Commentary: Fertility Concerns and Treatment-Related QOL After Breast Cancer, January 2024

Future fertility is an important consideration for many young women diagnosed with breast cancer, and oncofertility counseling in women with a germline BRCA mutation can carry additional complexities. Examples include concern regarding transmission of the pathogenic gene to offspring, the effect of the deficient gene itself on ovarian function, and the recommendation to pursue risk-reducing bilateral salpingo-oophorectomy at a young age. The safety of pregnancy after breast cancer diagnosis has been demonstrated in several prior studies,¹ but data in BRCA carriers have been limited to date. A retrospective cohort study conducted at 78 worldwide centers, including 4732 BRCA carriers diagnosed with breast cancer at age ≤ 40 years, investigated the incidence of pregnancy and maternal and fetal outcomes among these women (Lambertini et al). A total of 659 women had at least one pregnancy each after breast cancer; the cumulative incidence of pregnancy at 10 years was 22% (95% CI 21%-24%), and median time from breast cancer diagnosis to conception was 3.5 years (interquartile range 2.2-5.3 years). There was no significant difference in disease-free survival between those with or without pregnancy after breast cancer (adjusted hazard ratio 0.99; 95% CI 0.81-1.20, P = .90). Continued oncofertility research efforts are essential as the treatment landscape for early-stage breast cancer continues to evolve. Long-term follow-up of the POSITIVE trial included a small group of BRCA carriers and has shown reassuring results regarding interruption of endocrine therapy during attempts at conceiving.²

Young women diagnosed with breast cancer have been shown to experience higher rates of symptoms that may adversely affect quality of life (QOL), including depression, weight gain, vasomotor symptoms, and sexual dysfunction; they may also have a harder time managing these issues.³ Chemotherapy-related amenorrhea (CRA) is one of the side effects of breast cancer treatment that can affect premenopausal women, and is associated with both patient- (age, body mass index) and treatment-related (regimen, duration) factors.⁴ A study analyzing data derived from the prospective, longitudinal Cancer Toxicities Study included 1636 premenopausal women ≤ 50 years of age with stage I-III breast cancer treated with chemotherapy but not receiving ovarian suppression (Kabirian et al). A total of 83.0% of women reported CRA at year 1, 72.5% at year 2, and 66.1% at year 4. A higher likelihood of CRA was observed for women of older age vs those age 18-34 years (adjusted odds ratio [aOR] for 35-39 years 1.84; 40-44 years 5.90; and ≥ 45 years 21.29; P < .001 for all), those who received adjuvant tamoxifen (aOR 1.97; P < .001), and those who had hot flashes at baseline (aOR 1.83; P = .01). In the QOL analysis, 57.1% reported no recovery of menses. Persistent CRA was associated with worse insomnia, more systemic therapy–related adverse effects, and worse sexual functioning. These findings highlight the importance of identifying and discussing CRA with our patients, as this can have both physical and psychological effects in the survivorship setting.

The phase 3 KEYNOTE-522 trial has established immunotherapy plus an anthracycline-based chemotherapy backbone for the treatment of stage II-III triple-negative breast cancer (TNBC), with improvements in pathologic complete response (pCR) rates and survival outcomes.⁵ This regimen can present tolerance issues in clinical practice, and rare risks for cardiotoxicity and secondary hematologic malignancies are also relevant to consider. Furthermore, some patients may not be candidates for anthracycline-based treatment due to prior receipt of a drug in this class or cardiac comorbidities. De-escalation strategies are desired to lessen toxicity and maintain (or improve) outcomes. An open-label phase 2 trial (NeoPACT) investigated the efficacy of neoadjuvant carboplatin (AUC 6), docetaxel (75 mg/m²), and pembrolizumab (200 mg) every 21 days for six cycles among 115 patients with stage I-III TNBC (Sharma et al). The overall pCR and residual cancer burden (RCB 0+1) rates were 58% (95% CI 48%-67%) and 69% (95% CI 60%-78%), respectively. Estimated 3-year event-free survival was 86% (95% CI 77%-95%) in all patients, 98% in those with a pCR, and 68% in those with residual disease. This study also demonstrated a positive association of immune biomarkers and pathologic response. The most common grade ≥ 3 treatment-related adverse events were diarrhea (4.3%), anemia (3.5%), and peripheral sensory neuropathy (2.6%). The phase 3 SCARLET (Shorter Anthracycline-Free Chemoimmunotherapy Adapted to Pathologic Response in Early TNBC) trial is comparing the NeoPACT regimen with the standard KEYNOTE-522 regimen in early-stage TNBC and will be critical to further defining this treatment space.⁶ Presently, considering the described efficacy outcomes with the NeoPACT regimen, this regimen would be very reasonable to consider in patients who are not candidates for an anthracycline. Future prospective evaluation of immune biomarkers and additional predictors of response will also be valuable to further individualize treatment for our patients.

