Erin Roesch, MD

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

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

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

A subset of patients with HR+ metastatic breast cancer (mBC) may have primary resistance to endocrine therapy (ET), and the majority will develop progressive disease and secondary resistance at some point during their treatment course. The phase 3 PEARL trial randomly assigned 601 postmenopausal patients with HR+/HER2- mBC that was resistant to prior aromatase inhibitor therapy to capecitabine or palbociclib + ET (with exemestane or fulvestrant). There was no significant difference in OS between the palbociclib + ET and capecitabine arms in both the wild-type–ESR1 population (median OS 37.2 vs 34.8 months; adjusted HR 1.06; P = .683) and overall population (median OS 32.6 vs 30.9 months, adjusted HR 1.00; P = .995) (Martin et al). The randomized phase 2 Young-PEARL trial demonstrated a progression-free survival (PFS) benefit with palbociclib + exemestane + leuprolide vs capecitabine among 189 premenopausal women with HR+/HER2- mBC and relapse or progression on prior tamoxifen therapy (median PFS 20.1 vs 14.4 months; HR 0.659; P = .0235).² In this study, half of the patients were treatment-naive in the metastatic setting and had no prior aromatase inhibitor exposure. Considering the similar survival outcomes seen in PEARL in postmenopausal patients, the choice of therapy should include consideration of other variables, such as side effects, comorbidities, and OS results, which will be further informative in the premenopausal population.
 

Poorer outcomes associated with breast cancer in younger women (< 45 years of age) are driven by multiple factors, including delayed diagnosis, more aggressive biologic subtypes, and advanced stage at presentation. Survival outcomes for breast cancer diagnosed and treated during pregnancy are similar to nonpregnant patients. Postpartum breast cancer (PPBC) is a distinct entity, defined as breast cancer that is diagnosed within the first 5 years after childbirth, and is more likely to have inferior outcomes. A pooled data set from the Colorado Young Women Breast cohort and the Breast Cancer Health Disparities study (n = 2519 cases) showed that among women diagnosed at < 45 years, those who were nulliparous had better OS vs those with PPBC (HR 0.61), with a more prominent effect among stage I breast cancers (HR 0.30) and in very young women diagnosed at ≤ 35 years (HR 0.44) (Shagisultanova et al). At 15 years of follow-up, among very young women diagnosed at ≤ 35 years, those with PPBC had an OS of 63% compared with 71% for nulliparous women and 67% for women who had given birth more than 5 years ago. There are various factors that likely contribute to poorer outcomes seen with PPBC, including mammary gland involution and a lactation effect. Research efforts focused on aspects, such as the tumor immune microenvironment in the postpartum state, lactation studies, and perhaps identification of a postpartum signature, will enhance our understanding with the goal to optimize outcomes for young women with PPBC.^[3]
 

The treatment of male breast cancer in the advanced or metastatic setting is largely extrapolated from female studies. Registry data have shown differences in clinicopathologic characteristics between metastatic male breast cancer (mMBC) and metastatic female breast cancer (mFBC). For example, there is a higher proportion of simultaneous lung and bone involvement and a lower proportion of HER2+/HR- triple-negative subtypes, and simultaneous bone and liver metastasis in mMBC vs mFBC.⁴ An analysis including 207 male patients with breast cancer with bone metastases in the Surveillance, Epidemiology, and End Results (SEER) database demonstrated 3-year OS and cancer-specific survival (CSS) rates of 36.7% and 39.5%, respectively. Inferior OS and CSS were associated with age > 60 years (for OS: HR 1.671; P = .014; for CSS: HR 1.806; P = .009), triple-negative subtype (for OS: HR 3.029, P = .003; for CSS: HR 3.025, P = .004), and lack of surgery (for OS: HR 1.746; P = .012; for CSS: HR 1.734; P = .023), whereas brain metastasis had a worse OS (HR 2.045; P = .028) but not CSS (Zhou et al). These findings highlight the importance of getting a better understanding of mMBC disease biology and the opportunity to tailor treatment approaches for this population of patients.
 

Additional References
 

1. Waks AG, Desai NV, Li T, et al. A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2-positive breast cancer. NPJ Breast Cancer. 2022;8:63. Doi: 10.1038/s41523-022-00429-7
2. Park YH, Kim TY, Kim GM, et al; Korean Cancer Study Group (KCSG). Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): A multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2019;20(12):1750-1759. Doi: 10.1016/S1470-2045(19)30565-0
3. Lefrère H, Lenaerts L, Borges VF, et al. Postpartum breast cancer: mechanisms underlying its worse prognosis, treatment implications, and fertility preservation. Int J Gynecol Cancer. 2021;31:412-422. Doi: 10.1136/ijgc-2020-002072
4. Xie J, Ying YY, Xu B, Li Y, Zhang X, Li C. Metastasis pattern and prognosis of male breast cancer patients in US: a population-based study from SEER database. Ther Adv Med Oncol. 2019;11:1758835919889003. Doi: 10.1177/1758835919889003

A subset of patients with HR+ metastatic breast cancer (mBC) may have primary resistance to endocrine therapy (ET), and the majority will develop progressive disease and secondary resistance at some point during their treatment course. The phase 3 PEARL trial randomly assigned 601 postmenopausal patients with HR+/HER2- mBC that was resistant to prior aromatase inhibitor therapy to capecitabine or palbociclib + ET (with exemestane or fulvestrant). There was no significant difference in OS between the palbociclib + ET and capecitabine arms in both the wild-type–ESR1 population (median OS 37.2 vs 34.8 months; adjusted HR 1.06; P = .683) and overall population (median OS 32.6 vs 30.9 months, adjusted HR 1.00; P = .995) (Martin et al). The randomized phase 2 Young-PEARL trial demonstrated a progression-free survival (PFS) benefit with palbociclib + exemestane + leuprolide vs capecitabine among 189 premenopausal women with HR+/HER2- mBC and relapse or progression on prior tamoxifen therapy (median PFS 20.1 vs 14.4 months; HR 0.659; P = .0235).² In this study, half of the patients were treatment-naive in the metastatic setting and had no prior aromatase inhibitor exposure. Considering the similar survival outcomes seen in PEARL in postmenopausal patients, the choice of therapy should include consideration of other variables, such as side effects, comorbidities, and OS results, which will be further informative in the premenopausal population.
 

Poorer outcomes associated with breast cancer in younger women (< 45 years of age) are driven by multiple factors, including delayed diagnosis, more aggressive biologic subtypes, and advanced stage at presentation. Survival outcomes for breast cancer diagnosed and treated during pregnancy are similar to nonpregnant patients. Postpartum breast cancer (PPBC) is a distinct entity, defined as breast cancer that is diagnosed within the first 5 years after childbirth, and is more likely to have inferior outcomes. A pooled data set from the Colorado Young Women Breast cohort and the Breast Cancer Health Disparities study (n = 2519 cases) showed that among women diagnosed at < 45 years, those who were nulliparous had better OS vs those with PPBC (HR 0.61), with a more prominent effect among stage I breast cancers (HR 0.30) and in very young women diagnosed at ≤ 35 years (HR 0.44) (Shagisultanova et al). At 15 years of follow-up, among very young women diagnosed at ≤ 35 years, those with PPBC had an OS of 63% compared with 71% for nulliparous women and 67% for women who had given birth more than 5 years ago. There are various factors that likely contribute to poorer outcomes seen with PPBC, including mammary gland involution and a lactation effect. Research efforts focused on aspects, such as the tumor immune microenvironment in the postpartum state, lactation studies, and perhaps identification of a postpartum signature, will enhance our understanding with the goal to optimize outcomes for young women with PPBC.^[3]
 

The treatment of male breast cancer in the advanced or metastatic setting is largely extrapolated from female studies. Registry data have shown differences in clinicopathologic characteristics between metastatic male breast cancer (mMBC) and metastatic female breast cancer (mFBC). For example, there is a higher proportion of simultaneous lung and bone involvement and a lower proportion of HER2+/HR- triple-negative subtypes, and simultaneous bone and liver metastasis in mMBC vs mFBC.⁴ An analysis including 207 male patients with breast cancer with bone metastases in the Surveillance, Epidemiology, and End Results (SEER) database demonstrated 3-year OS and cancer-specific survival (CSS) rates of 36.7% and 39.5%, respectively. Inferior OS and CSS were associated with age > 60 years (for OS: HR 1.671; P = .014; for CSS: HR 1.806; P = .009), triple-negative subtype (for OS: HR 3.029, P = .003; for CSS: HR 3.025, P = .004), and lack of surgery (for OS: HR 1.746; P = .012; for CSS: HR 1.734; P = .023), whereas brain metastasis had a worse OS (HR 2.045; P = .028) but not CSS (Zhou et al). These findings highlight the importance of getting a better understanding of mMBC disease biology and the opportunity to tailor treatment approaches for this population of patients.
 

