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Nanoparticle encapsulation may unlock HCC therapy
Nanoparticle encapsulation may enable targeting of aberrant glucose metabolism in hepatocellular carcinoma (HCC), potentially amplifying the effects of existing therapies and overcoming resistance mechanisms, according to investigators.
In a preclinical trial involving cell lines, xenograft tumors, and mouse models, encapsulated 2-deoxy-D-glucose (2DG) nanoparticles enhanced the antineoplastic effects of sorafenib and checkpoint inhibitors and suppressed anti-programmed cell death protein 1 (PD1)–resistant tumors, reported lead author Kyo Sasaki, PhD, of Kyushu University in Fukuoka, Japan, and colleagues.
As a glycolysis inhibitor, 2DG acts against the Warburg effect, a cancer immune-resistance mechanism “in which a substantial amount of pyruvate is reduced to lactic acid instead of being directed into mitochondria,” the investigators wrote. Their report is in Cellular and Molecular Gastroenterology and Hepatology.
But this isn’t new information, and Dr. Sasaki and colleagues weren’t the first to address the Warburg effect with 2DG; two clinical trials reported signs of efficacy in patients with solid tumors, one in 2010 and the other in 2013.
“However, 2DG does not seem to have a significant effect on tumor growth at a dose that does not induce serious adverse effects,” wrote Dr. Sasaki and colleagues. “These results suggest a need to develop an efficient drug delivery system for 2DG.”
The investigators turned to nanoparticles, which accumulate in tumor tissue more than healthy tissue, thereby limiting off-target toxicity. Specifically, they encapsulated 2DG in nanoparticles of poly(lactic-co-glycolic acid) (PLGA), a Food and Drug Administration–approved biodegradable polymer.
After characterizing the physical properties of the encapsulated 2DG nanoparticles (2DG-PLGA-NPs), and observing tumor localization in nude mice with xenograft liver tumors, the investigators assessed cytotoxic effects.
Treatment resulted in “significant growth reduction” of not only xenograft liver tumors, but also xenograft renal, colon, and pancreatic tumors, “indicating the potential antitumor effects of this method against various tumors.” Furthermore, mice treated with encapsulated 2DG nanoparticles had significantly less weight loss compared with those receiving conventional 2DG, suggesting a reduction in 2DG-related adverse effects.
Additional experiments involving two immunocompetent mouse models with multiple large liver tumors added data to support to the relative efficacy of encapsulated versus nonencapsulated 2DG. Both mouse models had significant reductions in liver tumors when treated with 2DG-PLGA-NPs; in contrast, treatment with 2DG alone reduced tumor number in only one of the two mouse models and to a lesser degree than treatment with 2DG nanoparticles.
Further in vivo and ex vivo testing revealed that encapsulated 2DG nanoparticles exerted their cytotoxic effects via endoplasmic reticulum stress, oxidative stress, and inactivation of mTOR. Simultaneously, treatment was associated with CD8+ T-cell migration into tumor tissue via increased glucose uptake and IFN-gamma production in CD8+ T cells, reduced lactate production in tumors, and increased production of CXCL9/CXCL10/CXCL11 in both the tumors and CD8+ T cells.
According to the investigators, these findings suggested that 2DG-PLGA-NPs might upregulate PD-1 positive T cells in tumors, thereby enhancing the effects of a checkpoint inhibitor. Indeed, when syngeneic mice with anti-PD-1–resistant tumors were treated with encapsulated 2DG nanoparticles, the investigators observed significant reductions in tumor growth, compared with treatment using an isotype control, PLGA alone, or an anti-PD-1 antibody. And in nude mice with xenograft tumors, combination therapy with 2DG-PLGA-NPs and sorafenib significantly reduced tumor growth, compared with no treatment, 2DG, PLGA, or PLGA with sorafenib.
“2DG-PLGA-NPs amplified the antitumor effect of anti-PD1 or sorafenib, and showed an antitumor effect against anti-PD1–resistant tumors,” the investigators wrote.
Dr. Sasaki and colleagues also noted that encapsulated 2DG nanoparticles did not accumulate in nontumorous cirrhotic hepatocytes, which suggests that treatment would be safe for patients with chronic liver diseases.
“Another practical concern is the extent to which 2DG is effectively taken up by HCC cells,” the investigators wrote.
PET showed that the hepatic accumulation rate of F-2-fluoro-2-deoxyglucose (F-FDG), a radioactive tracer of 2DG, was 50% in well-differentiated HCC, and “much higher” in sorafenib-resistant HCC cells and poorly and moderately differentiated HCC cells.
“Thus, 2DG-PLGA-NPs are expected to be good therapeutic agent candidates for patients with advanced HCC,” the investigators concluded.
The investigators disclosed no conflicts of interest. Some authors received grants from the Japan Society for the Promotion of Science.
Treatment of cancer remains a large task, also in the far future. Noninvasive imaging of tumors and thereby potential early diagnosis will very likely be the key for an ever-improving cancer therapy. The so-called Warburg effect of tumors remains a key dogma in oncologic diagnosis: Most tumors consume glucose at a higher rate than normal tissues. However, energetically, this glucose consumption is quite inefficient, and questions remain here. A dogma that maybe never gets “old” was challenged and apparently is revisited here using cutting edge nanotechnologies.
Novel avenues appear to get opened by drug encapsulation as presented by Dr. Sasaki and colleagues. Drug encapsulation in general allows at first a very basic principle: protecting the body from the drug, and also the drug from the body. Notably, only drug encapsulation through nanomedicines enables mRNA-based vaccines for the current pandemic. Here, encapsulation has pointed to a way to beat tumors with their own armory and survival mechanism: Hitting the glucose metabolism.
Nevertheless, the highly efficient route into the malignant cells is surely worth additional investigation: Which molecular routes are taken by the encapsulated drug here? Do the particles also accumulate in macrophages? If yes, in which, and if not, how can the PLGA formulation overcome the accumulation in macrophages, the “big eaters,” that are known to clear vast amounts of nanomaterials from the body?
Matthias Bartneck, PhD, PD, is a group leader specialized in liver immunology at Uniklinik RWTH Aachen (Germany). He has received strong support to develop cell type–specific interventions with tailored drugs for encapsulated nucleic acids, particularly different types of RNA. Dr. Bartneck is actively developing smart nanomedicines to find new cures for liver disease with high unmet need. He has no conflicts.