Additional References

1. Lambertini M, Blondeaux E, Bruzzone M, et al. Pregnancy after breast cancer: A systematic review and meta-analysis. J Clin Oncol. 2021;39:3293-3305. doi: 10.1200/JCO.21.00535
2. Partridge AH, Niman SM, Ruggeri M, et al, for the International Breast Cancer Study Group and POSITIVE Trial Collaborators. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023;388:1645-1656. doi: 10.1056/NEJMoa2212856
3. Howard-Anderson J, Ganz PA, Bower JE, Stanton AL. Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: A systematic review. J Natl Cancer Inst. 2012;104:386-405. doi: 10.1093/jnci/djr541
4. Turnbull AK, Patel S, Martinez-Perez C, et al. Risk of chemotherapy-related amenorrhoea (CRA) in premenopausal women undergoing chemotherapy for early stage breast cancer. Breast Cancer Res Treat. 2021;186:237-245. doi: 10.1007/s10549-020-05951-5
5. Schmid P, Cortes J, Dent R, et al; KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567. doi: 10.1056/NEJMoa2112651
6. US National Cancer Institute, Cancer Therapy Evaluation Program. Shorter anthracycline-free chemoimmunotherapy adapted to pathological response in early TNBC (SCARLET); SWOG S2212. Source

Future fertility is an important consideration for many young women diagnosed with breast cancer, and oncofertility counseling in women with a germline BRCA mutation can carry additional complexities. Examples include concern regarding transmission of the pathogenic gene to offspring, the effect of the deficient gene itself on ovarian function, and the recommendation to pursue risk-reducing bilateral salpingo-oophorectomy at a young age. The safety of pregnancy after breast cancer diagnosis has been demonstrated in several prior studies,¹ but data in BRCA carriers have been limited to date. A retrospective cohort study conducted at 78 worldwide centers, including 4732 BRCA carriers diagnosed with breast cancer at age ≤ 40 years, investigated the incidence of pregnancy and maternal and fetal outcomes among these women (Lambertini et al). A total of 659 women had at least one pregnancy each after breast cancer; the cumulative incidence of pregnancy at 10 years was 22% (95% CI 21%-24%), and median time from breast cancer diagnosis to conception was 3.5 years (interquartile range 2.2-5.3 years). There was no significant difference in disease-free survival between those with or without pregnancy after breast cancer (adjusted hazard ratio 0.99; 95% CI 0.81-1.20, P = .90). Continued oncofertility research efforts are essential as the treatment landscape for early-stage breast cancer continues to evolve. Long-term follow-up of the POSITIVE trial included a small group of BRCA carriers and has shown reassuring results regarding interruption of endocrine therapy during attempts at conceiving.²

Young women diagnosed with breast cancer have been shown to experience higher rates of symptoms that may adversely affect quality of life (QOL), including depression, weight gain, vasomotor symptoms, and sexual dysfunction; they may also have a harder time managing these issues.³ Chemotherapy-related amenorrhea (CRA) is one of the side effects of breast cancer treatment that can affect premenopausal women, and is associated with both patient- (age, body mass index) and treatment-related (regimen, duration) factors.⁴ A study analyzing data derived from the prospective, longitudinal Cancer Toxicities Study included 1636 premenopausal women ≤ 50 years of age with stage I-III breast cancer treated with chemotherapy but not receiving ovarian suppression (Kabirian et al). A total of 83.0% of women reported CRA at year 1, 72.5% at year 2, and 66.1% at year 4. A higher likelihood of CRA was observed for women of older age vs those age 18-34 years (adjusted odds ratio [aOR] for 35-39 years 1.84; 40-44 years 5.90; and ≥ 45 years 21.29; P < .001 for all), those who received adjuvant tamoxifen (aOR 1.97; P < .001), and those who had hot flashes at baseline (aOR 1.83; P = .01). In the QOL analysis, 57.1% reported no recovery of menses. Persistent CRA was associated with worse insomnia, more systemic therapy–related adverse effects, and worse sexual functioning. These findings highlight the importance of identifying and discussing CRA with our patients, as this can have both physical and psychological effects in the survivorship setting.