Additional References
 

1. Waks AG, Desai NV, Li T, et al. A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2-positive breast cancer. NPJ Breast Cancer. 2022;8:63. Doi: 10.1038/s41523-022-00429-7
2. Park YH, Kim TY, Kim GM, et al; Korean Cancer Study Group (KCSG). Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): A multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2019;20(12):1750-1759. Doi: 10.1016/S1470-2045(19)30565-0
3. Lefrère H, Lenaerts L, Borges VF, et al. Postpartum breast cancer: mechanisms underlying its worse prognosis, treatment implications, and fertility preservation. Int J Gynecol Cancer. 2021;31:412-422. Doi: 10.1136/ijgc-2020-002072
4. Xie J, Ying YY, Xu B, Li Y, Zhang X, Li C. Metastasis pattern and prognosis of male breast cancer patients in US: a population-based study from SEER database. Ther Adv Med Oncol. 2019;11:1758835919889003. Doi: 10.1177/1758835919889003

A subset of patients with HR+ metastatic breast cancer (mBC) may have primary resistance to endocrine therapy (ET), and the majority will develop progressive disease and secondary resistance at some point during their treatment course. The phase 3 PEARL trial randomly assigned 601 postmenopausal patients with HR+/HER2- mBC that was resistant to prior aromatase inhibitor therapy to capecitabine or palbociclib + ET (with exemestane or fulvestrant). There was no significant difference in OS between the palbociclib + ET and capecitabine arms in both the wild-type–ESR1 population (median OS 37.2 vs 34.8 months; adjusted HR 1.06; P = .683) and overall population (median OS 32.6 vs 30.9 months, adjusted HR 1.00; P = .995) (Martin et al). The randomized phase 2 Young-PEARL trial demonstrated a progression-free survival (PFS) benefit with palbociclib + exemestane + leuprolide vs capecitabine among 189 premenopausal women with HR+/HER2- mBC and relapse or progression on prior tamoxifen therapy (median PFS 20.1 vs 14.4 months; HR 0.659; P = .0235).² In this study, half of the patients were treatment-naive in the metastatic setting and had no prior aromatase inhibitor exposure. Considering the similar survival outcomes seen in PEARL in postmenopausal patients, the choice of therapy should include consideration of other variables, such as side effects, comorbidities, and OS results, which will be further informative in the premenopausal population.
 

Poorer outcomes associated with breast cancer in younger women (< 45 years of age) are driven by multiple factors, including delayed diagnosis, more aggressive biologic subtypes, and advanced stage at presentation. Survival outcomes for breast cancer diagnosed and treated during pregnancy are similar to nonpregnant patients. Postpartum breast cancer (PPBC) is a distinct entity, defined as breast cancer that is diagnosed within the first 5 years after childbirth, and is more likely to have inferior outcomes. A pooled data set from the Colorado Young Women Breast cohort and the Breast Cancer Health Disparities study (n = 2519 cases) showed that among women diagnosed at < 45 years, those who were nulliparous had better OS vs those with PPBC (HR 0.61), with a more prominent effect among stage I breast cancers (HR 0.30) and in very young women diagnosed at ≤ 35 years (HR 0.44) (Shagisultanova et al). At 15 years of follow-up, among very young women diagnosed at ≤ 35 years, those with PPBC had an OS of 63% compared with 71% for nulliparous women and 67% for women who had given birth more than 5 years ago. There are various factors that likely contribute to poorer outcomes seen with PPBC, including mammary gland involution and a lactation effect. Research efforts focused on aspects, such as the tumor immune microenvironment in the postpartum state, lactation studies, and perhaps identification of a postpartum signature, will enhance our understanding with the goal to optimize outcomes for young women with PPBC.^[3]
 

The treatment of male breast cancer in the advanced or metastatic setting is largely extrapolated from female studies. Registry data have shown differences in clinicopathologic characteristics between metastatic male breast cancer (mMBC) and metastatic female breast cancer (mFBC). For example, there is a higher proportion of simultaneous lung and bone involvement and a lower proportion of HER2+/HR- triple-negative subtypes, and simultaneous bone and liver metastasis in mMBC vs mFBC.⁴ An analysis including 207 male patients with breast cancer with bone metastases in the Surveillance, Epidemiology, and End Results (SEER) database demonstrated 3-year OS and cancer-specific survival (CSS) rates of 36.7% and 39.5%, respectively. Inferior OS and CSS were associated with age > 60 years (for OS: HR 1.671; P = .014; for CSS: HR 1.806; P = .009), triple-negative subtype (for OS: HR 3.029, P = .003; for CSS: HR 3.025, P = .004), and lack of surgery (for OS: HR 1.746; P = .012; for CSS: HR 1.734; P = .023), whereas brain metastasis had a worse OS (HR 2.045; P = .028) but not CSS (Zhou et al). These findings highlight the importance of getting a better understanding of mMBC disease biology and the opportunity to tailor treatment approaches for this population of patients.
 

Additional References
 

1. Waks AG, Desai NV, Li T, et al. A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2-positive breast cancer. NPJ Breast Cancer. 2022;8:63. Doi: 10.1038/s41523-022-00429-7
2. Park YH, Kim TY, Kim GM, et al; Korean Cancer Study Group (KCSG). Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): A multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2019;20(12):1750-1759. Doi: 10.1016/S1470-2045(19)30565-0
3. Lefrère H, Lenaerts L, Borges VF, et al. Postpartum breast cancer: mechanisms underlying its worse prognosis, treatment implications, and fertility preservation. Int J Gynecol Cancer. 2021;31:412-422. Doi: 10.1136/ijgc-2020-002072
4. Xie J, Ying YY, Xu B, Li Y, Zhang X, Li C. Metastasis pattern and prognosis of male breast cancer patients in US: a population-based study from SEER database. Ther Adv Med Oncol. 2019;11:1758835919889003. Doi: 10.1177/1758835919889003

A meta-analysis including over 5000 patients with metastatic hormone receptor–positive (HR+) and HER2- breast cancer showed a significant overall survival (OS) benefit with the addition of cyclin-dependent kinase (CDK) 4/6 inhibitors to endocrine therapy (hazard ratio 1.33; P < .001), albeit with higher rates of toxicities, including neutropenia, leukopenia, and diarrhea.³The MONALEESA-2 study randomly assigned 668 postmenopausal women with metastatic HR+/HER2- breast cancer, treatment-naive in the advanced setting, to either ribociclib or placebo plus letrozole. Updated results with a median follow-up of 6.6 years demonstrated a significant OS benefit with ribociclib + letrozole compared with placebo + letrozole (median OS 63.9 months vs 51.4 months; hazard ratio 0.76; P = .008) (Hortobagyi and colleagues). An OS > 5 years with ribociclib plus endocrine therapy is certainly impressive, and efficacy as well as respective toxicities of the various CDK 4/6 inhibitors are factors taken into consideration when choosing the appropriate therapy for an individual patient.

The optimization of adjuvant endocrine therapy (ET) for HR+ early breast cancer, including use of ovarian suppression and extended adjuvant therapy, has improved outcomes for these women. However, there is a high-risk subset for whom the risk for distant recurrence persists. The phase 3 monarchE trial, which included 5637 patients with high-risk early breast cancer (≥ 4 positive nodes, or 1-3 nodes and either tumor size ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%), demonstrated benefits in invasive disease-free and distant-relapse-free survival with the addition of abemaciclib for 2 years to ET. A safety analysis of the monarchE study among patients who had received at least one dose of the study drug (n = 5591) demonstrated an overall manageable side-effect profile, with the majority of these toxicities addressed via dose holds/reductions or supportive medications (Rugo and colleagues). Abemaciclib + ET led to higher incidence of grade ≥ 3 adverse events vs ET alone (49.7% vs 16.3%), with neutropenia being the most frequent (grade 3 = 19.6%) although without significant clinical implications. Diarrhea was common (83.5%), although the majority was low grade (grade 1/2 = 75.7%), with grade 2/3 events characterized by early onset and short duration. Discontinuation of abemaciclib occurred in 18.5%, with two thirds due to grade 1/2 events and in over half without dose reduction.⁴ These findings show an acceptable safety profile with abemaciclib in the curative setting and highlight the importance of education, recognition, and early management of side effects to maintain patients on treatment.

The heterogeneity of tumor biology within the HR+ breast cancer subtype indicates the need to refine treatment regimens for an individual patient. Genomic assays (70-gene signature and 21-gene recurrence score) have helped tailor adjuvant systemic therapy and in many cases have identified women for whom chemotherapy can be omitted. CDK 4/6 inhibitors have shown impressive activity in the metastatic/advanced setting, although results from trials in the adjuvant setting have produced mixed results. The phase 2 NEOPAL trial evaluated the combination of letrozole + palbociclib vs chemotherapy (sequential anthracycline-taxane) among 106 postmenopausal women with high-risk, HR+/HER2- early breast cancer (luminal B or luminal A with nodal involvement). At a median follow-up of 40.4 months, 3-year PFS (hazard ratio 1.01; P = .98) and invasive disease-free survival (hazard ratio 0.83; P = .71) were similar in the letrozole + palbociclib and chemotherapy arms (Delaloge and colleagues). The phase 2 CORALLEEN trial,⁵  which investigated neoadjuvant letrozole + ribociclib vs chemotherapy in HR+/HER2- luminal B early breast cancer, demonstrated similar percentages of patients achieving downstaging via molecular assessment at the time of surgery. The neoadjuvant space represents a valuable setting to further study CDK 4/6 inhibitors as well as other novel therapies; endpoints including pathologic complete response and residual cancer burden correlating with long-term outcomes can provide a more rapid means to identify effective therapies. Translational biomarkers can be gathered and adjuvant strategies can be tailored based on response.

