destined not to cause clinical problems for the patient during her lifetime, or for which earlier diagnosis would impact survival.

We also know that treatment of these small ER-positive tumors carries risks for patients, as we may treat them by depriving a patient of estrogen for the rest of her life, with potential consequences of sexual dysfunction, osteoporosis, and perhaps cardiovascular disease depending on her age at the time of that diagnosis. Weighing the risks and benefits of not only treatment but also use of more sensitive screening techniques such as MRI is extremely important. Although Bakker and colleagues’ study results are interesting, we do not feel they support routinely recommending MRI for women found to have extremely dense breasts with mammography.

Overdiagnosis: A difficult concept

One reason overdiagnosis is so challenging to understand is that it can’t be directly measured, which makes comprehending it that much more problematic for clinicians and our patients.

One way to help grasp the overall issue is to compare screening mammography with cervical and colon cancer screening.

We are well aware that cervical cancer screening has reduced the incidence of mortality from invasive cervical cancer.⁸ We can argue very validly that the biggest success in any cancer screening program in history and globally has been cervical cancer screening. Our specialty, in particular, should feel proud about this. Screening colonoscopy also has repeatedly been found to reduce colon cancer mortality.⁹ For breast cancer, decades of media messaging have emphasized the benefits of screening mammograms; however, in contrast with cervical cancer screening and colonoscopy, screening mammography has not reduced the incidence of breast cancer presenting with metastatic or advanced disease. Danish authors pointed out in 2017 that screening mammography has not achieved the hoped for or the promised reduction in breast cancer mortality.¹⁰

A report published in the March 2022, issue of Annals of Internal Medicine used modeling techniques to estimate the incidence of overdiagnosis and concluded that, among women aged 50-74 years receiving biennial screening mammograms (consistent with USPSTF recommendations), more than 15% of screen-detected breast cancers would represent cases of overdiagnosis. Of note, the study authors found that, among screen-detected cancers, the proportion representing overdiagnosis among women in their 60s (16.7%) and early 70s (23.6%) was higher than among women in their 50s-60s (11.5%-11.6%).¹¹

The former Chief Medical and Scientific Officer for the American Cancer Society Otis Brawley, MD, has stated that, at the same time that breast cancer screening should not be abandoned, “We must acknowledge that overdiagnosis is common. The benefits of screening have been overstated, and some patients considered as ‘cured’ from breast cancer have, in fact, been harmed by unneeded treatment.”¹²

“Everybody loves early detection,” said Donald Berry, PhD, from MD Anderson Cancer Center, “but it comes with harms.” He points out that mortality rates have improved for breast cancer, but he attributes it to improved treatment. “The harms [of screening] we know, but the benefits of screening are very uncertain.”¹³

Continue to: Limitations of breast MRI...

Limitations of breast MRI

Overall, MRI is a diagnostic and monitoring test. It is costlier than mammography, and because it is not recommended in guidelines as a screening modality for most women, it is not typically covered by insurance. Abbreviated (rapid) MRI is a non-standardized imaging strategy being used at a few health centers. It has a shorter protocol overall than MRI, so it takes less time than current MRI and is less expensive, but there are few data on sensitivity and specificity. It is yet to be determined which populations could benefit from this newer technology.

As mentioned, 41% of women in the Bakker et al trial who were randomly assigned to breast MRI chose not to proceed with that exam even though it would have been at no cost to them.⁶ Anecdotally, some patients who have undergone MRI say they would forgo it a second time as a screening modality because it was a very unpleasant, stressful experience. It’s not a perfect test, although it is more sensitive than mammography.

Other options for following up dense-breast screening. Besides MRI and abbreviated MRI, the following modalities can be used to evaluate women found to have dense breasts with screening mammograms: CT mammography with contrast, molecular breast imaging, and ultrasonography.

Screening and treatment advances

3D mammography. In the US, the great majority of screening mammography now is performed with tomosynthesis, or what our patients sometimes call 3D mammography. In fact, it is approaching standard of care. Women whose screening mammography includes tomosynthesis are less likely to experience a so-called callback for additional imaging with diagnostic mammography or breast ultrasonography.¹⁴

Liquid biopsy. A potential major advancement for making decisions about when to treat cancers in general involves determining the biological behavior of a tumor, based on analysis of either circulating tumor DNA or proteins in the blood. As more experience with this new technology accumulates, the role of liquid biopsies for breast cancer will expand.¹⁵ Liquid biopsies for screening remain investigational for now, but they hold tremendous potential.