The phase 3 KEYNOTE-522 trial has established immunotherapy plus an anthracycline-based chemotherapy backbone for the treatment of stage II-III triple-negative breast cancer (TNBC), with improvements in pathologic complete response (pCR) rates and survival outcomes.⁵ This regimen can present tolerance issues in clinical practice, and rare risks for cardiotoxicity and secondary hematologic malignancies are also relevant to consider. Furthermore, some patients may not be candidates for anthracycline-based treatment due to prior receipt of a drug in this class or cardiac comorbidities. De-escalation strategies are desired to lessen toxicity and maintain (or improve) outcomes. An open-label phase 2 trial (NeoPACT) investigated the efficacy of neoadjuvant carboplatin (AUC 6), docetaxel (75 mg/m²), and pembrolizumab (200 mg) every 21 days for six cycles among 115 patients with stage I-III TNBC (Sharma et al). The overall pCR and residual cancer burden (RCB 0+1) rates were 58% (95% CI 48%-67%) and 69% (95% CI 60%-78%), respectively. Estimated 3-year event-free survival was 86% (95% CI 77%-95%) in all patients, 98% in those with a pCR, and 68% in those with residual disease. This study also demonstrated a positive association of immune biomarkers and pathologic response. The most common grade ≥ 3 treatment-related adverse events were diarrhea (4.3%), anemia (3.5%), and peripheral sensory neuropathy (2.6%). The phase 3 SCARLET (Shorter Anthracycline-Free Chemoimmunotherapy Adapted to Pathologic Response in Early TNBC) trial is comparing the NeoPACT regimen with the standard KEYNOTE-522 regimen in early-stage TNBC and will be critical to further defining this treatment space.⁶ Presently, considering the described efficacy outcomes with the NeoPACT regimen, this regimen would be very reasonable to consider in patients who are not candidates for an anthracycline. Future prospective evaluation of immune biomarkers and additional predictors of response will also be valuable to further individualize treatment for our patients.

Additional References

1. Lambertini M, Blondeaux E, Bruzzone M, et al. Pregnancy after breast cancer: A systematic review and meta-analysis. J Clin Oncol. 2021;39:3293-3305. doi: 10.1200/JCO.21.00535
2. Partridge AH, Niman SM, Ruggeri M, et al, for the International Breast Cancer Study Group and POSITIVE Trial Collaborators. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023;388:1645-1656. doi: 10.1056/NEJMoa2212856
3. Howard-Anderson J, Ganz PA, Bower JE, Stanton AL. Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: A systematic review. J Natl Cancer Inst. 2012;104:386-405. doi: 10.1093/jnci/djr541
4. Turnbull AK, Patel S, Martinez-Perez C, et al. Risk of chemotherapy-related amenorrhoea (CRA) in premenopausal women undergoing chemotherapy for early stage breast cancer. Breast Cancer Res Treat. 2021;186:237-245. doi: 10.1007/s10549-020-05951-5
5. Schmid P, Cortes J, Dent R, et al; KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567. doi: 10.1056/NEJMoa2112651
6. US National Cancer Institute, Cancer Therapy Evaluation Program. Shorter anthracycline-free chemoimmunotherapy adapted to pathological response in early TNBC (SCARLET); SWOG S2212. Source

Future fertility is an important consideration for many young women diagnosed with breast cancer, and oncofertility counseling in women with a germline BRCA mutation can carry additional complexities. Examples include concern regarding transmission of the pathogenic gene to offspring, the effect of the deficient gene itself on ovarian function, and the recommendation to pursue risk-reducing bilateral salpingo-oophorectomy at a young age. The safety of pregnancy after breast cancer diagnosis has been demonstrated in several prior studies,¹ but data in BRCA carriers have been limited to date. A retrospective cohort study conducted at 78 worldwide centers, including 4732 BRCA carriers diagnosed with breast cancer at age ≤ 40 years, investigated the incidence of pregnancy and maternal and fetal outcomes among these women (Lambertini et al). A total of 659 women had at least one pregnancy each after breast cancer; the cumulative incidence of pregnancy at 10 years was 22% (95% CI 21%-24%), and median time from breast cancer diagnosis to conception was 3.5 years (interquartile range 2.2-5.3 years). There was no significant difference in disease-free survival between those with or without pregnancy after breast cancer (adjusted hazard ratio 0.99; 95% CI 0.81-1.20, P = .90). Continued oncofertility research efforts are essential as the treatment landscape for early-stage breast cancer continues to evolve. Long-term follow-up of the POSITIVE trial included a small group of BRCA carriers and has shown reassuring results regarding interruption of endocrine therapy during attempts at conceiving.²