Treatment of cancer remains a large task, also in the far future. Noninvasive imaging of tumors and thereby potential early diagnosis will very likely be the key for an ever-improving cancer therapy. The so-called Warburg effect of tumors remains a key dogma in oncologic diagnosis: Most tumors consume glucose at a higher rate than normal tissues. However, energetically, this glucose consumption is quite inefficient, and questions remain here. A dogma that maybe never gets “old” was challenged and apparently is revisited here using cutting edge nanotechnologies.
Novel avenues appear to get opened by drug encapsulation as presented by Dr. Sasaki and colleagues. Drug encapsulation in general allows at first a very basic principle: protecting the body from the drug, and also the drug from the body. Notably, only drug encapsulation through nanomedicines enables mRNA-based vaccines for the current pandemic. Here, encapsulation has pointed to a way to beat tumors with their own armory and survival mechanism: Hitting the glucose metabolism.
Nevertheless, the highly efficient route into the malignant cells is surely worth additional investigation: Which molecular routes are taken by the encapsulated drug here? Do the particles also accumulate in macrophages? If yes, in which, and if not, how can the PLGA formulation overcome the accumulation in macrophages, the “big eaters,” that are known to clear vast amounts of nanomaterials from the body?
Matthias Bartneck, PhD, PD, is a group leader specialized in liver immunology at Uniklinik RWTH Aachen (Germany). He has received strong support to develop cell type–specific interventions with tailored drugs for encapsulated nucleic acids, particularly different types of RNA. Dr. Bartneck is actively developing smart nanomedicines to find new cures for liver disease with high unmet need. He has no conflicts.
Treatment of cancer remains a large task, also in the far future. Noninvasive imaging of tumors and thereby potential early diagnosis will very likely be the key for an ever-improving cancer therapy. The so-called Warburg effect of tumors remains a key dogma in oncologic diagnosis: Most tumors consume glucose at a higher rate than normal tissues. However, energetically, this glucose consumption is quite inefficient, and questions remain here. A dogma that maybe never gets “old” was challenged and apparently is revisited here using cutting edge nanotechnologies.
Novel avenues appear to get opened by drug encapsulation as presented by Dr. Sasaki and colleagues. Drug encapsulation in general allows at first a very basic principle: protecting the body from the drug, and also the drug from the body. Notably, only drug encapsulation through nanomedicines enables mRNA-based vaccines for the current pandemic. Here, encapsulation has pointed to a way to beat tumors with their own armory and survival mechanism: Hitting the glucose metabolism.
Nevertheless, the highly efficient route into the malignant cells is surely worth additional investigation: Which molecular routes are taken by the encapsulated drug here? Do the particles also accumulate in macrophages? If yes, in which, and if not, how can the PLGA formulation overcome the accumulation in macrophages, the “big eaters,” that are known to clear vast amounts of nanomaterials from the body?
Matthias Bartneck, PhD, PD, is a group leader specialized in liver immunology at Uniklinik RWTH Aachen (Germany). He has received strong support to develop cell type–specific interventions with tailored drugs for encapsulated nucleic acids, particularly different types of RNA. Dr. Bartneck is actively developing smart nanomedicines to find new cures for liver disease with high unmet need. He has no conflicts.
Nanoparticle encapsulation may enable targeting of aberrant glucose metabolism in hepatocellular carcinoma (HCC), potentially amplifying the effects of existing therapies and overcoming resistance mechanisms, according to investigators.
In a preclinical trial involving cell lines, xenograft tumors, and mouse models, encapsulated 2-deoxy-D-glucose (2DG) nanoparticles enhanced the antineoplastic effects of sorafenib and checkpoint inhibitors and suppressed anti-programmed cell death protein 1 (PD1)–resistant tumors, reported lead author Kyo Sasaki, PhD, of Kyushu University in Fukuoka, Japan, and colleagues.
As a glycolysis inhibitor, 2DG acts against the Warburg effect, a cancer immune-resistance mechanism “in which a substantial amount of pyruvate is reduced to lactic acid instead of being directed into mitochondria,” the investigators wrote. Their report is in Cellular and Molecular Gastroenterology and Hepatology.
But this isn’t new information, and Dr. Sasaki and colleagues weren’t the first to address the Warburg effect with 2DG; two clinical trials reported signs of efficacy in patients with solid tumors, one in 2010 and the other in 2013.
“However, 2DG does not seem to have a significant effect on tumor growth at a dose that does not induce serious adverse effects,” wrote Dr. Sasaki and colleagues. “These results suggest a need to develop an efficient drug delivery system for 2DG.”
The investigators turned to nanoparticles, which accumulate in tumor tissue more than healthy tissue, thereby limiting off-target toxicity. Specifically, they encapsulated 2DG in nanoparticles of poly(lactic-co-glycolic acid) (PLGA), a Food and Drug Administration–approved biodegradable polymer.
After characterizing the physical properties of the encapsulated 2DG nanoparticles (2DG-PLGA-NPs), and observing tumor localization in nude mice with xenograft liver tumors, the investigators assessed cytotoxic effects.
Treatment resulted in “significant growth reduction” of not only xenograft liver tumors, but also xenograft renal, colon, and pancreatic tumors, “indicating the potential antitumor effects of this method against various tumors.” Furthermore, mice treated with encapsulated 2DG nanoparticles had significantly less weight loss compared with those receiving conventional 2DG, suggesting a reduction in 2DG-related adverse effects.
Additional experiments involving two immunocompetent mouse models with multiple large liver tumors added data to support to the relative efficacy of encapsulated versus nonencapsulated 2DG. Both mouse models had significant reductions in liver tumors when treated with 2DG-PLGA-NPs; in contrast, treatment with 2DG alone reduced tumor number in only one of the two mouse models and to a lesser degree than treatment with 2DG nanoparticles.
Further in vivo and ex vivo testing revealed that encapsulated 2DG nanoparticles exerted their cytotoxic effects via endoplasmic reticulum stress, oxidative stress, and inactivation of mTOR. Simultaneously, treatment was associated with CD8+ T-cell migration into tumor tissue via increased glucose uptake and IFN-gamma production in CD8+ T cells, reduced lactate production in tumors, and increased production of CXCL9/CXCL10/CXCL11 in both the tumors and CD8+ T cells.