Additional References

1. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382:610-621. Doi:  10.1056/NEJMoa1914510 Source
2. Hurvitz S, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan (T-DXd; DS-8201a) versus trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): Subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;General Session, GS3-01. Source
3. Li J, Huo X, Zhao F, et al. Association of cyclin-dependent kinases 4 and 6 inhibitors with survival in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis. JAMA Netw Open. 2020;3:e2020312. Doi: 10.1001/jamanetworkopen.2020.20312 Source
4. Harbeck N, Rastogi P, Martin M, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: Updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32:1571-1581. Doi: 10.1016/j.annonc.2021.09.015 Source
5. Prat A, Saura C, Pascual T, et al. Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2- negative, luminal B breast cancer (CORALLEEN): An open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2020;21:33-43. Doi: 10.1016/S1470-2045(19)30786-7 Source

A meta-analysis including over 5000 patients with metastatic hormone receptor–positive (HR+) and HER2- breast cancer showed a significant overall survival (OS) benefit with the addition of cyclin-dependent kinase (CDK) 4/6 inhibitors to endocrine therapy (hazard ratio 1.33; P < .001), albeit with higher rates of toxicities, including neutropenia, leukopenia, and diarrhea.³The MONALEESA-2 study randomly assigned 668 postmenopausal women with metastatic HR+/HER2- breast cancer, treatment-naive in the advanced setting, to either ribociclib or placebo plus letrozole. Updated results with a median follow-up of 6.6 years demonstrated a significant OS benefit with ribociclib + letrozole compared with placebo + letrozole (median OS 63.9 months vs 51.4 months; hazard ratio 0.76; P = .008) (Hortobagyi and colleagues). An OS > 5 years with ribociclib plus endocrine therapy is certainly impressive, and efficacy as well as respective toxicities of the various CDK 4/6 inhibitors are factors taken into consideration when choosing the appropriate therapy for an individual patient.

The optimization of adjuvant endocrine therapy (ET) for HR+ early breast cancer, including use of ovarian suppression and extended adjuvant therapy, has improved outcomes for these women. However, there is a high-risk subset for whom the risk for distant recurrence persists. The phase 3 monarchE trial, which included 5637 patients with high-risk early breast cancer (≥ 4 positive nodes, or 1-3 nodes and either tumor size ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%), demonstrated benefits in invasive disease-free and distant-relapse-free survival with the addition of abemaciclib for 2 years to ET. A safety analysis of the monarchE study among patients who had received at least one dose of the study drug (n = 5591) demonstrated an overall manageable side-effect profile, with the majority of these toxicities addressed via dose holds/reductions or supportive medications (Rugo and colleagues). Abemaciclib + ET led to higher incidence of grade ≥ 3 adverse events vs ET alone (49.7% vs 16.3%), with neutropenia being the most frequent (grade 3 = 19.6%) although without significant clinical implications. Diarrhea was common (83.5%), although the majority was low grade (grade 1/2 = 75.7%), with grade 2/3 events characterized by early onset and short duration. Discontinuation of abemaciclib occurred in 18.5%, with two thirds due to grade 1/2 events and in over half without dose reduction.⁴ These findings show an acceptable safety profile with abemaciclib in the curative setting and highlight the importance of education, recognition, and early management of side effects to maintain patients on treatment.

The heterogeneity of tumor biology within the HR+ breast cancer subtype indicates the need to refine treatment regimens for an individual patient. Genomic assays (70-gene signature and 21-gene recurrence score) have helped tailor adjuvant systemic therapy and in many cases have identified women for whom chemotherapy can be omitted. CDK 4/6 inhibitors have shown impressive activity in the metastatic/advanced setting, although results from trials in the adjuvant setting have produced mixed results. The phase 2 NEOPAL trial evaluated the combination of letrozole + palbociclib vs chemotherapy (sequential anthracycline-taxane) among 106 postmenopausal women with high-risk, HR+/HER2- early breast cancer (luminal B or luminal A with nodal involvement). At a median follow-up of 40.4 months, 3-year PFS (hazard ratio 1.01; P = .98) and invasive disease-free survival (hazard ratio 0.83; P = .71) were similar in the letrozole + palbociclib and chemotherapy arms (Delaloge and colleagues). The phase 2 CORALLEEN trial,⁵  which investigated neoadjuvant letrozole + ribociclib vs chemotherapy in HR+/HER2- luminal B early breast cancer, demonstrated similar percentages of patients achieving downstaging via molecular assessment at the time of surgery. The neoadjuvant space represents a valuable setting to further study CDK 4/6 inhibitors as well as other novel therapies; endpoints including pathologic complete response and residual cancer burden correlating with long-term outcomes can provide a more rapid means to identify effective therapies. Translational biomarkers can be gathered and adjuvant strategies can be tailored based on response.

Additional References

1. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382:610-621. Doi:  10.1056/NEJMoa1914510 Source
2. Hurvitz S, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan (T-DXd; DS-8201a) versus trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): Subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;General Session, GS3-01. Source
3. Li J, Huo X, Zhao F, et al. Association of cyclin-dependent kinases 4 and 6 inhibitors with survival in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis. JAMA Netw Open. 2020;3:e2020312. Doi: 10.1001/jamanetworkopen.2020.20312 Source
4. Harbeck N, Rastogi P, Martin M, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: Updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32:1571-1581. Doi: 10.1016/j.annonc.2021.09.015 Source
5. Prat A, Saura C, Pascual T, et al. Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2- negative, luminal B breast cancer (CORALLEEN): An open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2020;21:33-43. Doi: 10.1016/S1470-2045(19)30786-7 Source

A meta-analysis including over 5000 patients with metastatic hormone receptor–positive (HR+) and HER2- breast cancer showed a significant overall survival (OS) benefit with the addition of cyclin-dependent kinase (CDK) 4/6 inhibitors to endocrine therapy (hazard ratio 1.33; P < .001), albeit with higher rates of toxicities, including neutropenia, leukopenia, and diarrhea.³The MONALEESA-2 study randomly assigned 668 postmenopausal women with metastatic HR+/HER2- breast cancer, treatment-naive in the advanced setting, to either ribociclib or placebo plus letrozole. Updated results with a median follow-up of 6.6 years demonstrated a significant OS benefit with ribociclib + letrozole compared with placebo + letrozole (median OS 63.9 months vs 51.4 months; hazard ratio 0.76; P = .008) (Hortobagyi and colleagues). An OS > 5 years with ribociclib plus endocrine therapy is certainly impressive, and efficacy as well as respective toxicities of the various CDK 4/6 inhibitors are factors taken into consideration when choosing the appropriate therapy for an individual patient.

The optimization of adjuvant endocrine therapy (ET) for HR+ early breast cancer, including use of ovarian suppression and extended adjuvant therapy, has improved outcomes for these women. However, there is a high-risk subset for whom the risk for distant recurrence persists. The phase 3 monarchE trial, which included 5637 patients with high-risk early breast cancer (≥ 4 positive nodes, or 1-3 nodes and either tumor size ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%), demonstrated benefits in invasive disease-free and distant-relapse-free survival with the addition of abemaciclib for 2 years to ET. A safety analysis of the monarchE study among patients who had received at least one dose of the study drug (n = 5591) demonstrated an overall manageable side-effect profile, with the majority of these toxicities addressed via dose holds/reductions or supportive medications (Rugo and colleagues). Abemaciclib + ET led to higher incidence of grade ≥ 3 adverse events vs ET alone (49.7% vs 16.3%), with neutropenia being the most frequent (grade 3 = 19.6%) although without significant clinical implications. Diarrhea was common (83.5%), although the majority was low grade (grade 1/2 = 75.7%), with grade 2/3 events characterized by early onset and short duration. Discontinuation of abemaciclib occurred in 18.5%, with two thirds due to grade 1/2 events and in over half without dose reduction.⁴ These findings show an acceptable safety profile with abemaciclib in the curative setting and highlight the importance of education, recognition, and early management of side effects to maintain patients on treatment.

The heterogeneity of tumor biology within the HR+ breast cancer subtype indicates the need to refine treatment regimens for an individual patient. Genomic assays (70-gene signature and 21-gene recurrence score) have helped tailor adjuvant systemic therapy and in many cases have identified women for whom chemotherapy can be omitted. CDK 4/6 inhibitors have shown impressive activity in the metastatic/advanced setting, although results from trials in the adjuvant setting have produced mixed results. The phase 2 NEOPAL trial evaluated the combination of letrozole + palbociclib vs chemotherapy (sequential anthracycline-taxane) among 106 postmenopausal women with high-risk, HR+/HER2- early breast cancer (luminal B or luminal A with nodal involvement). At a median follow-up of 40.4 months, 3-year PFS (hazard ratio 1.01; P = .98) and invasive disease-free survival (hazard ratio 0.83; P = .71) were similar in the letrozole + palbociclib and chemotherapy arms (Delaloge and colleagues). The phase 2 CORALLEEN trial,⁵  which investigated neoadjuvant letrozole + ribociclib vs chemotherapy in HR+/HER2- luminal B early breast cancer, demonstrated similar percentages of patients achieving downstaging via molecular assessment at the time of surgery. The neoadjuvant space represents a valuable setting to further study CDK 4/6 inhibitors as well as other novel therapies; endpoints including pathologic complete response and residual cancer burden correlating with long-term outcomes can provide a more rapid means to identify effective therapies. Translational biomarkers can be gathered and adjuvant strategies can be tailored based on response.

Additional References

1. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382:610-621. Doi:  10.1056/NEJMoa1914510 Source
2. Hurvitz S, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan (T-DXd; DS-8201a) versus trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): Subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;General Session, GS3-01. Source
3. Li J, Huo X, Zhao F, et al. Association of cyclin-dependent kinases 4 and 6 inhibitors with survival in patients with hormone receptor-positive metastatic breast cancer: A systematic review and meta-analysis. JAMA Netw Open. 2020;3:e2020312. Doi: 10.1001/jamanetworkopen.2020.20312 Source
4. Harbeck N, Rastogi P, Martin M, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: Updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol. 2021;32:1571-1581. Doi: 10.1016/j.annonc.2021.09.015 Source
5. Prat A, Saura C, Pascual T, et al. Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2- negative, luminal B breast cancer (CORALLEEN): An open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2020;21:33-43. Doi: 10.1016/S1470-2045(19)30786-7 Source

Based on the work you do at the Cleveland Clinic Taussig Cancer Institute, what is your standard approach to managing  early stage cancer patients?