Noninvasive proteomics. With the development of noninvasive proteomic biomarkers obtained from blood, saliva, or nipple aspiration fluid, there exists the possibility of not just evaluating an image of a tumor seen on a mammogram, but actually studying the biological characteristics of that lesion.¹⁶ The cost of this technology is far less in terms of resources than MRI or molecular-based imaging, and actually reveals the flaws with using image-based screening. With proteomics, we can tell whether or not a lump is generating proteins that are going to make that disease biologically meaningful, and treatment decisions can be based on that information. This idea has the potential to disrupt our current breast cancer screening paradigm.

Advocacy’s role in mandating legislation

Many advocacy groups lobby on Capitol Hill for legislation related to health care, but we don’t feel that is the best way to make scientific decisions, and it’s not the way to do medicine. Passionate people, who truly believe that their outcome would have been different had something else been done, have every right to advocate, and should. However, without longer-term data focusing on breast cancer and overall mortality, rather than surrogate outcomes like interval cancers, it is not clear that routinely recommending supplemental MRI will improve survival for women with extremely dense breasts. Unfortunately, overall, earlier diagnosis of highly aggressive breast cancer tumors does not result in better outcomes for patients. ●

We have been interested in the quiz series focused on breast cancer screening for women with dense breasts presented in OBG Management by DenseBreast-Info.org. However, we have concerns with the answer as presented in the December 2021 issue, “Average-risk women with dense breasts—What breast screening is appropriate?” (OBG Manag. 2021;33(12):18-19. doi: 10.12788/obgm.0155.) The main question asks about appropriate imaging beyond mammography/tomosynthesis for women with extremely dense breasts and no other risk factors for breast cancer. The authors recommend magnetic resonance imaging (MRI), ultrasonography, or contrast-enhanced mammography (if MRI is not an option). This advice, however, does not follow current guidelines from the American College of Obstetricians and Gynecologists (ACOG) and other professional organizations. We can certainly understand that an advocacy group would want ObGyns to be proactive about adjunctive imaging in average-risk women with heterogeneously dense or extremely dense breasts. However, at this point in time, there are no clear data to support a recommendation for adding universal MRI in this population, for many reasons that we will discuss herein.

The concerns with breast cancer in particular

Breast cancer is not cervical cancer. It isn’t one disease. It is a multitude of diseases that happen to show up in the breast. Some are relatively slow-growing—the kinds of cancers that lend themselves to screening and to early intervention. But other cancers are rapidly-growing; they show up no matter how often or what modality we use for screening. Our goal should be to find an approach to screening that can diagnose breast cancer at a stage where we can intervene and positively impact breast cancer specific and overall mortality.

Screening guidelines vary

The variety of screening guidelines published by different professional organizations reflect differing assumptions and sets of values related to the early diagnosis and treatment of breast cancer. (For a comprehensive table of current screening guidelines, see https://www.cdc.gov/cancer/breast/pdf/breast-cancer-screening-guidelines-508.pdf.)

ACOG’s approach—to offer screening at age 40 but to begin by at least age 50 and, through shared decision making with the patient, screen every 1 or 2 years—is focused on capturing as many cases as we can identify, while minimizing the harms of false-positives.¹ The perspective of the US Preventive Services Task Force (USPSTF) recommendations (to screen every 2 years beginning at age 50) is at the population level, a cost-effective approach that will have the greatest benefit while minimizing harms in the population at large.² The American Society of Breast Surgeons recommends screening to begin by age 40.³ Like the breast surgeons, radiologists dedicated to breast imaging are focused on an individual rather than a population level. They strive to identify each and every instance of possible cancer, and therefore recommend annual screening beginning at age 40.⁴ However, with more aggressive screening in average-risk women many cases of ductal carcinoma in situ (DCIS) are identified—a lesion that, if not detected, may not impact the woman’s health during her lifetime—representing what some might call “overdiagnosis.” Yet there may be some instances in which the DCIS might affect an individual woman’s health. Unfortunately, we can’t prospectively distinguish between the first and the second types of cases.

Continue to: Research on breast cancer screening varies by design...

Research on breast cancer screening varies by design

There has not been a randomized clinical trial conducted on screening mammography since the days of the analog mammogram. The research that has been conducted is difficult to compare due to variations in screening ages and intervals, technology sensitivity, and patient adherence with recommended screening. Treatments for breast cancer also have changed dramatically over time, so the findings of older studies may no longer be relevant to current breast cancer screening. The kind of analysis that needs to be done is an interrupted time series, where you can look at the trajectory of breast cancer survival and whether screening mammography shifts that survival in any way.

