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Commentary: New Treatments and Fertility Preservation in BC, October 2022

Dr. Roesch scans the journals, so you don't have to!

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Erin Roesch, MD

The combination of endocrine therapy plus cyclin-dependent kinase (CDK) 4/6 inhibitors has led to significant survival benefits in the first-line setting for hormone receptor–positive (HR+)/ human epidermal growth factor receptor 2–negative (HER2-) metastatic breast cancer. However, the development of endocrine resistance poses a future challenge because sequential single-agent chemotherapy has historically been pursued in later lines of treatment.

The phase 3 TROPiCS-02 trial compared the trophoblast cell-surface antigen 2 (Trop-2)–directed antibody-drug conjugate sacituzumab govitecan with physician's choice of chemotherapy. There were 543 patients with HR+/HER2- locally recurrent inoperable or metastatic breast cancer that was also endocrine resistant and had been treated with two to four prior lines of chemotherapy in the advanced setting (Rugo et al). Sacituzumab govitecan led to a 34% reduction in risk for progression or death vs physician's choice of chemotherapy (hazard ratio 0.66; P = .0003; median progression-free survival [PFS], 5.5 months vs 4.0 months, respectively). The PFS at 6 and 12 months was 46% vs 30% and 21% vs 7% for sacituzumab govitecan and physician's choice chemotherapy, respectively. Grade ≥ 3 neutropenia and diarrhea were more common with sacituzumab govitecan than with physician's choice of chemotherapy (51% vs 9%) and were managed with supportive care measures.

Sacituzumab govitecan has previously proven an active drug for metastatic triple-negative breast cancer, and the final results from the phase 3 ASCENT study1 confirmed a significant survival benefit with sacituzumab govitecan vs single-agent chemotherapy for patients with metastatic triple-negative breast cancer in the second-line or greater setting (median overall survival [OS] 12.1 vs 6.7 months; hazard ratio 0.48; P < .0001). Sacituzumab govitecan and other antibody-drug conjugates are emerging as active therapies for all subtypes of breast cancer, and more treatment options will inevitably yield future questions surrounding sequencing and resistance mechanisms.

The phase 3 NALA trial2 demonstrated superior outcomes with the combination of neratinib plus capecitabine vs lapatinib plus capecitabine among patients with previously treated HER2+ metastatic breast cancer (hazard ratio 0.76; 1-year PFS 29% vs 15%). Findings from a single-center retrospective study including 72 patients with HER2+ advanced breast cancer who received either neratinib plus capecitabine or neratinib alone support efficacy and tolerability in the real-world setting (Cunningham et al). Among all patients, the median PFS was 5.9 months and median OS was 15.0 months; for those with brain metastases (n = 38), median PFS and median OS were 5.7 and 12.5 months, respectively. The gastrointestinal toxicity of neratinib can affect its clinical use, and a total of 64% of patients in this study reported diarrhea (10% reported grade 3) despite using antidiarrheal prophylaxis.

The treatment algorithm for HER2+ metastatic breast cancer has been evolving at a rapid pace, specifically for second-line and beyond. Neratinib remains a relevant therapy choice for these patients. The central nervous system activity of neratinib and other tyrosine kinase inhibitors, such as tucatinib, often make these the preferred treatment options for patients with brain metastases and stimulate the idea of prevention of brain metastases at an earlier time point.

Young women with breast cancer encounter unique challenges related to the stage of life during which they are diagnosed. It is essential to consider the effect of cancer treatment on fertility, including direct effects of chemotherapy and the duration of endocrine therapy (5-10 years) that can delay attempts at conceiving. Potential concerns surrounding fertility preservation (FP) include the theoretical risk of increased estradiol levels and treatment delay to allow these procedures to occur; however, various studies have supported the safety of FP.3

A prospective cohort study including 1257 women of reproductive age who were diagnosed with breast cancer and underwent FP treatment demonstrated similar disease-specific mortality in women who underwent hormonal FP (adjusted hazard ratio [aHR] 0.59; 95% CI 0.32-1.09), those who underwent nonhormonal FP (aHR 0.51, 95% CI 0.20-1.29), and women who did not pursue FP (Marklund et al). Furthermore, among 723 women with detailed information on relapse there was no significant difference in rate of relapse or death among those who underwent hormonal FP (aHR 0.81; 95% CI 0.49-1.37) vs those who underwent nonhormonal FP (aHR 0.75; 95% CI 0.35-1.62).

The growing body of evidence in this field highlights the importance of oncofertility awareness for both patients and providers. Young women diagnosed with breast cancer should be offered referrals to fertility specialists when interested and educated on the safety of these approaches as it relates to breast cancer outcomes.

A multicenter retrospective study compared the efficacy and safety of controlled ovarian hyperstimulation with letrozole (LetCOH) or without letrozole (cCOH) among 97 young women (≤ 40 years) diagnosed with early-stage breast cancer (Goldrat et al). The LetCOH group had lower peak estradiol levels (343 pg/mL vs 1009 pg/mL; P < .001) and higher oocyte maturation rates compared with the cCOH group, but a similar number of mature oocytes collected (P = .281). Disease recurrence occurred more frequently in the LetCOH group than in the cCOH group (17% vs 7.2%), and five patients in total had a distant recurrence (four undergoing LetCOH vs one undergoing cCOH).

The LetCOH group did have larger tumors and a higher number of HER2+ cancers. These findings suggest that a COH protocol using letrozole can yield FP outcomes similar to those of the conventional protocol while minimizing exposure to high levels of estradiol. Extended follow-up and future prospective studies will be essential to gain survival data and further define the roles of various FP procedures.

Additional References

  1. Bardia A, Tolaney SM, Loirat D, et al. Sacituzumab govitecan (SG) versus treatment of physician's choice (TPC) in patients (pts) with previously treated, metastatic triple-negative breast cancer (mTNBC): final results from the phase 3 ASCENT study. J Clin Oncol. 2022;40(16 Suppl):107 Doi: 10.1200/JCO.2022.40.16_suppl.1071
  2. Saura C, Oliveira M, Feng YH, et al. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial. J Clin Oncol. 2020;38:3138-3149. Doi: 10.1200/JCO.20.00147
  3. Moravek MB, Confino R, Lawson AK, et al. Predictors and outcomes in breast cancer patients who did or did not pursue fertility preservation. Breast Cancer Res Treat. 2021;186:429-437. Doi: 10.1007/s10549-020-06031-4

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