Dr. Roesch: The approach to managing patients with early stage breast cancer very much depends on the subtype of breast cancer. Clinical stage at presentation and patient factors are considered here. For example, patients with small hormone receptor-positive tumors will often have surgery first, while patients with triple-negative or HER2-positive tumors will often receive preoperative or neoadjuvant chemotherapy.

In situations where there is a need or a desire for downstaging or shrinking of the primary tumor or lymph nodes in the axilla, we will also discuss neoadjuvant systemic therapy. For hormone receptor-positive tumors, endocrine or anti-estrogen therapy will be incorporated into their treatment regimen at some point in the future.

The role of chemotherapy for hormone receptor-positive breast cancer depends on a variety of factors, including pathologic staging, which we obtain at the time of surgery. Exceptions may include very small tumors or patients who have medical comorbidities that affect their candidacy for chemotherapy where the risk may outweigh the benefit.

Are there specific steps you take in managing and treating early stage triple-negative breast cancer?

Dr. Roesch: Most patients with early stage triple-negative breast cancer receive neoadjuvant or preoperative chemotherapy. As I mentioned above, this has the benefits of downstaging the primary tumor itself and the lymph nodes in the axilla as well as providing prognostic information. This approach can also help guide adjuvant therapy recommendations. Additionally, we often discuss the role of genetic counseling for these patients.

Are there targeted therapies you rely upon?

Dr. Roesch: This has been an evolving field with dramatic advances in the past couple of years. One is immunotherapy. There was a phase III study called the KEYONTE-522 trial, which demonstrated improvements in pathologic response rate and event-free survival with a regimen of neoadjuvant pembrolizumab plus chemotherapy followed by the pembrolizumab given in the adjuvant setting, compared to chemotherapy approach alone (1).

For patients who meet criteria for this study, which is essentially stage II/III triple-negative breast cancer, we have adopted this regimen in the neoadjuvant setting. Additionally, we consider adjuvant capecitabine for patients who have received neoadjuvant chemotherapy with an anthracycline, taxane or both and who have residual disease at the time of surgery. This is based on the CREATE-X trial, which showed a survival benefit for patients with triple-negative breast cancer in this situation (2).

Lastly, the PARP inhibitor, olaparib, was recently approved by the FDA in the adjuvant setting for BRCA mutation carriers diagnosed with HER-2-negative high-risk early breast cancer who have received neoadjuvant or adjuvant chemotherapy. This treatment also demonstrated survival benefit and is an exciting new option for these patients (3).

A critical question in my mind that has arisen out of these new developments is sequencing of these therapies. For example, if I have a patient who received the KEYNOTE-522 regimen with the immunotherapy agent, pembrolizumab, and has residual disease after surgery, how do we administer the capecitabine with the pembrolizumab? And what about radiation? What if a patient is a BRCA mutation carrier? These are all very relevant questions, which we are encountering every day, and the approach we take is often individualized.

This sounds very exciting. Can you talk about the research on managing early triple-negative breast cancer and what the future might hold?

Dr. Roesch: This is a very exciting time for both us as oncologists and our patients as there is a very rapid pace of new therapies being explored in the context of clinical trials. First, I'd like to mention the adjuvant vaccine trial we have at Cleveland Clinic for patients diagnosed with early stage triple-negative breast cancer at high risk of recurrence. This trial is investigating an alpha lactalbumin vaccine, which has been selected as a vaccine target because it is a breast-specific differentiation protein expressed at high levels in many human breast cancers, particularly in triple-negative breast cancer. The current trial's main objective is to determine the maximum tolerated dose of the vaccine, and other endpoints include looking at biomarkers of immune responses (4).

The I-SPY2 trial is another very exciting study we have open at Cleveland Clinic. This is a multicenter phase II trial using response adaptive randomization within molecular subtypes, which is defined by the receptor status and MammaPrint risk, which is a genomic assay, to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. Patients undergo serial MRIs and biopsies with information on the likelihood of them achieving a pathologic complete response (pCR) provided back in real time, which will then allow for therapy escalation or de-escalation. The goal here is individualized precision therapy based on the specific intrinsic subtype of the tumor itself and response with the ultimate goal being to achieve a pCR (5).

Again, this is a very exciting time for us as medical providers and our patients because new therapies are being developed and studied in clinical trials every day.

Based on the work you do at the Cleveland Clinic Taussig Cancer Institute, what is your standard approach to managing  early stage cancer patients?

Dr. Roesch: The approach to managing patients with early stage breast cancer very much depends on the subtype of breast cancer. Clinical stage at presentation and patient factors are considered here. For example, patients with small hormone receptor-positive tumors will often have surgery first, while patients with triple-negative or HER2-positive tumors will often receive preoperative or neoadjuvant chemotherapy.

In situations where there is a need or a desire for downstaging or shrinking of the primary tumor or lymph nodes in the axilla, we will also discuss neoadjuvant systemic therapy. For hormone receptor-positive tumors, endocrine or anti-estrogen therapy will be incorporated into their treatment regimen at some point in the future.

The role of chemotherapy for hormone receptor-positive breast cancer depends on a variety of factors, including pathologic staging, which we obtain at the time of surgery. Exceptions may include very small tumors or patients who have medical comorbidities that affect their candidacy for chemotherapy where the risk may outweigh the benefit.

Are there specific steps you take in managing and treating early stage triple-negative breast cancer?

Dr. Roesch: Most patients with early stage triple-negative breast cancer receive neoadjuvant or preoperative chemotherapy. As I mentioned above, this has the benefits of downstaging the primary tumor itself and the lymph nodes in the axilla as well as providing prognostic information. This approach can also help guide adjuvant therapy recommendations. Additionally, we often discuss the role of genetic counseling for these patients.

Are there targeted therapies you rely upon?

Dr. Roesch: This has been an evolving field with dramatic advances in the past couple of years. One is immunotherapy. There was a phase III study called the KEYONTE-522 trial, which demonstrated improvements in pathologic response rate and event-free survival with a regimen of neoadjuvant pembrolizumab plus chemotherapy followed by the pembrolizumab given in the adjuvant setting, compared to chemotherapy approach alone (1).

For patients who meet criteria for this study, which is essentially stage II/III triple-negative breast cancer, we have adopted this regimen in the neoadjuvant setting. Additionally, we consider adjuvant capecitabine for patients who have received neoadjuvant chemotherapy with an anthracycline, taxane or both and who have residual disease at the time of surgery. This is based on the CREATE-X trial, which showed a survival benefit for patients with triple-negative breast cancer in this situation (2).

Lastly, the PARP inhibitor, olaparib, was recently approved by the FDA in the adjuvant setting for BRCA mutation carriers diagnosed with HER-2-negative high-risk early breast cancer who have received neoadjuvant or adjuvant chemotherapy. This treatment also demonstrated survival benefit and is an exciting new option for these patients (3).

A critical question in my mind that has arisen out of these new developments is sequencing of these therapies. For example, if I have a patient who received the KEYNOTE-522 regimen with the immunotherapy agent, pembrolizumab, and has residual disease after surgery, how do we administer the capecitabine with the pembrolizumab? And what about radiation? What if a patient is a BRCA mutation carrier? These are all very relevant questions, which we are encountering every day, and the approach we take is often individualized.

This sounds very exciting. Can you talk about the research on managing early triple-negative breast cancer and what the future might hold?

Dr. Roesch: This is a very exciting time for both us as oncologists and our patients as there is a very rapid pace of new therapies being explored in the context of clinical trials. First, I'd like to mention the adjuvant vaccine trial we have at Cleveland Clinic for patients diagnosed with early stage triple-negative breast cancer at high risk of recurrence. This trial is investigating an alpha lactalbumin vaccine, which has been selected as a vaccine target because it is a breast-specific differentiation protein expressed at high levels in many human breast cancers, particularly in triple-negative breast cancer. The current trial's main objective is to determine the maximum tolerated dose of the vaccine, and other endpoints include looking at biomarkers of immune responses (4).

The I-SPY2 trial is another very exciting study we have open at Cleveland Clinic. This is a multicenter phase II trial using response adaptive randomization within molecular subtypes, which is defined by the receptor status and MammaPrint risk, which is a genomic assay, to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. Patients undergo serial MRIs and biopsies with information on the likelihood of them achieving a pathologic complete response (pCR) provided back in real time, which will then allow for therapy escalation or de-escalation. The goal here is individualized precision therapy based on the specific intrinsic subtype of the tumor itself and response with the ultimate goal being to achieve a pCR (5).

Again, this is a very exciting time for us as medical providers and our patients because new therapies are being developed and studied in clinical trials every day.

Based on the work you do at the Cleveland Clinic Taussig Cancer Institute, what is your standard approach to managing  early stage cancer patients?

Dr. Roesch: The approach to managing patients with early stage breast cancer very much depends on the subtype of breast cancer. Clinical stage at presentation and patient factors are considered here. For example, patients with small hormone receptor-positive tumors will often have surgery first, while patients with triple-negative or HER2-positive tumors will often receive preoperative or neoadjuvant chemotherapy.

In situations where there is a need or a desire for downstaging or shrinking of the primary tumor or lymph nodes in the axilla, we will also discuss neoadjuvant systemic therapy. For hormone receptor-positive tumors, endocrine or anti-estrogen therapy will be incorporated into their treatment regimen at some point in the future.