One specific study from Australia measured the impact of newer available breast cancer treatments, including tamoxifen for women with receptor-positive tumors and newer chemotherapy strategies.⁵ The authors analyzed screening mammography trends in one large province where women aged 50 to 69 were offered biennial screening. Trends from the 1990s showed that more women were being screened over time. Simultaneously, however, advances in therapy were entering clinical practice. The researchers pointed to a substantial decline in mortality from breast cancer from the early 1980s until 2013. But their conclusion was that none of the decline in mortality for breast cancer could be attributed to screening mammography when they looked at time trends; from their perspective all of the important decline in breast cancer mortality resulted from better treatment. They concluded that government programs should not support screening mammography.⁵

That is a recommendation that we do not support. However, we do recognize the conundrum that mammography is less sensitive among those who have dense breasts. In order to have congruent professional guidelines, we support research funding to determine which types, starting ages, and intervals of screening would be best in various patient populations. The USPSTF cites data from studies performed in the 1980s based on outdated technology; more recent (and relevant) randomized clinical trials have not been performed, and yet this information is critical to provide sufficient evidence to develop appropriate guidelines.

Our recommendations for gathering new data

The kind of data we would find most valuable would assess how different screening strategies impact overall mortality and breast cancer-specific mortality. It would require decades of follow-up—which of course means that screening technology will change over that time. A surrogate for evaluating overall survival is to look at interval cancers, which are all breast cancers diagnosed following negative mammograms and prior to the next screening. These cancers may or may not be biologically active, again focusing us on the need to look at overall survival of the patient. In addition, reducing breast cancer mortality may not reduce overall mortality, because the treatment for breast cancer may cause heart disease, or osteoporosis, or something else that impacts overall survival. These are important considerations for women and physicians who are making choices on treatment. What matters to a patient are 2 overlapping questions:

• Do I have a life-threatening condition or do I not?
• Has screening identified a condition that might lead to treatment that’s unnecessary?

The problem is that with breast cancer we can’t tell the difference. We do not understand the biological potential of a lesion when we evaluate an image on MRI, or computed tomography (CT), or mammography.

A re-look at presented data

A trial conducted by Bakker and colleagues⁶ was discussed by the authors of the DenseBreast-info.org quiz in which they recommended breast MRI for all women with extremely dense breasts (but no other risk factors for breast cancer) detected on screening mammograms.⁷ The Bakker study was large and conducted in the Netherlands. The primary outcome of the trial was to compare the incidence of interval breast cancers of women aged 50 to 75 randomly assigned to MRI versus those assigned to continued screening mammography every 2 years. Importantly, among the more than 8,000 women who were assigned to MRI, 59%, or fewer than two-thirds, chose to actually undergo MRI.

Among women randomized to MRI, 20 interval cancers were found—4 were diagnosed in those who actually had MRIs, and 16 were diagnosed among women who were randomized to MRI but didn’t undergo the study. Among women assigned to screening mammography only, 161 interval cancers were diagnosed among more than 32,000 women screened. The primary outcome findings were 2.5 interval cancers per 1,000 screenings among women randomly assigned to MRI, and 5 interval cancers per 1,000 screenings among those randomly assigned to mammography only.⁶

Because the trial included women aged 50 and older, we can’t apply these results to younger women, who often undergo screening mammography in the United States. In addition, the majority of the population in the Netherlands are of Western European ethnicity, a less-diverse population of women than in the United States. Furthermore, among the tumors that were detected in the MRI group, a larger proportion were DCIS, early-stage tumors, well differentiated, and hormone receptor-positive. This observation supports that many of the MRI-detected tumors were cases of overdiagnosis, or the detection of tumors destined not to cause clinical problems for the patient during her lifetime, or for which earlier diagnosis would impact survival.

We also know that treatment of these small ER-positive tumors carries risks for patients, as we may treat them by depriving a patient of estrogen for the rest of her life, with potential consequences of sexual dysfunction, osteoporosis, and perhaps cardiovascular disease depending on her age at the time of that diagnosis. Weighing the risks and benefits of not only treatment but also use of more sensitive screening techniques such as MRI is extremely important. Although Bakker and colleagues’ study results are interesting, we do not feel they support routinely recommending MRI for women found to have extremely dense breasts with mammography.

Overdiagnosis: A difficult concept

One reason overdiagnosis is so challenging to understand is that it can’t be directly measured, which makes comprehending it that much more problematic for clinicians and our patients.

One way to help grasp the overall issue is to compare screening mammography with cervical and colon cancer screening.