According to the investigators, these findings suggested that 2DG-PLGA-NPs might upregulate PD-1 positive T cells in tumors, thereby enhancing the effects of a checkpoint inhibitor. Indeed, when syngeneic mice with anti-PD-1–resistant tumors were treated with encapsulated 2DG nanoparticles, the investigators observed significant reductions in tumor growth, compared with treatment using an isotype control, PLGA alone, or an anti-PD-1 antibody. And in nude mice with xenograft tumors, combination therapy with 2DG-PLGA-NPs and sorafenib significantly reduced tumor growth, compared with no treatment, 2DG, PLGA, or PLGA with sorafenib.
“2DG-PLGA-NPs amplified the antitumor effect of anti-PD1 or sorafenib, and showed an antitumor effect against anti-PD1–resistant tumors,” the investigators wrote.
Dr. Sasaki and colleagues also noted that encapsulated 2DG nanoparticles did not accumulate in nontumorous cirrhotic hepatocytes, which suggests that treatment would be safe for patients with chronic liver diseases.
“Another practical concern is the extent to which 2DG is effectively taken up by HCC cells,” the investigators wrote.
PET showed that the hepatic accumulation rate of F-2-fluoro-2-deoxyglucose (F-FDG), a radioactive tracer of 2DG, was 50% in well-differentiated HCC, and “much higher” in sorafenib-resistant HCC cells and poorly and moderately differentiated HCC cells.
“Thus, 2DG-PLGA-NPs are expected to be good therapeutic agent candidates for patients with advanced HCC,” the investigators concluded.
The investigators disclosed no conflicts of interest. Some authors received grants from the Japan Society for the Promotion of Science.
Nanoparticle encapsulation may enable targeting of aberrant glucose metabolism in hepatocellular carcinoma (HCC), potentially amplifying the effects of existing therapies and overcoming resistance mechanisms, according to investigators.
In a preclinical trial involving cell lines, xenograft tumors, and mouse models, encapsulated 2-deoxy-D-glucose (2DG) nanoparticles enhanced the antineoplastic effects of sorafenib and checkpoint inhibitors and suppressed anti-programmed cell death protein 1 (PD1)–resistant tumors, reported lead author Kyo Sasaki, PhD, of Kyushu University in Fukuoka, Japan, and colleagues.
As a glycolysis inhibitor, 2DG acts against the Warburg effect, a cancer immune-resistance mechanism “in which a substantial amount of pyruvate is reduced to lactic acid instead of being directed into mitochondria,” the investigators wrote. Their report is in Cellular and Molecular Gastroenterology and Hepatology.
But this isn’t new information, and Dr. Sasaki and colleagues weren’t the first to address the Warburg effect with 2DG; two clinical trials reported signs of efficacy in patients with solid tumors, one in 2010 and the other in 2013.
“However, 2DG does not seem to have a significant effect on tumor growth at a dose that does not induce serious adverse effects,” wrote Dr. Sasaki and colleagues. “These results suggest a need to develop an efficient drug delivery system for 2DG.”
The investigators turned to nanoparticles, which accumulate in tumor tissue more than healthy tissue, thereby limiting off-target toxicity. Specifically, they encapsulated 2DG in nanoparticles of poly(lactic-co-glycolic acid) (PLGA), a Food and Drug Administration–approved biodegradable polymer.
After characterizing the physical properties of the encapsulated 2DG nanoparticles (2DG-PLGA-NPs), and observing tumor localization in nude mice with xenograft liver tumors, the investigators assessed cytotoxic effects.
Treatment resulted in “significant growth reduction” of not only xenograft liver tumors, but also xenograft renal, colon, and pancreatic tumors, “indicating the potential antitumor effects of this method against various tumors.” Furthermore, mice treated with encapsulated 2DG nanoparticles had significantly less weight loss compared with those receiving conventional 2DG, suggesting a reduction in 2DG-related adverse effects.
Additional experiments involving two immunocompetent mouse models with multiple large liver tumors added data to support to the relative efficacy of encapsulated versus nonencapsulated 2DG. Both mouse models had significant reductions in liver tumors when treated with 2DG-PLGA-NPs; in contrast, treatment with 2DG alone reduced tumor number in only one of the two mouse models and to a lesser degree than treatment with 2DG nanoparticles.
Further in vivo and ex vivo testing revealed that encapsulated 2DG nanoparticles exerted their cytotoxic effects via endoplasmic reticulum stress, oxidative stress, and inactivation of mTOR. Simultaneously, treatment was associated with CD8+ T-cell migration into tumor tissue via increased glucose uptake and IFN-gamma production in CD8+ T cells, reduced lactate production in tumors, and increased production of CXCL9/CXCL10/CXCL11 in both the tumors and CD8+ T cells.
According to the investigators, these findings suggested that 2DG-PLGA-NPs might upregulate PD-1 positive T cells in tumors, thereby enhancing the effects of a checkpoint inhibitor. Indeed, when syngeneic mice with anti-PD-1–resistant tumors were treated with encapsulated 2DG nanoparticles, the investigators observed significant reductions in tumor growth, compared with treatment using an isotype control, PLGA alone, or an anti-PD-1 antibody. And in nude mice with xenograft tumors, combination therapy with 2DG-PLGA-NPs and sorafenib significantly reduced tumor growth, compared with no treatment, 2DG, PLGA, or PLGA with sorafenib.
“2DG-PLGA-NPs amplified the antitumor effect of anti-PD1 or sorafenib, and showed an antitumor effect against anti-PD1–resistant tumors,” the investigators wrote.
Dr. Sasaki and colleagues also noted that encapsulated 2DG nanoparticles did not accumulate in nontumorous cirrhotic hepatocytes, which suggests that treatment would be safe for patients with chronic liver diseases.
“Another practical concern is the extent to which 2DG is effectively taken up by HCC cells,” the investigators wrote.
PET showed that the hepatic accumulation rate of F-2-fluoro-2-deoxyglucose (F-FDG), a radioactive tracer of 2DG, was 50% in well-differentiated HCC, and “much higher” in sorafenib-resistant HCC cells and poorly and moderately differentiated HCC cells.