The role of chemotherapy for hormone receptor-positive breast cancer depends on a variety of factors, including pathologic staging, which we obtain at the time of surgery. Exceptions may include very small tumors or patients who have medical comorbidities that affect their candidacy for chemotherapy where the risk may outweigh the benefit.

Are there specific steps you take in managing and treating early stage triple-negative breast cancer?

Dr. Roesch: Most patients with early stage triple-negative breast cancer receive neoadjuvant or preoperative chemotherapy. As I mentioned above, this has the benefits of downstaging the primary tumor itself and the lymph nodes in the axilla as well as providing prognostic information. This approach can also help guide adjuvant therapy recommendations. Additionally, we often discuss the role of genetic counseling for these patients.

Are there targeted therapies you rely upon?

Dr. Roesch: This has been an evolving field with dramatic advances in the past couple of years. One is immunotherapy. There was a phase III study called the KEYONTE-522 trial, which demonstrated improvements in pathologic response rate and event-free survival with a regimen of neoadjuvant pembrolizumab plus chemotherapy followed by the pembrolizumab given in the adjuvant setting, compared to chemotherapy approach alone (1).

For patients who meet criteria for this study, which is essentially stage II/III triple-negative breast cancer, we have adopted this regimen in the neoadjuvant setting. Additionally, we consider adjuvant capecitabine for patients who have received neoadjuvant chemotherapy with an anthracycline, taxane or both and who have residual disease at the time of surgery. This is based on the CREATE-X trial, which showed a survival benefit for patients with triple-negative breast cancer in this situation (2).

Lastly, the PARP inhibitor, olaparib, was recently approved by the FDA in the adjuvant setting for BRCA mutation carriers diagnosed with HER-2-negative high-risk early breast cancer who have received neoadjuvant or adjuvant chemotherapy. This treatment also demonstrated survival benefit and is an exciting new option for these patients (3).

A critical question in my mind that has arisen out of these new developments is sequencing of these therapies. For example, if I have a patient who received the KEYNOTE-522 regimen with the immunotherapy agent, pembrolizumab, and has residual disease after surgery, how do we administer the capecitabine with the pembrolizumab? And what about radiation? What if a patient is a BRCA mutation carrier? These are all very relevant questions, which we are encountering every day, and the approach we take is often individualized.

This sounds very exciting. Can you talk about the research on managing early triple-negative breast cancer and what the future might hold?

Dr. Roesch: This is a very exciting time for both us as oncologists and our patients as there is a very rapid pace of new therapies being explored in the context of clinical trials. First, I'd like to mention the adjuvant vaccine trial we have at Cleveland Clinic for patients diagnosed with early stage triple-negative breast cancer at high risk of recurrence. This trial is investigating an alpha lactalbumin vaccine, which has been selected as a vaccine target because it is a breast-specific differentiation protein expressed at high levels in many human breast cancers, particularly in triple-negative breast cancer. The current trial's main objective is to determine the maximum tolerated dose of the vaccine, and other endpoints include looking at biomarkers of immune responses (4).

The I-SPY2 trial is another very exciting study we have open at Cleveland Clinic. This is a multicenter phase II trial using response adaptive randomization within molecular subtypes, which is defined by the receptor status and MammaPrint risk, which is a genomic assay, to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. Patients undergo serial MRIs and biopsies with information on the likelihood of them achieving a pathologic complete response (pCR) provided back in real time, which will then allow for therapy escalation or de-escalation. The goal here is individualized precision therapy based on the specific intrinsic subtype of the tumor itself and response with the ultimate goal being to achieve a pCR (5).

Again, this is a very exciting time for us as medical providers and our patients because new therapies are being developed and studied in clinical trials every day.

Studies have demonstrated inferior survival outcomes associated with delays in time to surgery and adjuvant chemotherapy for early breast cancer. The timing of adjuvant endocrine therapy is also notable because of the favorable effect on recurrence risk and survival with these agents in early HR+ breast cancer. A cohort study from the National Cancer Database including 144,103 women demonstrated a 31% increase in the risk for death (hazard ratio [HR] 1.31; P < .001) with a time to adjuvant hormone therapy (TTH) > 150 days (6.4% of patients) compared with those with TTH ≤ 150 days (93.6% of patients). Factors associated with delay in TTH included Black race, nonprivate insurance, metropolitan residence (vs. urban or rural), community hospital setting (vs. academic), higher comorbidity index, poorly differentiated tumors, higher stage, breast conservation surgery (vs. mastectomy), and radiation therapy. This study highlights the need to avoid unnecessary delays in adjuvant hormone therapy and encourages further exploration of barriers to timely initiation of breast cancer therapies to maximize outcomes for patients.

The role of reproductive hormones in breast cancer risk and carcinogenesis has been extensively studied and hormonal therapies are an essential component of the management of HR+ breast cancer. Lan and colleagues performed a retrospective analysis including 196 premenopausal and 137 postmenopausal women treated with neoadjuvant chemotherapy for breast cancer, investigating the correlation between pretreatment levels of reproductive hormone levels with pathologic and survival outcomes. Higher likelihood of achieving pathologic complete response was seen in premenopausal women with lower vs. higher testosterone levels (odds ratio [OR] 0.996; P = .026) and in postmenopausal women with higher vs. lower follicle-stimulating hormone levels (OR 1.045; P = .005). Furthermore, lower progesterone levels in premenopausal patients was associated with inferior overall survival (OS) (3-year OS 72.9% vs. 97.4% for lowest tertile progesterone vs. higher tertiles; P = .007). These data suggest a potential role of reproductive hormones in the preoperative evaluation for breast cancer patients. Also, the complex actions of progesterone and "crosstalk" between estrogen receptors and progesterone receptors continue to be elucidated and ongoing studies are evaluating progestin combined with endocrine therapy.

The CLEOPATRA trial has established the regimen of trastuzumab plus pertuzumab plus docetaxel as first-line therapy for metastatic HER2-positive (HER2+) breast cancer with an absolute survival benefit of 16.3 months vs. trastuzumab plus docetaxel. A retrospective study conducted in Ontario, Canada, explored real-world outcomes of pertuzumab plus trastuzumab plus chemotherapy among 1158 patients and demonstrated a similar magnitude of survival improvement with the addition of pertuzumab (14.9 months) (Dai et al). The median OS was higher among patients receiving pertuzumab compared with control (40.2 vs. 25.3 months), and although the median OS was shorter in the real-world setting than in the CLEOPATRA trial, they had similar HRs for mortality reduction (0.66 for real-world and 0.69 for trial). Furthermore, there was no increase in cardiotoxicity and lower cumulative incidence of hospitalization at 1 year with pertuzumab vs. control (11.7% vs. 19.0%; P < .001). This study adds to the existing body of data supporting first-line treatment with pertuzumab plus trastuzumab plus chemotherapy for metastatic HER2+ breast cancer. The treatment landscape for these patients is certainly dynamic with the development of novel therapies and combinations in this space and resultant shifts in the current algorithm.

Recommended Additional Reading:

Hortobagyi GN et al. LBA17 Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB). Ann Oncol. 2021;32:S1290-S1291. Doi: 10.1016/j.annonc.2021.08.2090

Chavez-MacGregor M et al. Delayed initiation of adjuvant chemotherapy among patients with breast cancer. JAMA Oncol. 2016;2:322-329. Doi:10.1001/jamaoncol.2015.3856

Trabert B et al. Progesterone and breast cancer. Endocr Rev. 2020;41:320-344. Doi: 10.1210/endrev/bnz001

Swain SM et al; on behalf of the CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:519-530. Doi: 10.1016/S1470-2045(19)30863-0

Studies have demonstrated inferior survival outcomes associated with delays in time to surgery and adjuvant chemotherapy for early breast cancer. The timing of adjuvant endocrine therapy is also notable because of the favorable effect on recurrence risk and survival with these agents in early HR+ breast cancer. A cohort study from the National Cancer Database including 144,103 women demonstrated a 31% increase in the risk for death (hazard ratio [HR] 1.31; P < .001) with a time to adjuvant hormone therapy (TTH) > 150 days (6.4% of patients) compared with those with TTH ≤ 150 days (93.6% of patients). Factors associated with delay in TTH included Black race, nonprivate insurance, metropolitan residence (vs. urban or rural), community hospital setting (vs. academic), higher comorbidity index, poorly differentiated tumors, higher stage, breast conservation surgery (vs. mastectomy), and radiation therapy. This study highlights the need to avoid unnecessary delays in adjuvant hormone therapy and encourages further exploration of barriers to timely initiation of breast cancer therapies to maximize outcomes for patients.

The role of reproductive hormones in breast cancer risk and carcinogenesis has been extensively studied and hormonal therapies are an essential component of the management of HR+ breast cancer. Lan and colleagues performed a retrospective analysis including 196 premenopausal and 137 postmenopausal women treated with neoadjuvant chemotherapy for breast cancer, investigating the correlation between pretreatment levels of reproductive hormone levels with pathologic and survival outcomes. Higher likelihood of achieving pathologic complete response was seen in premenopausal women with lower vs. higher testosterone levels (odds ratio [OR] 0.996; P = .026) and in postmenopausal women with higher vs. lower follicle-stimulating hormone levels (OR 1.045; P = .005). Furthermore, lower progesterone levels in premenopausal patients was associated with inferior overall survival (OS) (3-year OS 72.9% vs. 97.4% for lowest tertile progesterone vs. higher tertiles; P = .007). These data suggest a potential role of reproductive hormones in the preoperative evaluation for breast cancer patients. Also, the complex actions of progesterone and "crosstalk" between estrogen receptors and progesterone receptors continue to be elucidated and ongoing studies are evaluating progestin combined with endocrine therapy.