We are well aware that cervical cancer screening has reduced the incidence of mortality from invasive cervical cancer.⁸ We can argue very validly that the biggest success in any cancer screening program in history and globally has been cervical cancer screening. Our specialty, in particular, should feel proud about this. Screening colonoscopy also has repeatedly been found to reduce colon cancer mortality.⁹ For breast cancer, decades of media messaging have emphasized the benefits of screening mammograms; however, in contrast with cervical cancer screening and colonoscopy, screening mammography has not reduced the incidence of breast cancer presenting with metastatic or advanced disease. Danish authors pointed out in 2017 that screening mammography has not achieved the hoped for or the promised reduction in breast cancer mortality.¹⁰

A report published in the March 2022, issue of Annals of Internal Medicine used modeling techniques to estimate the incidence of overdiagnosis and concluded that, among women aged 50-74 years receiving biennial screening mammograms (consistent with USPSTF recommendations), more than 15% of screen-detected breast cancers would represent cases of overdiagnosis. Of note, the study authors found that, among screen-detected cancers, the proportion representing overdiagnosis among women in their 60s (16.7%) and early 70s (23.6%) was higher than among women in their 50s-60s (11.5%-11.6%).¹¹

The former Chief Medical and Scientific Officer for the American Cancer Society Otis Brawley, MD, has stated that, at the same time that breast cancer screening should not be abandoned, “We must acknowledge that overdiagnosis is common. The benefits of screening have been overstated, and some patients considered as ‘cured’ from breast cancer have, in fact, been harmed by unneeded treatment.”¹²

“Everybody loves early detection,” said Donald Berry, PhD, from MD Anderson Cancer Center, “but it comes with harms.” He points out that mortality rates have improved for breast cancer, but he attributes it to improved treatment. “The harms [of screening] we know, but the benefits of screening are very uncertain.”¹³

Continue to: Limitations of breast MRI...

Limitations of breast MRI

Overall, MRI is a diagnostic and monitoring test. It is costlier than mammography, and because it is not recommended in guidelines as a screening modality for most women, it is not typically covered by insurance. Abbreviated (rapid) MRI is a non-standardized imaging strategy being used at a few health centers. It has a shorter protocol overall than MRI, so it takes less time than current MRI and is less expensive, but there are few data on sensitivity and specificity. It is yet to be determined which populations could benefit from this newer technology.

As mentioned, 41% of women in the Bakker et al trial who were randomly assigned to breast MRI chose not to proceed with that exam even though it would have been at no cost to them.⁶ Anecdotally, some patients who have undergone MRI say they would forgo it a second time as a screening modality because it was a very unpleasant, stressful experience. It’s not a perfect test, although it is more sensitive than mammography.

Other options for following up dense-breast screening. Besides MRI and abbreviated MRI, the following modalities can be used to evaluate women found to have dense breasts with screening mammograms: CT mammography with contrast, molecular breast imaging, and ultrasonography.

Screening and treatment advances

3D mammography. In the US, the great majority of screening mammography now is performed with tomosynthesis, or what our patients sometimes call 3D mammography. In fact, it is approaching standard of care. Women whose screening mammography includes tomosynthesis are less likely to experience a so-called callback for additional imaging with diagnostic mammography or breast ultrasonography.¹⁴

Liquid biopsy. A potential major advancement for making decisions about when to treat cancers in general involves determining the biological behavior of a tumor, based on analysis of either circulating tumor DNA or proteins in the blood. As more experience with this new technology accumulates, the role of liquid biopsies for breast cancer will expand.¹⁵ Liquid biopsies for screening remain investigational for now, but they hold tremendous potential.

Noninvasive proteomics. With the development of noninvasive proteomic biomarkers obtained from blood, saliva, or nipple aspiration fluid, there exists the possibility of not just evaluating an image of a tumor seen on a mammogram, but actually studying the biological characteristics of that lesion.¹⁶ The cost of this technology is far less in terms of resources than MRI or molecular-based imaging, and actually reveals the flaws with using image-based screening. With proteomics, we can tell whether or not a lump is generating proteins that are going to make that disease biologically meaningful, and treatment decisions can be based on that information. This idea has the potential to disrupt our current breast cancer screening paradigm.

Advocacy’s role in mandating legislation

Many advocacy groups lobby on Capitol Hill for legislation related to health care, but we don’t feel that is the best way to make scientific decisions, and it’s not the way to do medicine. Passionate people, who truly believe that their outcome would have been different had something else been done, have every right to advocate, and should. However, without longer-term data focusing on breast cancer and overall mortality, rather than surrogate outcomes like interval cancers, it is not clear that routinely recommending supplemental MRI will improve survival for women with extremely dense breasts. Unfortunately, overall, earlier diagnosis of highly aggressive breast cancer tumors does not result in better outcomes for patients. ●

Heavy drinking during early adulthood may raise the risk for alcohol-related cancers, even after drinking stops or decreases in middle age, according to a new study from Australia.