“Thus, 2DG-PLGA-NPs are expected to be good therapeutic agent candidates for patients with advanced HCC,” the investigators concluded.
The investigators disclosed no conflicts of interest. Some authors received grants from the Japan Society for the Promotion of Science.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Real-world effectiveness of erenumab in migraine
Key clinical point: Erenumab 70 mg was effective for the treatment of high-frequency episodic migraine (HFEM) or chronic migraine (CM) in a real-world setting.
Major finding: Erenumab was effective with a rapid progressive decrease in monthly migraine days (week 12: HEFM, 4.5 days; CM, 9.3 days). More than 50% of HEFM and 75% of CM patients responded to the treatment.
Study details: The data come from a real-life prospective cohort study of 372 patients affected by HEFM or CM with 3 or more prior preventive therapeutic failures.
Disclosures: This work was partially supported by the Italian Ministry of Health (Institutional Funding Ricerca Corrente). C Altamura, N Brunelli, A Fallacara, CM Costa, D Santangelo, A Salerno, B Mercuri, and A Carnevale declared no conflicts of interest. The remaining authors reported ties with various institutions and/or pharmaceutical companies.
Source: Barbanti P et al. Headache. 2020 Dec 18. doi: 10.1111/head.14032.
Key clinical point: Erenumab 70 mg was effective for the treatment of high-frequency episodic migraine (HFEM) or chronic migraine (CM) in a real-world setting.
Major finding: Erenumab was effective with a rapid progressive decrease in monthly migraine days (week 12: HEFM, 4.5 days; CM, 9.3 days). More than 50% of HEFM and 75% of CM patients responded to the treatment.
Study details: The data come from a real-life prospective cohort study of 372 patients affected by HEFM or CM with 3 or more prior preventive therapeutic failures.
Disclosures: This work was partially supported by the Italian Ministry of Health (Institutional Funding Ricerca Corrente). C Altamura, N Brunelli, A Fallacara, CM Costa, D Santangelo, A Salerno, B Mercuri, and A Carnevale declared no conflicts of interest. The remaining authors reported ties with various institutions and/or pharmaceutical companies.
Source: Barbanti P et al. Headache. 2020 Dec 18. doi: 10.1111/head.14032.
Key clinical point: Erenumab 70 mg was effective for the treatment of high-frequency episodic migraine (HFEM) or chronic migraine (CM) in a real-world setting.
Major finding: Erenumab was effective with a rapid progressive decrease in monthly migraine days (week 12: HEFM, 4.5 days; CM, 9.3 days). More than 50% of HEFM and 75% of CM patients responded to the treatment.
Study details: The data come from a real-life prospective cohort study of 372 patients affected by HEFM or CM with 3 or more prior preventive therapeutic failures.
Disclosures: This work was partially supported by the Italian Ministry of Health (Institutional Funding Ricerca Corrente). C Altamura, N Brunelli, A Fallacara, CM Costa, D Santangelo, A Salerno, B Mercuri, and A Carnevale declared no conflicts of interest. The remaining authors reported ties with various institutions and/or pharmaceutical companies.
Source: Barbanti P et al. Headache. 2020 Dec 18. doi: 10.1111/head.14032.
Reversion from chronic to episodic migraine with erenumab
Key clinical point: Chronic migraine patients who achieved early reversal to episodic migraine are likely to have persistent reversion with long-term erenumab treatment.
Major finding: At 12 weeks, 54.1% (95% confidence interval [CI], 46.6%-61.6%) of patients showed reversal to episodic migraine. Continued treatment with erenumab showed a long-term persistent reversion in 96.8% (95% CI, 91.1%-99.3%) of patients at week 64.
Study details: Data on 181 migraine patients come from a post hoc analysis of a 12-week randomized double-blind trial and a 52-week open-label extension.
Disclosures: The study was funded by Amgen Inc. The authors reported ties with various institutions and/or pharmaceutical companies. F Zhang, GA Rippon, S Cheng, and DD Mikol are employed by and own stock in Amgen.
Source: Lipton RB et al. Cephalalgia. 2020 Dec 3. doi: 10.1177/0333102420973994.
Key clinical point: Chronic migraine patients who achieved early reversal to episodic migraine are likely to have persistent reversion with long-term erenumab treatment.
Major finding: At 12 weeks, 54.1% (95% confidence interval [CI], 46.6%-61.6%) of patients showed reversal to episodic migraine. Continued treatment with erenumab showed a long-term persistent reversion in 96.8% (95% CI, 91.1%-99.3%) of patients at week 64.
Study details: Data on 181 migraine patients come from a post hoc analysis of a 12-week randomized double-blind trial and a 52-week open-label extension.
Disclosures: The study was funded by Amgen Inc. The authors reported ties with various institutions and/or pharmaceutical companies. F Zhang, GA Rippon, S Cheng, and DD Mikol are employed by and own stock in Amgen.
Source: Lipton RB et al. Cephalalgia. 2020 Dec 3. doi: 10.1177/0333102420973994.
Key clinical point: Chronic migraine patients who achieved early reversal to episodic migraine are likely to have persistent reversion with long-term erenumab treatment.
Major finding: At 12 weeks, 54.1% (95% confidence interval [CI], 46.6%-61.6%) of patients showed reversal to episodic migraine. Continued treatment with erenumab showed a long-term persistent reversion in 96.8% (95% CI, 91.1%-99.3%) of patients at week 64.
Study details: Data on 181 migraine patients come from a post hoc analysis of a 12-week randomized double-blind trial and a 52-week open-label extension.
Disclosures: The study was funded by Amgen Inc. The authors reported ties with various institutions and/or pharmaceutical companies. F Zhang, GA Rippon, S Cheng, and DD Mikol are employed by and own stock in Amgen.
Source: Lipton RB et al. Cephalalgia. 2020 Dec 3. doi: 10.1177/0333102420973994.
Early breast cancer: Real-world recurrence with IORT higher than previously reported
Key clinical point: Rates of ipsilateral breast tumor recurrence (IBTR) in patients with early breast cancer treated with lumpectomy and intraoperative radiation therapy (IORT) are higher than that reported in TARGIT-A trial and with traditional whole-breast radiation therapy or other forms of partial breast irradiation.