The CLEOPATRA trial has established the regimen of trastuzumab plus pertuzumab plus docetaxel as first-line therapy for metastatic HER2-positive (HER2+) breast cancer with an absolute survival benefit of 16.3 months vs. trastuzumab plus docetaxel. A retrospective study conducted in Ontario, Canada, explored real-world outcomes of pertuzumab plus trastuzumab plus chemotherapy among 1158 patients and demonstrated a similar magnitude of survival improvement with the addition of pertuzumab (14.9 months) (Dai et al). The median OS was higher among patients receiving pertuzumab compared with control (40.2 vs. 25.3 months), and although the median OS was shorter in the real-world setting than in the CLEOPATRA trial, they had similar HRs for mortality reduction (0.66 for real-world and 0.69 for trial). Furthermore, there was no increase in cardiotoxicity and lower cumulative incidence of hospitalization at 1 year with pertuzumab vs. control (11.7% vs. 19.0%; P < .001). This study adds to the existing body of data supporting first-line treatment with pertuzumab plus trastuzumab plus chemotherapy for metastatic HER2+ breast cancer. The treatment landscape for these patients is certainly dynamic with the development of novel therapies and combinations in this space and resultant shifts in the current algorithm.

Recommended Additional Reading:

Hortobagyi GN et al. LBA17 Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB). Ann Oncol. 2021;32:S1290-S1291. Doi: 10.1016/j.annonc.2021.08.2090

Chavez-MacGregor M et al. Delayed initiation of adjuvant chemotherapy among patients with breast cancer. JAMA Oncol. 2016;2:322-329. Doi:10.1001/jamaoncol.2015.3856

Trabert B et al. Progesterone and breast cancer. Endocr Rev. 2020;41:320-344. Doi: 10.1210/endrev/bnz001

Swain SM et al; on behalf of the CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:519-530. Doi: 10.1016/S1470-2045(19)30863-0

Studies have demonstrated inferior survival outcomes associated with delays in time to surgery and adjuvant chemotherapy for early breast cancer. The timing of adjuvant endocrine therapy is also notable because of the favorable effect on recurrence risk and survival with these agents in early HR+ breast cancer. A cohort study from the National Cancer Database including 144,103 women demonstrated a 31% increase in the risk for death (hazard ratio [HR] 1.31; P < .001) with a time to adjuvant hormone therapy (TTH) > 150 days (6.4% of patients) compared with those with TTH ≤ 150 days (93.6% of patients). Factors associated with delay in TTH included Black race, nonprivate insurance, metropolitan residence (vs. urban or rural), community hospital setting (vs. academic), higher comorbidity index, poorly differentiated tumors, higher stage, breast conservation surgery (vs. mastectomy), and radiation therapy. This study highlights the need to avoid unnecessary delays in adjuvant hormone therapy and encourages further exploration of barriers to timely initiation of breast cancer therapies to maximize outcomes for patients.

The role of reproductive hormones in breast cancer risk and carcinogenesis has been extensively studied and hormonal therapies are an essential component of the management of HR+ breast cancer. Lan and colleagues performed a retrospective analysis including 196 premenopausal and 137 postmenopausal women treated with neoadjuvant chemotherapy for breast cancer, investigating the correlation between pretreatment levels of reproductive hormone levels with pathologic and survival outcomes. Higher likelihood of achieving pathologic complete response was seen in premenopausal women with lower vs. higher testosterone levels (odds ratio [OR] 0.996; P = .026) and in postmenopausal women with higher vs. lower follicle-stimulating hormone levels (OR 1.045; P = .005). Furthermore, lower progesterone levels in premenopausal patients was associated with inferior overall survival (OS) (3-year OS 72.9% vs. 97.4% for lowest tertile progesterone vs. higher tertiles; P = .007). These data suggest a potential role of reproductive hormones in the preoperative evaluation for breast cancer patients. Also, the complex actions of progesterone and "crosstalk" between estrogen receptors and progesterone receptors continue to be elucidated and ongoing studies are evaluating progestin combined with endocrine therapy.

The CLEOPATRA trial has established the regimen of trastuzumab plus pertuzumab plus docetaxel as first-line therapy for metastatic HER2-positive (HER2+) breast cancer with an absolute survival benefit of 16.3 months vs. trastuzumab plus docetaxel. A retrospective study conducted in Ontario, Canada, explored real-world outcomes of pertuzumab plus trastuzumab plus chemotherapy among 1158 patients and demonstrated a similar magnitude of survival improvement with the addition of pertuzumab (14.9 months) (Dai et al). The median OS was higher among patients receiving pertuzumab compared with control (40.2 vs. 25.3 months), and although the median OS was shorter in the real-world setting than in the CLEOPATRA trial, they had similar HRs for mortality reduction (0.66 for real-world and 0.69 for trial). Furthermore, there was no increase in cardiotoxicity and lower cumulative incidence of hospitalization at 1 year with pertuzumab vs. control (11.7% vs. 19.0%; P < .001). This study adds to the existing body of data supporting first-line treatment with pertuzumab plus trastuzumab plus chemotherapy for metastatic HER2+ breast cancer. The treatment landscape for these patients is certainly dynamic with the development of novel therapies and combinations in this space and resultant shifts in the current algorithm.

Recommended Additional Reading:

Hortobagyi GN et al. LBA17 Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB). Ann Oncol. 2021;32:S1290-S1291. Doi: 10.1016/j.annonc.2021.08.2090

Chavez-MacGregor M et al. Delayed initiation of adjuvant chemotherapy among patients with breast cancer. JAMA Oncol. 2016;2:322-329. Doi:10.1001/jamaoncol.2015.3856

Trabert B et al. Progesterone and breast cancer. Endocr Rev. 2020;41:320-344. Doi: 10.1210/endrev/bnz001

Swain SM et al; on behalf of the CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:519-530. Doi: 10.1016/S1470-2045(19)30863-0

The predilection for brain metastases in human epidermal growth factor receptor 2 (HER2)-positive breast cancer has historically presented a therapeutic challenge, and agents with enhanced central nervous system (CNS) penetrance are certainly desired. Pyrotinib is a small molecule irreversible tyrosine kinase inhibitor against epidermal growth factor receptor (EGFR), HER2, and HER4. Yan et al investigated the activity and safety of pyrotinib + capecitabine in the single-arm, two-cohort, phase 2 PERMEATE study among 78 patients with HER2-positive metastatic breast cancer (MBC) with brain metastases. The intracranial objective response rate was 74.6% in radiotherapy-naive patients and 42.1% in those progressing after prior radiotherapy. The combination showed good tolerability with the most common grade 3 treatment-related adverse events of diarrhea and neutropenia. Additional studies have shown impressive CNS activity with other HER2-targeted therapies including tucatinib + capecitabine + trastuzumab combination, as well as trastuzumab deruxtecan (HER2CLIMB and DESTINY-Breast03 trials, respectively). The evolution of these agents in both the metastatic and early settings will continue to transform the treatment algorithm for HER2-positive breast cancer. A particularly interesting concept is whether earlier use of drugs with better CNS efficacy can reduce risk or prevent development of brain metastases.

Endocrine therapy in early-stage hormone receptor-positive (HR+) breast cancer leads to significant reductions in recurrence and breast cancer mortality. A meta-analysis was performed by Early Breast Cancer Trialists' Collaborative Group including four trials (ABCSG XII, SOFT, TEXT and HOBOE), 7030 premenopausal patients with early-stage ER+ breast cancer, who received an aromatase inhibitor or tamoxifen for 3-5 years with ovarian suppression. Rates of breast cancer recurrence were lower with an aromatase inhibitor vs tamoxifen, with the main benefit seen during years 0-4 (relative risk [RR] 0.68, P < .0001) and an absolute reduction in 5-year recurrence risk of 3.2% (6.9% vs 10.1%). Aromatase inhibitor use was associated with decreased distant recurrence risk (RR 0.83), but there was no significant difference for breast cancer or all-cause mortality. The favored endocrine therapy approach for an individual patient is often complex and based on overall risk, comorbidities and toxicity concerns, as well as patient preference. Longer follow-up of trials with endocrine therapy and ovarian suppression will provide further insight on mortality impact.

Aromatase inhibitor (AI)-associated musculoskeletal symptoms are not infrequent and can contribute to treatment discontinuation. Current management practices include use of non-steroidal anti-inflammatory drugs (NSAID), weight loss and exercise, trial of alternative AI or tamoxifen, use of serotonin and norepinephrine reuptake inhibitors (SNRI) (duloxetine) and acupuncture. Martinez et al reported on outcomes of the non-selective NSAID, sulindac (150mg twice daily for 12 months), in a phase 2 study among postmenopausal women with early HR+ breast cancer who were stable on AI therapy for at least 3 months. At 12 months, patients receiving sulindac (n = 43) reported improvements (decreases) in Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index (-5.85, P = .003), pain (-5.40, P = .043), stiffness (-9.53, P < .001) and physical function (-5.61, P = .006); those in the observation group (n = 40) did not experience improvements in these variables. The most significant improvement with sulindac was seen in those with a higher degree of baseline symptoms and in overweight/obese patients. These findings support further investigation into abbreviated NSAID use and strategies focused on exercise and healthy body weight maintenance for breast cancer patients.