Although alcohol is a known risk factor for cancer, people generally do not expect their heavy drinking in early adulthood to affect their cancer risk many years later, lead author Harindra Jayasekara, MBBS, MD, PhD, with Cancer Council Victoria and University of Melbourne, said in an interview. But in this analysis, “we found evidence consistent with early initiation and chronic progression of carcinogenesis linked to alcohol and its toxic metabolites.”

Courtesy Debora Cartagena, USCDCP

Impact on cancer risk

For men, relative to lifetime abstention, heavy drinking trajectories were associated with an increased risk for alcohol-related cancer overall.

The strongest associations were for the early decreasing heavy trajectory (hazard ratio, 1.75) and the late decreasing heavy trajectory (HR, 1.94), with the increasing heavy trajectory not far behind (HR, 1.45).

The strength of these associations did not change appreciably in analyses excluding current smokers at baseline.

Among men, the early decreasing heavy and late decreasing heavy intake trajectories were similarly associated with an increased risk for colorectal cancer (HR, 1.56 for early, and HR, 1.74 for late). The corresponding HR for the increasing heavy trajectory was 1.36.

For women, compared with lifetime abstention, the alcohol intake trajectory classified as increasing moderate (30-59 g/day) was associated with a greater risk for alcohol-related cancer overall (HR, 1.25). The strength of this association weakened slightly when current smokers were excluded.

Compared with lifetime abstention, the increasing moderate trajectory in women was similarly associated with an increased risk for breast cancer (HR, 1.30) and colorectal cancer (HR, 1.23).

The 2018 World Cancer Research Fund and American Institute for Cancer Research global cancer prevention recommendation on alcohol is to “avoid any alcohol,” study investigator Julie Bassett, PhD, MSc, with Cancer Council Victoria, said in an interview. “As much as it is important to limit alcohol intake during middle age to prevent cancer, we have shown that limiting intake during early adulthood is also important.”
 

‘Striking’ findings

Reached for comment, Timothy Brennan, MD, MPH, chief of clinical services at the Addiction Institute of Mount Sinai in New York, said it is “striking” that heavy drinking in early adulthood led to an increased risk for alcohol-related cancers, even among people who drank much less in middle age.

“We’ve known for decades that alcohol is not harmless, but this data adds to the growing body of literature regarding the significant dangers of heavy drinking during early adulthood,” said Dr. Brennan, who wasn’t involved in the study.

Dr. Brennan cautioned, however, that the authors studied alcohol-related cancers, and “there are likely many other [cancer] risk factors that were not analyzed in this dataset.”

Nevertheless, this evidence helps counter the “troubling narrative” that “it is somehow normal and safe to drink excessively in young adulthood.”

“It is most certainly not safe,” Dr. Brennan told this news organization . “We see in this study that drinking excessively in young adulthood can raise the risk of cancer much later in life.”

The study had no commercial funding. Dr. Bassett, Dr. Jayasekara, and Dr. Brennan have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Heavy drinking during early adulthood may raise the risk for alcohol-related cancers, even after drinking stops or decreases in middle age, according to a new study from Australia.

Although alcohol is a known risk factor for cancer, people generally do not expect their heavy drinking in early adulthood to affect their cancer risk many years later, lead author Harindra Jayasekara, MBBS, MD, PhD, with Cancer Council Victoria and University of Melbourne, said in an interview. But in this analysis, “we found evidence consistent with early initiation and chronic progression of carcinogenesis linked to alcohol and its toxic metabolites.”

Courtesy Debora Cartagena, USCDCP

Impact on cancer risk

For men, relative to lifetime abstention, heavy drinking trajectories were associated with an increased risk for alcohol-related cancer overall.

The strongest associations were for the early decreasing heavy trajectory (hazard ratio, 1.75) and the late decreasing heavy trajectory (HR, 1.94), with the increasing heavy trajectory not far behind (HR, 1.45).

The strength of these associations did not change appreciably in analyses excluding current smokers at baseline.

Among men, the early decreasing heavy and late decreasing heavy intake trajectories were similarly associated with an increased risk for colorectal cancer (HR, 1.56 for early, and HR, 1.74 for late). The corresponding HR for the increasing heavy trajectory was 1.36.