Major finding: At 5 years, the absolute IBTR rate was 6.6% for the entire IORT-treated cohort. IBTR rate was 8% and 1.2% for patients who received primary IORT and unintentional IORT boost treatment, respectively. No recurrences were observed in the delayed IORT or intentional-boost IORT cohorts.
Study details: Findings from an updated analysis of TARGIT-R with a 5-year follow-up assessment in 667 patients with early-stage breast cancer who underwent lumpectomy and IORT.
Disclosures: The study did not receive any funding. The lead author did not report any conflicts of interest, but some co-investigators reported relationships with various pharmaceutical companies.
Source: Valente SA et al. Ann Surg Oncol. 2021 Jan 12. doi: 10.1245/s10434-020-09432-3.
Key clinical point: Rates of ipsilateral breast tumor recurrence (IBTR) in patients with early breast cancer treated with lumpectomy and intraoperative radiation therapy (IORT) are higher than that reported in TARGIT-A trial and with traditional whole-breast radiation therapy or other forms of partial breast irradiation.
Major finding: At 5 years, the absolute IBTR rate was 6.6% for the entire IORT-treated cohort. IBTR rate was 8% and 1.2% for patients who received primary IORT and unintentional IORT boost treatment, respectively. No recurrences were observed in the delayed IORT or intentional-boost IORT cohorts.
Study details: Findings from an updated analysis of TARGIT-R with a 5-year follow-up assessment in 667 patients with early-stage breast cancer who underwent lumpectomy and IORT.
Disclosures: The study did not receive any funding. The lead author did not report any conflicts of interest, but some co-investigators reported relationships with various pharmaceutical companies.
Source: Valente SA et al. Ann Surg Oncol. 2021 Jan 12. doi: 10.1245/s10434-020-09432-3.
Key clinical point: Rates of ipsilateral breast tumor recurrence (IBTR) in patients with early breast cancer treated with lumpectomy and intraoperative radiation therapy (IORT) are higher than that reported in TARGIT-A trial and with traditional whole-breast radiation therapy or other forms of partial breast irradiation.
Major finding: At 5 years, the absolute IBTR rate was 6.6% for the entire IORT-treated cohort. IBTR rate was 8% and 1.2% for patients who received primary IORT and unintentional IORT boost treatment, respectively. No recurrences were observed in the delayed IORT or intentional-boost IORT cohorts.
Study details: Findings from an updated analysis of TARGIT-R with a 5-year follow-up assessment in 667 patients with early-stage breast cancer who underwent lumpectomy and IORT.
Disclosures: The study did not receive any funding. The lead author did not report any conflicts of interest, but some co-investigators reported relationships with various pharmaceutical companies.
Source: Valente SA et al. Ann Surg Oncol. 2021 Jan 12. doi: 10.1245/s10434-020-09432-3.
TNBC: Capecitabine maintenance improves DFS but not OS
Key clinical point: Low-dose capecitabine maintenance therapy for 1 year after standard adjuvant chemotherapy resulted in significantly better disease-free survival (DFS) but not overall survival (OS) in women with early triple-negative breast cancer (TNBC).
Major finding: Capecitabine vs. observation group had significantly higher estimated 5-year DFS (82.8% vs. 73%; hazard ratio [HR], 0.64; P = .03) and distant DFS (85.8% vs. 75.8%; HR, 0.60; P = .02) but not OS (85.5% vs. 81.3%; HR, 0.75; P = .22). Hand-foot syndrome (45.2%) was the most common adverse event in the capecitabine group, with 7.7% of patients experiencing grade 3 event.
Study details: Phase 3 SYSUCC-001 trial randomly allocated 434 women with early TNBC to receive either low-dose capecitabine maintenance (n=221) or undergo observation (n=213) within 4 weeks after completion of standard adjuvant chemotherapy.
Disclosures: This study was funded by Sun Yat-sen University, the National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, and F. Hoffmann-La Roche Ltd. The study investigators did not report any conflict of interest.
Source: Wang X et al. JAMA. 2021 Jan 5. doi: 10.1001/jama.2020.23370.
Key clinical point: Low-dose capecitabine maintenance therapy for 1 year after standard adjuvant chemotherapy resulted in significantly better disease-free survival (DFS) but not overall survival (OS) in women with early triple-negative breast cancer (TNBC).
Major finding: Capecitabine vs. observation group had significantly higher estimated 5-year DFS (82.8% vs. 73%; hazard ratio [HR], 0.64; P = .03) and distant DFS (85.8% vs. 75.8%; HR, 0.60; P = .02) but not OS (85.5% vs. 81.3%; HR, 0.75; P = .22). Hand-foot syndrome (45.2%) was the most common adverse event in the capecitabine group, with 7.7% of patients experiencing grade 3 event.
Study details: Phase 3 SYSUCC-001 trial randomly allocated 434 women with early TNBC to receive either low-dose capecitabine maintenance (n=221) or undergo observation (n=213) within 4 weeks after completion of standard adjuvant chemotherapy.
Disclosures: This study was funded by Sun Yat-sen University, the National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, and F. Hoffmann-La Roche Ltd. The study investigators did not report any conflict of interest.
Source: Wang X et al. JAMA. 2021 Jan 5. doi: 10.1001/jama.2020.23370.
Key clinical point: Low-dose capecitabine maintenance therapy for 1 year after standard adjuvant chemotherapy resulted in significantly better disease-free survival (DFS) but not overall survival (OS) in women with early triple-negative breast cancer (TNBC).
Major finding: Capecitabine vs. observation group had significantly higher estimated 5-year DFS (82.8% vs. 73%; hazard ratio [HR], 0.64; P = .03) and distant DFS (85.8% vs. 75.8%; HR, 0.60; P = .02) but not OS (85.5% vs. 81.3%; HR, 0.75; P = .22). Hand-foot syndrome (45.2%) was the most common adverse event in the capecitabine group, with 7.7% of patients experiencing grade 3 event.
Study details: Phase 3 SYSUCC-001 trial randomly allocated 434 women with early TNBC to receive either low-dose capecitabine maintenance (n=221) or undergo observation (n=213) within 4 weeks after completion of standard adjuvant chemotherapy.