The treatment landscape for early-stage triple-negative breast cancer (TNBC) continues to evolve with integration of new drugs into our armamentarium, and use of pathologic complete response (pCR) as a surrogate for outcome and for tailoring adjuvant therapy. Geyer et al reported on event-free survival outcomes with a 4.5 year follow-up of the phase 3 BrighTNess trial, which included 634 patients with stage II-III TNBC. Significant improvement in event-free survival (EFS) was seen in the carboplatin + veliparib + paclitaxel arm vs. paclitaxel alone (HR 0.63, P = .02), but no difference in EFS in carboplatin + veliparib + paclitaxel vs. carboplatin + paclitaxel (HR 1.12, P = .62). The EFS rates at 4 years were 78% (carboplatin + veliparib + paclitaxel), 79% (carboplatin + paclitaxel) and 69% (paclitaxel alone). The phase 3 KEYNOTE-522 trial demonstrated improvement in EFS with the addition of neoadjuvant pembrolizumab to chemotherapy (carboplatin/paclitaxel followed by AC) followed by adjuvant pembrolizumab compared to chemotherapy alone in patients with stage II-III TNBC. The emergence of new therapies for early TNBC, including immunotherapy and  poly (ADP-ribose) polymerase (PARP) inhibitors (the latter for patients with germline BRCA mutations), has created more treatment options for patients along with questions regarding combinations and sequencing.  

Recommended Additional Reading:

Lin N et al. Updated results of tucatinib vs placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;Spotlight Poster Session, PD4-04 Abstract 858. https://www.abstractsonline.com/pp8/#!/10462/presentation/482

Hurvitz S et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;General Session, GS3-01. https://www.abstractsonline.com/pp8/#!/10462/presentation/649

Rosati MS, Di Seri M, Baciarello G, et al. Etoricoxib and anastrozole in adjuvant early breast cancer: ETAN trial (phase III). J Clin Oncol. 2011;29:suppl.533. https://ascopubs.org/doi/10.1200/jco.2011.29.15_suppl.533

Schmid P et al for the KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386(6):556-567. https://www.nejm.org/doi/full/10.1056/NEJMoa2112651

The predilection for brain metastases in human epidermal growth factor receptor 2 (HER2)-positive breast cancer has historically presented a therapeutic challenge, and agents with enhanced central nervous system (CNS) penetrance are certainly desired. Pyrotinib is a small molecule irreversible tyrosine kinase inhibitor against epidermal growth factor receptor (EGFR), HER2, and HER4. Yan et al investigated the activity and safety of pyrotinib + capecitabine in the single-arm, two-cohort, phase 2 PERMEATE study among 78 patients with HER2-positive metastatic breast cancer (MBC) with brain metastases. The intracranial objective response rate was 74.6% in radiotherapy-naive patients and 42.1% in those progressing after prior radiotherapy. The combination showed good tolerability with the most common grade 3 treatment-related adverse events of diarrhea and neutropenia. Additional studies have shown impressive CNS activity with other HER2-targeted therapies including tucatinib + capecitabine + trastuzumab combination, as well as trastuzumab deruxtecan (HER2CLIMB and DESTINY-Breast03 trials, respectively). The evolution of these agents in both the metastatic and early settings will continue to transform the treatment algorithm for HER2-positive breast cancer. A particularly interesting concept is whether earlier use of drugs with better CNS efficacy can reduce risk or prevent development of brain metastases.

Endocrine therapy in early-stage hormone receptor-positive (HR+) breast cancer leads to significant reductions in recurrence and breast cancer mortality. A meta-analysis was performed by Early Breast Cancer Trialists' Collaborative Group including four trials (ABCSG XII, SOFT, TEXT and HOBOE), 7030 premenopausal patients with early-stage ER+ breast cancer, who received an aromatase inhibitor or tamoxifen for 3-5 years with ovarian suppression. Rates of breast cancer recurrence were lower with an aromatase inhibitor vs tamoxifen, with the main benefit seen during years 0-4 (relative risk [RR] 0.68, P < .0001) and an absolute reduction in 5-year recurrence risk of 3.2% (6.9% vs 10.1%). Aromatase inhibitor use was associated with decreased distant recurrence risk (RR 0.83), but there was no significant difference for breast cancer or all-cause mortality. The favored endocrine therapy approach for an individual patient is often complex and based on overall risk, comorbidities and toxicity concerns, as well as patient preference. Longer follow-up of trials with endocrine therapy and ovarian suppression will provide further insight on mortality impact.

Aromatase inhibitor (AI)-associated musculoskeletal symptoms are not infrequent and can contribute to treatment discontinuation. Current management practices include use of non-steroidal anti-inflammatory drugs (NSAID), weight loss and exercise, trial of alternative AI or tamoxifen, use of serotonin and norepinephrine reuptake inhibitors (SNRI) (duloxetine) and acupuncture. Martinez et al reported on outcomes of the non-selective NSAID, sulindac (150mg twice daily for 12 months), in a phase 2 study among postmenopausal women with early HR+ breast cancer who were stable on AI therapy for at least 3 months. At 12 months, patients receiving sulindac (n = 43) reported improvements (decreases) in Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index (-5.85, P = .003), pain (-5.40, P = .043), stiffness (-9.53, P < .001) and physical function (-5.61, P = .006); those in the observation group (n = 40) did not experience improvements in these variables. The most significant improvement with sulindac was seen in those with a higher degree of baseline symptoms and in overweight/obese patients. These findings support further investigation into abbreviated NSAID use and strategies focused on exercise and healthy body weight maintenance for breast cancer patients.

The treatment landscape for early-stage triple-negative breast cancer (TNBC) continues to evolve with integration of new drugs into our armamentarium, and use of pathologic complete response (pCR) as a surrogate for outcome and for tailoring adjuvant therapy. Geyer et al reported on event-free survival outcomes with a 4.5 year follow-up of the phase 3 BrighTNess trial, which included 634 patients with stage II-III TNBC. Significant improvement in event-free survival (EFS) was seen in the carboplatin + veliparib + paclitaxel arm vs. paclitaxel alone (HR 0.63, P = .02), but no difference in EFS in carboplatin + veliparib + paclitaxel vs. carboplatin + paclitaxel (HR 1.12, P = .62). The EFS rates at 4 years were 78% (carboplatin + veliparib + paclitaxel), 79% (carboplatin + paclitaxel) and 69% (paclitaxel alone). The phase 3 KEYNOTE-522 trial demonstrated improvement in EFS with the addition of neoadjuvant pembrolizumab to chemotherapy (carboplatin/paclitaxel followed by AC) followed by adjuvant pembrolizumab compared to chemotherapy alone in patients with stage II-III TNBC. The emergence of new therapies for early TNBC, including immunotherapy and  poly (ADP-ribose) polymerase (PARP) inhibitors (the latter for patients with germline BRCA mutations), has created more treatment options for patients along with questions regarding combinations and sequencing.  

Recommended Additional Reading:

Lin N et al. Updated results of tucatinib vs placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;Spotlight Poster Session, PD4-04 Abstract 858. https://www.abstractsonline.com/pp8/#!/10462/presentation/482

Hurvitz S et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;General Session, GS3-01. https://www.abstractsonline.com/pp8/#!/10462/presentation/649

Rosati MS, Di Seri M, Baciarello G, et al. Etoricoxib and anastrozole in adjuvant early breast cancer: ETAN trial (phase III). J Clin Oncol. 2011;29:suppl.533. https://ascopubs.org/doi/10.1200/jco.2011.29.15_suppl.533

Schmid P et al for the KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386(6):556-567. https://www.nejm.org/doi/full/10.1056/NEJMoa2112651

The predilection for brain metastases in human epidermal growth factor receptor 2 (HER2)-positive breast cancer has historically presented a therapeutic challenge, and agents with enhanced central nervous system (CNS) penetrance are certainly desired. Pyrotinib is a small molecule irreversible tyrosine kinase inhibitor against epidermal growth factor receptor (EGFR), HER2, and HER4. Yan et al investigated the activity and safety of pyrotinib + capecitabine in the single-arm, two-cohort, phase 2 PERMEATE study among 78 patients with HER2-positive metastatic breast cancer (MBC) with brain metastases. The intracranial objective response rate was 74.6% in radiotherapy-naive patients and 42.1% in those progressing after prior radiotherapy. The combination showed good tolerability with the most common grade 3 treatment-related adverse events of diarrhea and neutropenia. Additional studies have shown impressive CNS activity with other HER2-targeted therapies including tucatinib + capecitabine + trastuzumab combination, as well as trastuzumab deruxtecan (HER2CLIMB and DESTINY-Breast03 trials, respectively). The evolution of these agents in both the metastatic and early settings will continue to transform the treatment algorithm for HER2-positive breast cancer. A particularly interesting concept is whether earlier use of drugs with better CNS efficacy can reduce risk or prevent development of brain metastases.

Endocrine therapy in early-stage hormone receptor-positive (HR+) breast cancer leads to significant reductions in recurrence and breast cancer mortality. A meta-analysis was performed by Early Breast Cancer Trialists' Collaborative Group including four trials (ABCSG XII, SOFT, TEXT and HOBOE), 7030 premenopausal patients with early-stage ER+ breast cancer, who received an aromatase inhibitor or tamoxifen for 3-5 years with ovarian suppression. Rates of breast cancer recurrence were lower with an aromatase inhibitor vs tamoxifen, with the main benefit seen during years 0-4 (relative risk [RR] 0.68, P < .0001) and an absolute reduction in 5-year recurrence risk of 3.2% (6.9% vs 10.1%). Aromatase inhibitor use was associated with decreased distant recurrence risk (RR 0.83), but there was no significant difference for breast cancer or all-cause mortality. The favored endocrine therapy approach for an individual patient is often complex and based on overall risk, comorbidities and toxicity concerns, as well as patient preference. Longer follow-up of trials with endocrine therapy and ovarian suppression will provide further insight on mortality impact.