For women, compared with lifetime abstention, the alcohol intake trajectory classified as increasing moderate (30-59 g/day) was associated with a greater risk for alcohol-related cancer overall (HR, 1.25). The strength of this association weakened slightly when current smokers were excluded.

Compared with lifetime abstention, the increasing moderate trajectory in women was similarly associated with an increased risk for breast cancer (HR, 1.30) and colorectal cancer (HR, 1.23).

The 2018 World Cancer Research Fund and American Institute for Cancer Research global cancer prevention recommendation on alcohol is to “avoid any alcohol,” study investigator Julie Bassett, PhD, MSc, with Cancer Council Victoria, said in an interview. “As much as it is important to limit alcohol intake during middle age to prevent cancer, we have shown that limiting intake during early adulthood is also important.”
 

‘Striking’ findings

Reached for comment, Timothy Brennan, MD, MPH, chief of clinical services at the Addiction Institute of Mount Sinai in New York, said it is “striking” that heavy drinking in early adulthood led to an increased risk for alcohol-related cancers, even among people who drank much less in middle age.

“We’ve known for decades that alcohol is not harmless, but this data adds to the growing body of literature regarding the significant dangers of heavy drinking during early adulthood,” said Dr. Brennan, who wasn’t involved in the study.

Dr. Brennan cautioned, however, that the authors studied alcohol-related cancers, and “there are likely many other [cancer] risk factors that were not analyzed in this dataset.”

Nevertheless, this evidence helps counter the “troubling narrative” that “it is somehow normal and safe to drink excessively in young adulthood.”

“It is most certainly not safe,” Dr. Brennan told this news organization . “We see in this study that drinking excessively in young adulthood can raise the risk of cancer much later in life.”

The study had no commercial funding. Dr. Bassett, Dr. Jayasekara, and Dr. Brennan have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Heavy drinking during early adulthood may raise the risk for alcohol-related cancers, even after drinking stops or decreases in middle age, according to a new study from Australia.

Although alcohol is a known risk factor for cancer, people generally do not expect their heavy drinking in early adulthood to affect their cancer risk many years later, lead author Harindra Jayasekara, MBBS, MD, PhD, with Cancer Council Victoria and University of Melbourne, said in an interview. But in this analysis, “we found evidence consistent with early initiation and chronic progression of carcinogenesis linked to alcohol and its toxic metabolites.”

Courtesy Debora Cartagena, USCDCP

Impact on cancer risk

For men, relative to lifetime abstention, heavy drinking trajectories were associated with an increased risk for alcohol-related cancer overall.

The strongest associations were for the early decreasing heavy trajectory (hazard ratio, 1.75) and the late decreasing heavy trajectory (HR, 1.94), with the increasing heavy trajectory not far behind (HR, 1.45).

The strength of these associations did not change appreciably in analyses excluding current smokers at baseline.

Among men, the early decreasing heavy and late decreasing heavy intake trajectories were similarly associated with an increased risk for colorectal cancer (HR, 1.56 for early, and HR, 1.74 for late). The corresponding HR for the increasing heavy trajectory was 1.36.

For women, compared with lifetime abstention, the alcohol intake trajectory classified as increasing moderate (30-59 g/day) was associated with a greater risk for alcohol-related cancer overall (HR, 1.25). The strength of this association weakened slightly when current smokers were excluded.

Compared with lifetime abstention, the increasing moderate trajectory in women was similarly associated with an increased risk for breast cancer (HR, 1.30) and colorectal cancer (HR, 1.23).

The 2018 World Cancer Research Fund and American Institute for Cancer Research global cancer prevention recommendation on alcohol is to “avoid any alcohol,” study investigator Julie Bassett, PhD, MSc, with Cancer Council Victoria, said in an interview. “As much as it is important to limit alcohol intake during middle age to prevent cancer, we have shown that limiting intake during early adulthood is also important.”
 

‘Striking’ findings

Reached for comment, Timothy Brennan, MD, MPH, chief of clinical services at the Addiction Institute of Mount Sinai in New York, said it is “striking” that heavy drinking in early adulthood led to an increased risk for alcohol-related cancers, even among people who drank much less in middle age.

“We’ve known for decades that alcohol is not harmless, but this data adds to the growing body of literature regarding the significant dangers of heavy drinking during early adulthood,” said Dr. Brennan, who wasn’t involved in the study.

Dr. Brennan cautioned, however, that the authors studied alcohol-related cancers, and “there are likely many other [cancer] risk factors that were not analyzed in this dataset.”

Nevertheless, this evidence helps counter the “troubling narrative” that “it is somehow normal and safe to drink excessively in young adulthood.”