Disclosures: This study was funded by Sun Yat-sen University, the National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, and F. Hoffmann-La Roche Ltd. The study investigators did not report any conflict of interest.
Source: Wang X et al. JAMA. 2021 Jan 5. doi: 10.1001/jama.2020.23370.
MBC: Pertuzumab-associated rash and diarrhea predict survival outcomes
Key clinical point: In patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) treated with pertuzumab, trastuzumab, and docetaxel, rash during treatment and diarrhea after docetaxel discontinuation are predictors of survival outcomes.
Major finding: Development of rash during docetaxel administration predicted progression-free survival (PFS; adjusted hazard ratio [aHR], 0.71; P = .006) and overall survival (OS; aHR, 0.66; P = .01). Development of rash after docetaxel interruption also predicted PFS (aHR, 0.55; P = .002) and OS (aHR, 0.52; P = .018). Diarrhea was prognostic only for PFS (aHR, 0.65; P = .011) after docetaxel discontinuation.
Study details: The data come from a retrospective analysis of CLEOPATRA trial involving 777 patients with de novo or recurrent advanced HER2-positive MBC treated with docetaxel plus trastuzumab with or without pertuzumab.
Disclosures: No specific funding source was identified. Some authors reported receiving travel grants, consultation fees, and honoraria from various pharmaceutical companies.
Source: Ferreira AR et al. Eur J Cancer. 2020 Dec 31. doi: 10.1016/j.ejca.2020.11.023.
Key clinical point: In patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) treated with pertuzumab, trastuzumab, and docetaxel, rash during treatment and diarrhea after docetaxel discontinuation are predictors of survival outcomes.
Major finding: Development of rash during docetaxel administration predicted progression-free survival (PFS; adjusted hazard ratio [aHR], 0.71; P = .006) and overall survival (OS; aHR, 0.66; P = .01). Development of rash after docetaxel interruption also predicted PFS (aHR, 0.55; P = .002) and OS (aHR, 0.52; P = .018). Diarrhea was prognostic only for PFS (aHR, 0.65; P = .011) after docetaxel discontinuation.
Study details: The data come from a retrospective analysis of CLEOPATRA trial involving 777 patients with de novo or recurrent advanced HER2-positive MBC treated with docetaxel plus trastuzumab with or without pertuzumab.
Disclosures: No specific funding source was identified. Some authors reported receiving travel grants, consultation fees, and honoraria from various pharmaceutical companies.
Source: Ferreira AR et al. Eur J Cancer. 2020 Dec 31. doi: 10.1016/j.ejca.2020.11.023.
Key clinical point: In patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) treated with pertuzumab, trastuzumab, and docetaxel, rash during treatment and diarrhea after docetaxel discontinuation are predictors of survival outcomes.
Major finding: Development of rash during docetaxel administration predicted progression-free survival (PFS; adjusted hazard ratio [aHR], 0.71; P = .006) and overall survival (OS; aHR, 0.66; P = .01). Development of rash after docetaxel interruption also predicted PFS (aHR, 0.55; P = .002) and OS (aHR, 0.52; P = .018). Diarrhea was prognostic only for PFS (aHR, 0.65; P = .011) after docetaxel discontinuation.
Study details: The data come from a retrospective analysis of CLEOPATRA trial involving 777 patients with de novo or recurrent advanced HER2-positive MBC treated with docetaxel plus trastuzumab with or without pertuzumab.
Disclosures: No specific funding source was identified. Some authors reported receiving travel grants, consultation fees, and honoraria from various pharmaceutical companies.
Source: Ferreira AR et al. Eur J Cancer. 2020 Dec 31. doi: 10.1016/j.ejca.2020.11.023.
Heterogeneity in risk factors for symptom- vs. screen-detected breast cancer
Key clinical point: Hormone therapy (HT) use and benign breast disease (BBD) history are more strongly associated with a higher risk for symptom-detected breast cancer (sym-BC), whereas alcohol intake and obesity are associated with an increased screen-detected BC (scrn-BC) risk.
Major finding: Factors more strongly associated with higher sym-BC vs. scrn-BC risk were estrogen HT use (adjusted hazard ratio [aHR], 1.40; 95% confidence interval [CI], 1.15-1.71 vs. aHR, 0.95; 95% CI, 0.83-1.09), combined HT use (aHR, 2.07; 95% CI, 1.72-2.48 vs. aHR, 1.45; 95% CI, 1.27-1.65), and BBD history (aHR, 95% CI, 1.85; 1.64-2.08 vs. aHR, 1.43; 95% CI, 1.33-1.55). Factors more strongly associated with scrn-BC vs. sym-BC risk were alcohol intake (per drink aHR, 1.28; 95% CI, 1.18-1.39 vs. aHR, 1.07; 95% CI, 0.94-1.22) and body mass index ³30 kg/m2 (aHR, 1.22; 95% CI, 1.01-1.48 vs. aHR, 0.76; 95% CI, 0.56-1.01).
Study details: The data come from an analysis of 77,206 women followed-up for a median of 14.8 years. BC was detected through screening or by symptoms in 2,711 and 1,281 women, respectively.
Disclosures: The study was supported by the American Cancer Society. The authors declared no conflicts of interest.
Source: Gaudet MM et al. Breast Cancer Res Treat. 2021 Jan 4. doi: 10.1007/s10549-020-06025-2.
Key clinical point: Hormone therapy (HT) use and benign breast disease (BBD) history are more strongly associated with a higher risk for symptom-detected breast cancer (sym-BC), whereas alcohol intake and obesity are associated with an increased screen-detected BC (scrn-BC) risk.
Major finding: Factors more strongly associated with higher sym-BC vs. scrn-BC risk were estrogen HT use (adjusted hazard ratio [aHR], 1.40; 95% confidence interval [CI], 1.15-1.71 vs. aHR, 0.95; 95% CI, 0.83-1.09), combined HT use (aHR, 2.07; 95% CI, 1.72-2.48 vs. aHR, 1.45; 95% CI, 1.27-1.65), and BBD history (aHR, 95% CI, 1.85; 1.64-2.08 vs. aHR, 1.43; 95% CI, 1.33-1.55). Factors more strongly associated with scrn-BC vs. sym-BC risk were alcohol intake (per drink aHR, 1.28; 95% CI, 1.18-1.39 vs. aHR, 1.07; 95% CI, 0.94-1.22) and body mass index ³30 kg/m2 (aHR, 1.22; 95% CI, 1.01-1.48 vs. aHR, 0.76; 95% CI, 0.56-1.01).