Young women diagnosed with breast cancer have been shown to experience higher rates of symptoms that may adversely affect quality of life (QOL), including depression, weight gain, vasomotor symptoms, and sexual dysfunction; they may also have a harder time managing these issues.³ Chemotherapy-related amenorrhea (CRA) is one of the side effects of breast cancer treatment that can affect premenopausal women, and is associated with both patient- (age, body mass index) and treatment-related (regimen, duration) factors.⁴ A study analyzing data derived from the prospective, longitudinal Cancer Toxicities Study included 1636 premenopausal women ≤ 50 years of age with stage I-III breast cancer treated with chemotherapy but not receiving ovarian suppression (Kabirian et al). A total of 83.0% of women reported CRA at year 1, 72.5% at year 2, and 66.1% at year 4. A higher likelihood of CRA was observed for women of older age vs those age 18-34 years (adjusted odds ratio [aOR] for 35-39 years 1.84; 40-44 years 5.90; and ≥ 45 years 21.29; P < .001 for all), those who received adjuvant tamoxifen (aOR 1.97; P < .001), and those who had hot flashes at baseline (aOR 1.83; P = .01). In the QOL analysis, 57.1% reported no recovery of menses. Persistent CRA was associated with worse insomnia, more systemic therapy–related adverse effects, and worse sexual functioning. These findings highlight the importance of identifying and discussing CRA with our patients, as this can have both physical and psychological effects in the survivorship setting.

The phase 3 KEYNOTE-522 trial has established immunotherapy plus an anthracycline-based chemotherapy backbone for the treatment of stage II-III triple-negative breast cancer (TNBC), with improvements in pathologic complete response (pCR) rates and survival outcomes.⁵ This regimen can present tolerance issues in clinical practice, and rare risks for cardiotoxicity and secondary hematologic malignancies are also relevant to consider. Furthermore, some patients may not be candidates for anthracycline-based treatment due to prior receipt of a drug in this class or cardiac comorbidities. De-escalation strategies are desired to lessen toxicity and maintain (or improve) outcomes. An open-label phase 2 trial (NeoPACT) investigated the efficacy of neoadjuvant carboplatin (AUC 6), docetaxel (75 mg/m²), and pembrolizumab (200 mg) every 21 days for six cycles among 115 patients with stage I-III TNBC (Sharma et al). The overall pCR and residual cancer burden (RCB 0+1) rates were 58% (95% CI 48%-67%) and 69% (95% CI 60%-78%), respectively. Estimated 3-year event-free survival was 86% (95% CI 77%-95%) in all patients, 98% in those with a pCR, and 68% in those with residual disease. This study also demonstrated a positive association of immune biomarkers and pathologic response. The most common grade ≥ 3 treatment-related adverse events were diarrhea (4.3%), anemia (3.5%), and peripheral sensory neuropathy (2.6%). The phase 3 SCARLET (Shorter Anthracycline-Free Chemoimmunotherapy Adapted to Pathologic Response in Early TNBC) trial is comparing the NeoPACT regimen with the standard KEYNOTE-522 regimen in early-stage TNBC and will be critical to further defining this treatment space.⁶ Presently, considering the described efficacy outcomes with the NeoPACT regimen, this regimen would be very reasonable to consider in patients who are not candidates for an anthracycline. Future prospective evaluation of immune biomarkers and additional predictors of response will also be valuable to further individualize treatment for our patients.

Additional References

1. Lambertini M, Blondeaux E, Bruzzone M, et al. Pregnancy after breast cancer: A systematic review and meta-analysis. J Clin Oncol. 2021;39:3293-3305. doi: 10.1200/JCO.21.00535
2. Partridge AH, Niman SM, Ruggeri M, et al, for the International Breast Cancer Study Group and POSITIVE Trial Collaborators. Interrupting endocrine therapy to attempt pregnancy after breast cancer. N Engl J Med. 2023;388:1645-1656. doi: 10.1056/NEJMoa2212856
3. Howard-Anderson J, Ganz PA, Bower JE, Stanton AL. Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: A systematic review. J Natl Cancer Inst. 2012;104:386-405. doi: 10.1093/jnci/djr541
4. Turnbull AK, Patel S, Martinez-Perez C, et al. Risk of chemotherapy-related amenorrhoea (CRA) in premenopausal women undergoing chemotherapy for early stage breast cancer. Breast Cancer Res Treat. 2021;186:237-245. doi: 10.1007/s10549-020-05951-5
5. Schmid P, Cortes J, Dent R, et al; KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567. doi: 10.1056/NEJMoa2112651
6. US National Cancer Institute, Cancer Therapy Evaluation Program. Shorter anthracycline-free chemoimmunotherapy adapted to pathological response in early TNBC (SCARLET); SWOG S2212. Source