“It is most certainly not safe,” Dr. Brennan told this news organization . “We see in this study that drinking excessively in young adulthood can raise the risk of cancer much later in life.”

The study had no commercial funding. Dr. Bassett, Dr. Jayasekara, and Dr. Brennan have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Among women with ATM, CHEK2, or PALB2 pathogenic variants, annual MRI screening beginning at age 30 or 35, followed by concomitant MRI and mammography at age 40, could significantly reduce breast cancer mortality, according to a new model.

Adjunct screening with MRI is already recommended among women with the BRCA1 or BRCA2 mutations. ATM, CHEK2, and PALB2 are the most common of a more recently discovered group of pathogenic variants that confer a moderate to high risk of breast cancer.

In a study published online Feb. 17, 2022, in JAMA Oncology, researchers used two simulation models and risk estimates from the Cancer Risk Estimates Related to Susceptibility Consortium to predict that MRI screening at age 35 would produce a 54.4%-57.6% reduction in breast cancer mortality, with an estimated 4,661-5,001 false positive screenings and 1,280-1,368 benign biopsies per 1,000 women. At age 30, the model predicted 55.4-59.5% reduction in risk, 5,075-5,415 false positives, and 1,439-1,528 benign biopsies. Annual mammography at age 40 alone could reduce risk by 36%-39%.

The false positives and benign biopsies represent cumulative lifetime results.

“We’ve known for a long time that mammography is less sensitive in younger women than in older women and, of course, when women have a genetic predisposition, we’re very concerned about early-onset cancer. We’ve also known that when you do MRI at the same time as mammography, you find a lot more cancers. [There are] more false positives, but there is clearly a greater yield of cancer in that setting, and the cancers are found earlier,” senior author Mark Robson, MD, said in an interview.

The model showed that mammography screening in women under 40 added no survival benefit, and led to additional false positives and benign biopsies.

“We know that MRI’s detection rate for cancers in a head-to-head comparison with mammography is extremely high, and so I’m not surprised that there was such a difference from a mammography strategy. What I was excited by is just how impactful the MRI screen was in terms of projected reduction in the risk of death. I thought that great,” said Dr. Robson, who is chief of the breast medicine service at Memorial Sloan Kettering Cancer Center, New York.

The balance of mortality reduction versus false positives and benign biopsies will need to be weighed by others. “We didn’t feel like we could make those judgments, but what we were presenting was for people who do make these kinds of policies. The reason that we said 30-35 years (for MRI initiation) is because at that point, the false positive versus life-years gained curve starts to plateau. For instance, when we look at strategies of starting MRI at 25, you we don’t get significantly more life years gained, but we do get more false positives,” Dr. Robson said.

The researchers did not conduct a former cost-benefit analysis for initiating MRI screening at age 30-35.

The study “reinforces the value of MRI for women with these variants that are really just entering the clinical consciousness, and affirms that we need to be doing that in young women to help prevent death from breast cancer. I also think that we need to look at really what mammogram is adding in young women and consider whether or not we really need it at the policy level,” he said.

The study was funded by the National Cancer Institute and the Breast Cancer Research Foundation. Dr. Robson has conducted clinical trials with AstraZeneca, Merck, and Pfizer.

Among women with ATM, CHEK2, or PALB2 pathogenic variants, annual MRI screening beginning at age 30 or 35, followed by concomitant MRI and mammography at age 40, could significantly reduce breast cancer mortality, according to a new model.

Adjunct screening with MRI is already recommended among women with the BRCA1 or BRCA2 mutations. ATM, CHEK2, and PALB2 are the most common of a more recently discovered group of pathogenic variants that confer a moderate to high risk of breast cancer.

In a study published online Feb. 17, 2022, in JAMA Oncology, researchers used two simulation models and risk estimates from the Cancer Risk Estimates Related to Susceptibility Consortium to predict that MRI screening at age 35 would produce a 54.4%-57.6% reduction in breast cancer mortality, with an estimated 4,661-5,001 false positive screenings and 1,280-1,368 benign biopsies per 1,000 women. At age 30, the model predicted 55.4-59.5% reduction in risk, 5,075-5,415 false positives, and 1,439-1,528 benign biopsies. Annual mammography at age 40 alone could reduce risk by 36%-39%.

The false positives and benign biopsies represent cumulative lifetime results.

“We’ve known for a long time that mammography is less sensitive in younger women than in older women and, of course, when women have a genetic predisposition, we’re very concerned about early-onset cancer. We’ve also known that when you do MRI at the same time as mammography, you find a lot more cancers. [There are] more false positives, but there is clearly a greater yield of cancer in that setting, and the cancers are found earlier,” senior author Mark Robson, MD, said in an interview.