Study details: The data come from an analysis of 77,206 women followed-up for a median of 14.8 years. BC was detected through screening or by symptoms in 2,711 and 1,281 women, respectively.
Disclosures: The study was supported by the American Cancer Society. The authors declared no conflicts of interest.
Source: Gaudet MM et al. Breast Cancer Res Treat. 2021 Jan 4. doi: 10.1007/s10549-020-06025-2.
Key clinical point: Hormone therapy (HT) use and benign breast disease (BBD) history are more strongly associated with a higher risk for symptom-detected breast cancer (sym-BC), whereas alcohol intake and obesity are associated with an increased screen-detected BC (scrn-BC) risk.
Major finding: Factors more strongly associated with higher sym-BC vs. scrn-BC risk were estrogen HT use (adjusted hazard ratio [aHR], 1.40; 95% confidence interval [CI], 1.15-1.71 vs. aHR, 0.95; 95% CI, 0.83-1.09), combined HT use (aHR, 2.07; 95% CI, 1.72-2.48 vs. aHR, 1.45; 95% CI, 1.27-1.65), and BBD history (aHR, 95% CI, 1.85; 1.64-2.08 vs. aHR, 1.43; 95% CI, 1.33-1.55). Factors more strongly associated with scrn-BC vs. sym-BC risk were alcohol intake (per drink aHR, 1.28; 95% CI, 1.18-1.39 vs. aHR, 1.07; 95% CI, 0.94-1.22) and body mass index ³30 kg/m2 (aHR, 1.22; 95% CI, 1.01-1.48 vs. aHR, 0.76; 95% CI, 0.56-1.01).
Study details: The data come from an analysis of 77,206 women followed-up for a median of 14.8 years. BC was detected through screening or by symptoms in 2,711 and 1,281 women, respectively.
Disclosures: The study was supported by the American Cancer Society. The authors declared no conflicts of interest.
Source: Gaudet MM et al. Breast Cancer Res Treat. 2021 Jan 4. doi: 10.1007/s10549-020-06025-2.
HER+ early breast cancer: Fixed-dose SC pertuzumab-trastuzumab noninferior to IV dosing
Key clinical point: Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous (SC) injection was noninferior to intravenous (IV) dosing in patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer.
Major finding: Geometric mean ratio of cycle 7 pertuzumab serum Ctrough of the SC group to the IV group was 1.22 (90% confidence interval, 1.14-1.31). Total pathologic complete response was achieved by 59.5% and 59.7% of patients in IV and SC groups, respectively. Common grade 3-4 adverse events were similar.
Study details: In the phase 3 FeDeriCa trial, patients with HER2+ early breast cancer were randomly assigned to receive either fixed-dose SC (n = 248) or IV (n = 252) pertuzumab and trastuzumab along with neoadjuvant chemotherapy.
Disclosures: This study was funded by F Hoffmann-La Roche and Genentech. The lead author AR Tan reported receving financial support from F Hoffmann-La Roche, Genentech, Pfizer, Merck, Tesaro, Novartis, Immunomedics, Celgene, and AbbVie. His coauthors also reported relationships with various pharmaceutical companies including F Hoffmann-La Roche and Genentech.
Source: Tan AR et al. Lancet Oncol. 2020 Dec 21. doi: 10.1016/S1470-2045(20)30536-2.
Key clinical point: Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous (SC) injection was noninferior to intravenous (IV) dosing in patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer.
Major finding: Geometric mean ratio of cycle 7 pertuzumab serum Ctrough of the SC group to the IV group was 1.22 (90% confidence interval, 1.14-1.31). Total pathologic complete response was achieved by 59.5% and 59.7% of patients in IV and SC groups, respectively. Common grade 3-4 adverse events were similar.
Study details: In the phase 3 FeDeriCa trial, patients with HER2+ early breast cancer were randomly assigned to receive either fixed-dose SC (n = 248) or IV (n = 252) pertuzumab and trastuzumab along with neoadjuvant chemotherapy.
Disclosures: This study was funded by F Hoffmann-La Roche and Genentech. The lead author AR Tan reported receving financial support from F Hoffmann-La Roche, Genentech, Pfizer, Merck, Tesaro, Novartis, Immunomedics, Celgene, and AbbVie. His coauthors also reported relationships with various pharmaceutical companies including F Hoffmann-La Roche and Genentech.
Source: Tan AR et al. Lancet Oncol. 2020 Dec 21. doi: 10.1016/S1470-2045(20)30536-2.
Key clinical point: Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous (SC) injection was noninferior to intravenous (IV) dosing in patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer.
Major finding: Geometric mean ratio of cycle 7 pertuzumab serum Ctrough of the SC group to the IV group was 1.22 (90% confidence interval, 1.14-1.31). Total pathologic complete response was achieved by 59.5% and 59.7% of patients in IV and SC groups, respectively. Common grade 3-4 adverse events were similar.
Study details: In the phase 3 FeDeriCa trial, patients with HER2+ early breast cancer were randomly assigned to receive either fixed-dose SC (n = 248) or IV (n = 252) pertuzumab and trastuzumab along with neoadjuvant chemotherapy.
Disclosures: This study was funded by F Hoffmann-La Roche and Genentech. The lead author AR Tan reported receving financial support from F Hoffmann-La Roche, Genentech, Pfizer, Merck, Tesaro, Novartis, Immunomedics, Celgene, and AbbVie. His coauthors also reported relationships with various pharmaceutical companies including F Hoffmann-La Roche and Genentech.
Source: Tan AR et al. Lancet Oncol. 2020 Dec 21. doi: 10.1016/S1470-2045(20)30536-2.
Adjuvant S-1 plus endocrine therapy improves invasive DFS in ER+/HER2− breast cancer
Key clinical point: In patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer (ER+/HER2− BC), adjuvant S-1 plus standard endocrine therapy (ET) significantly reduced invasive disease-free survival (IDFS) events compared with ET alone.
Major finding: IDFS events were observed in 16% vs. 11% of patients in ET-only vs. ET+S-1 groups (hazard ratio [HR], 0.63; P = .0003), respectively. The estimated 5-year IDFS was 87% in the ET+S-1 group vs. 82% in the ET-only group. However, adverse events were higher in patients receiving ET+S-1 therapy (99%) vs. ET alone (79%) but were majorly manageable.
Study details: Phase 3 trial included 1,930 women with ER+/HER− BC with intermediate to high risk for recurrence who were randomly allocated to receive either ET alone (n=973) or ET+S-1 (n=957) for a median follow-up of 52.2 months.
Disclosures: This study was sponsored by the Public Health Research Foundation, Japan, and funded by Taiho Pharmaceuticals. Masakazu Toi and other study authors reported funding and ties with various pharmaceutical companies including Taiho during and outside the conduct of the study.
Source: Toi M et al. Lancet Oncol. 2021 Jan 1. doi: 10.1016/S1470-2045(20)30534-9.
Key clinical point: In patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer (ER+/HER2− BC), adjuvant S-1 plus standard endocrine therapy (ET) significantly reduced invasive disease-free survival (IDFS) events compared with ET alone.
Major finding: IDFS events were observed in 16% vs. 11% of patients in ET-only vs. ET+S-1 groups (hazard ratio [HR], 0.63; P = .0003), respectively. The estimated 5-year IDFS was 87% in the ET+S-1 group vs. 82% in the ET-only group. However, adverse events were higher in patients receiving ET+S-1 therapy (99%) vs. ET alone (79%) but were majorly manageable.
Study details: Phase 3 trial included 1,930 women with ER+/HER− BC with intermediate to high risk for recurrence who were randomly allocated to receive either ET alone (n=973) or ET+S-1 (n=957) for a median follow-up of 52.2 months.
Disclosures: This study was sponsored by the Public Health Research Foundation, Japan, and funded by Taiho Pharmaceuticals. Masakazu Toi and other study authors reported funding and ties with various pharmaceutical companies including Taiho during and outside the conduct of the study.
Source: Toi M et al. Lancet Oncol. 2021 Jan 1. doi: 10.1016/S1470-2045(20)30534-9.
Key clinical point: In patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer (ER+/HER2− BC), adjuvant S-1 plus standard endocrine therapy (ET) significantly reduced invasive disease-free survival (IDFS) events compared with ET alone.
Major finding: IDFS events were observed in 16% vs. 11% of patients in ET-only vs. ET+S-1 groups (hazard ratio [HR], 0.63; P = .0003), respectively. The estimated 5-year IDFS was 87% in the ET+S-1 group vs. 82% in the ET-only group. However, adverse events were higher in patients receiving ET+S-1 therapy (99%) vs. ET alone (79%) but were majorly manageable.
Study details: Phase 3 trial included 1,930 women with ER+/HER− BC with intermediate to high risk for recurrence who were randomly allocated to receive either ET alone (n=973) or ET+S-1 (n=957) for a median follow-up of 52.2 months.
Disclosures: This study was sponsored by the Public Health Research Foundation, Japan, and funded by Taiho Pharmaceuticals. Masakazu Toi and other study authors reported funding and ties with various pharmaceutical companies including Taiho during and outside the conduct of the study.
Source: Toi M et al. Lancet Oncol. 2021 Jan 1. doi: 10.1016/S1470-2045(20)30534-9.
Does metabolic syndrome influence outcomes in triple-negative breast cancer?
Key clinical point: Metabolic syndrome (MS) is associated with poorer disease-free survival (DFS), but not with overall survival (OS) in patients with triple-negative breast cancer (TNBC). Hypertension was the only MS component associated with poor DFS and OS.
Major finding: MS was significantly associated with poor DFS (adjusted HR [aHR], 2.24; P = .030), but not OS (aHR, 1.92; P = .103). Hypertension was significantly associated with worse DFS (aHR, 3.63; P = .006) and OS (aHR, 3.45; P = .035).
Study details: Retrospective study of 177 patients with TNBC with (n=48) or without (n=129) MS who were followed-up for at least 5 years.
Disclosures: The study was supported by the Sharpe Strumia Foundation. The authors declared no conflicts of interest.
Source: Kennard K et al. Breast Cancer Res Treat. 2021 Jan 3. doi: 10.1007/s10549-020-06034-1.
Key clinical point: Metabolic syndrome (MS) is associated with poorer disease-free survival (DFS), but not with overall survival (OS) in patients with triple-negative breast cancer (TNBC). Hypertension was the only MS component associated with poor DFS and OS.
Major finding: MS was significantly associated with poor DFS (adjusted HR [aHR], 2.24; P = .030), but not OS (aHR, 1.92; P = .103). Hypertension was significantly associated with worse DFS (aHR, 3.63; P = .006) and OS (aHR, 3.45; P = .035).
Study details: Retrospective study of 177 patients with TNBC with (n=48) or without (n=129) MS who were followed-up for at least 5 years.
Disclosures: The study was supported by the Sharpe Strumia Foundation. The authors declared no conflicts of interest.
Source: Kennard K et al. Breast Cancer Res Treat. 2021 Jan 3. doi: 10.1007/s10549-020-06034-1.
Key clinical point: Metabolic syndrome (MS) is associated with poorer disease-free survival (DFS), but not with overall survival (OS) in patients with triple-negative breast cancer (TNBC). Hypertension was the only MS component associated with poor DFS and OS.
Major finding: MS was significantly associated with poor DFS (adjusted HR [aHR], 2.24; P = .030), but not OS (aHR, 1.92; P = .103). Hypertension was significantly associated with worse DFS (aHR, 3.63; P = .006) and OS (aHR, 3.45; P = .035).
Study details: Retrospective study of 177 patients with TNBC with (n=48) or without (n=129) MS who were followed-up for at least 5 years.
Disclosures: The study was supported by the Sharpe Strumia Foundation. The authors declared no conflicts of interest.
Source: Kennard K et al. Breast Cancer Res Treat. 2021 Jan 3. doi: 10.1007/s10549-020-06034-1.