The model showed that mammography screening in women under 40 added no survival benefit, and led to additional false positives and benign biopsies.

“We know that MRI’s detection rate for cancers in a head-to-head comparison with mammography is extremely high, and so I’m not surprised that there was such a difference from a mammography strategy. What I was excited by is just how impactful the MRI screen was in terms of projected reduction in the risk of death. I thought that great,” said Dr. Robson, who is chief of the breast medicine service at Memorial Sloan Kettering Cancer Center, New York.

The balance of mortality reduction versus false positives and benign biopsies will need to be weighed by others. “We didn’t feel like we could make those judgments, but what we were presenting was for people who do make these kinds of policies. The reason that we said 30-35 years (for MRI initiation) is because at that point, the false positive versus life-years gained curve starts to plateau. For instance, when we look at strategies of starting MRI at 25, you we don’t get significantly more life years gained, but we do get more false positives,” Dr. Robson said.

The researchers did not conduct a former cost-benefit analysis for initiating MRI screening at age 30-35.

The study “reinforces the value of MRI for women with these variants that are really just entering the clinical consciousness, and affirms that we need to be doing that in young women to help prevent death from breast cancer. I also think that we need to look at really what mammogram is adding in young women and consider whether or not we really need it at the policy level,” he said.

The study was funded by the National Cancer Institute and the Breast Cancer Research Foundation. Dr. Robson has conducted clinical trials with AstraZeneca, Merck, and Pfizer.

Among women with ATM, CHEK2, or PALB2 pathogenic variants, annual MRI screening beginning at age 30 or 35, followed by concomitant MRI and mammography at age 40, could significantly reduce breast cancer mortality, according to a new model.

Adjunct screening with MRI is already recommended among women with the BRCA1 or BRCA2 mutations. ATM, CHEK2, and PALB2 are the most common of a more recently discovered group of pathogenic variants that confer a moderate to high risk of breast cancer.

In a study published online Feb. 17, 2022, in JAMA Oncology, researchers used two simulation models and risk estimates from the Cancer Risk Estimates Related to Susceptibility Consortium to predict that MRI screening at age 35 would produce a 54.4%-57.6% reduction in breast cancer mortality, with an estimated 4,661-5,001 false positive screenings and 1,280-1,368 benign biopsies per 1,000 women. At age 30, the model predicted 55.4-59.5% reduction in risk, 5,075-5,415 false positives, and 1,439-1,528 benign biopsies. Annual mammography at age 40 alone could reduce risk by 36%-39%.

The false positives and benign biopsies represent cumulative lifetime results.

“We’ve known for a long time that mammography is less sensitive in younger women than in older women and, of course, when women have a genetic predisposition, we’re very concerned about early-onset cancer. We’ve also known that when you do MRI at the same time as mammography, you find a lot more cancers. [There are] more false positives, but there is clearly a greater yield of cancer in that setting, and the cancers are found earlier,” senior author Mark Robson, MD, said in an interview.

The model showed that mammography screening in women under 40 added no survival benefit, and led to additional false positives and benign biopsies.

“We know that MRI’s detection rate for cancers in a head-to-head comparison with mammography is extremely high, and so I’m not surprised that there was such a difference from a mammography strategy. What I was excited by is just how impactful the MRI screen was in terms of projected reduction in the risk of death. I thought that great,” said Dr. Robson, who is chief of the breast medicine service at Memorial Sloan Kettering Cancer Center, New York.

The balance of mortality reduction versus false positives and benign biopsies will need to be weighed by others. “We didn’t feel like we could make those judgments, but what we were presenting was for people who do make these kinds of policies. The reason that we said 30-35 years (for MRI initiation) is because at that point, the false positive versus life-years gained curve starts to plateau. For instance, when we look at strategies of starting MRI at 25, you we don’t get significantly more life years gained, but we do get more false positives,” Dr. Robson said.

The researchers did not conduct a former cost-benefit analysis for initiating MRI screening at age 30-35.

The study “reinforces the value of MRI for women with these variants that are really just entering the clinical consciousness, and affirms that we need to be doing that in young women to help prevent death from breast cancer. I also think that we need to look at really what mammogram is adding in young women and consider whether or not we really need it at the policy level,” he said.

The study was funded by the National Cancer Institute and the Breast Cancer Research Foundation. Dr. Robson has conducted clinical trials with AstraZeneca, Merck, and Pfizer.