Aromatase inhibitor (AI)-associated musculoskeletal symptoms are not infrequent and can contribute to treatment discontinuation. Current management practices include use of non-steroidal anti-inflammatory drugs (NSAID), weight loss and exercise, trial of alternative AI or tamoxifen, use of serotonin and norepinephrine reuptake inhibitors (SNRI) (duloxetine) and acupuncture. Martinez et al reported on outcomes of the non-selective NSAID, sulindac (150mg twice daily for 12 months), in a phase 2 study among postmenopausal women with early HR+ breast cancer who were stable on AI therapy for at least 3 months. At 12 months, patients receiving sulindac (n = 43) reported improvements (decreases) in Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index (-5.85, P = .003), pain (-5.40, P = .043), stiffness (-9.53, P < .001) and physical function (-5.61, P = .006); those in the observation group (n = 40) did not experience improvements in these variables. The most significant improvement with sulindac was seen in those with a higher degree of baseline symptoms and in overweight/obese patients. These findings support further investigation into abbreviated NSAID use and strategies focused on exercise and healthy body weight maintenance for breast cancer patients.

The treatment landscape for early-stage triple-negative breast cancer (TNBC) continues to evolve with integration of new drugs into our armamentarium, and use of pathologic complete response (pCR) as a surrogate for outcome and for tailoring adjuvant therapy. Geyer et al reported on event-free survival outcomes with a 4.5 year follow-up of the phase 3 BrighTNess trial, which included 634 patients with stage II-III TNBC. Significant improvement in event-free survival (EFS) was seen in the carboplatin + veliparib + paclitaxel arm vs. paclitaxel alone (HR 0.63, P = .02), but no difference in EFS in carboplatin + veliparib + paclitaxel vs. carboplatin + paclitaxel (HR 1.12, P = .62). The EFS rates at 4 years were 78% (carboplatin + veliparib + paclitaxel), 79% (carboplatin + paclitaxel) and 69% (paclitaxel alone). The phase 3 KEYNOTE-522 trial demonstrated improvement in EFS with the addition of neoadjuvant pembrolizumab to chemotherapy (carboplatin/paclitaxel followed by AC) followed by adjuvant pembrolizumab compared to chemotherapy alone in patients with stage II-III TNBC. The emergence of new therapies for early TNBC, including immunotherapy and  poly (ADP-ribose) polymerase (PARP) inhibitors (the latter for patients with germline BRCA mutations), has created more treatment options for patients along with questions regarding combinations and sequencing.  

Recommended Additional Reading:

Lin N et al. Updated results of tucatinib vs placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;Spotlight Poster Session, PD4-04 Abstract 858. https://www.abstractsonline.com/pp8/#!/10462/presentation/482

Hurvitz S et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021;General Session, GS3-01. https://www.abstractsonline.com/pp8/#!/10462/presentation/649

Rosati MS, Di Seri M, Baciarello G, et al. Etoricoxib and anastrozole in adjuvant early breast cancer: ETAN trial (phase III). J Clin Oncol. 2011;29:suppl.533. https://ascopubs.org/doi/10.1200/jco.2011.29.15_suppl.533

Schmid P et al for the KEYNOTE-522 Investigators. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386(6):556-567. https://www.nejm.org/doi/full/10.1056/NEJMoa2112651

Breast cancer diagnosis and treatment in young women can present unique challenges based on their life stage, including potential impact on fertility and future pregnancy. The role of GnRH analogues for ovarian protection during chemotherapy has been shown in both the POEMS-SWOG S0230 and PROMISE-GIM6 studies. Zong and colleagues conducted a phase 3 trial in China among premenopausal women with stage I-III breast cancer receiving cyclophosphamide-containing chemotherapy, with randomization to GnRHa + chemotherapy vs chemotherapy alone. Among 301 patients eligible for primary endpoint analysis, the premature ovarian insufficiency rate at 12 months was 10.3% for the GnRHa group vs 44.5% for the control group (odds ratio 0.23; P < 0.001). The rate of ovarian function recovery was also 46.4% higher in the GnRHa group. Furthermore, although survival outcomes were similar between groups, in patients <35 years of age, the tumor-free survival was higher in the GnRHa group vs control (93% vs 62%, P = 0.004) (Zong et al). These data reinforce the role of GnRHa as a means to reduce POI risk and support ovarian function recovery in young women undergoing chemotherapy for breast cancer. Measures of fertility and timing of pregnancy after breast cancer diagnosis continue to be areas of active research.

The treatment landscape for early-stage HER2-positive breast cancer continues to rapidly evolve with efforts to enhance efficacy and minimize toxicity for patients. The phase 3 KAITLIN study included 1846 patients with early-stage HER2-positive breast cancer (node-positive or node-negative, hormone receptor-negative and ≥T2 primary tumor) with randomization after surgery to adjuvant AC followed by taxane + trastuzumab + pertuzumab (AC-THP) or AC followed by T-DM1 + pertuzumab (AC-KP). In both the overall and node-positive populations, there was no significant difference in IDFS between the arms (stratified HR 0.98 and 0.97, respectively). In the overall population, the 3-year IDFS was 93.1% for AC-KP and 94.2% for AC-THP. Treatment completion rates were lower for AC-KP vs AC-THP (65.0% vs 88.4%), with T-DM1 discontinuation driven mostly by lab abnormalities (elevated liver function tests and thrombocytopenia) (Krop et al). Many patients diagnosed with early HER2-positive breast cancer (specifically those with tumors >2cm or node-positive) are treated with neoadjuvant chemotherapy + HER2-targeted therapy with subsequent tailoring of adjuvant treatment pending response, including use of T-DM1 if residual disease present. Future escalation and de-escalation strategies are being explored to further optimize outcomes and decrease side effects.

The addition of CDK 4/6 inhibitors to endocrine therapy has led to improved survival outcomes for patients diagnosed with advanced HR-positive-HER2-negative breast cancer. Lu and colleagues presented exploratory updated OS results among 672 patients with extended follow-up (median 53.5 months) from MONALEESA-7, which was a phase 3 randomized trial of ribociclib + endocrine therapy vs endocrine therapy alone among peri/pre-menopausal patients with HR-positive/HER2-negative advanced breast cancer. Median OS was 58.7 months vs 48.0 months for the ribociclib and placebo arms, respectively (HR 0.76), and a more pronounced benefit was seen in patients <40 years of age (median OS 51.3 months vs 40.5 months for ribociclib vs placebo arm; HR 0.65) (Lu et al). Furthermore, there was a significant delay in time to chemotherapy with ribociclib vs placebo (50.9 months vs 36.8 months; HR 0.69) which can certainly impact quality of life. A prior pooled analysis of the various MONALEESA trials demonstrated consistent PFS benefit with ribociclib across all intrinsic breast cancer subtypes, with the exception of basal-like and a more pronounced favorable impact in HER2-enriched. Future research to elucidate differences among CDK 4/6 inhibitors, influence of breast cancer subtype on their effect and how this can be translated to routine clinical practice are warranted.

Breast cancer diagnosis and treatment in young women can present unique challenges based on their life stage, including potential impact on fertility and future pregnancy. The role of GnRH analogues for ovarian protection during chemotherapy has been shown in both the POEMS-SWOG S0230 and PROMISE-GIM6 studies. Zong and colleagues conducted a phase 3 trial in China among premenopausal women with stage I-III breast cancer receiving cyclophosphamide-containing chemotherapy, with randomization to GnRHa + chemotherapy vs chemotherapy alone. Among 301 patients eligible for primary endpoint analysis, the premature ovarian insufficiency rate at 12 months was 10.3% for the GnRHa group vs 44.5% for the control group (odds ratio 0.23; P < 0.001). The rate of ovarian function recovery was also 46.4% higher in the GnRHa group. Furthermore, although survival outcomes were similar between groups, in patients <35 years of age, the tumor-free survival was higher in the GnRHa group vs control (93% vs 62%, P = 0.004) (Zong et al). These data reinforce the role of GnRHa as a means to reduce POI risk and support ovarian function recovery in young women undergoing chemotherapy for breast cancer. Measures of fertility and timing of pregnancy after breast cancer diagnosis continue to be areas of active research.

The treatment landscape for early-stage HER2-positive breast cancer continues to rapidly evolve with efforts to enhance efficacy and minimize toxicity for patients. The phase 3 KAITLIN study included 1846 patients with early-stage HER2-positive breast cancer (node-positive or node-negative, hormone receptor-negative and ≥T2 primary tumor) with randomization after surgery to adjuvant AC followed by taxane + trastuzumab + pertuzumab (AC-THP) or AC followed by T-DM1 + pertuzumab (AC-KP). In both the overall and node-positive populations, there was no significant difference in IDFS between the arms (stratified HR 0.98 and 0.97, respectively). In the overall population, the 3-year IDFS was 93.1% for AC-KP and 94.2% for AC-THP. Treatment completion rates were lower for AC-KP vs AC-THP (65.0% vs 88.4%), with T-DM1 discontinuation driven mostly by lab abnormalities (elevated liver function tests and thrombocytopenia) (Krop et al). Many patients diagnosed with early HER2-positive breast cancer (specifically those with tumors >2cm or node-positive) are treated with neoadjuvant chemotherapy + HER2-targeted therapy with subsequent tailoring of adjuvant treatment pending response, including use of T-DM1 if residual disease present. Future escalation and de-escalation strategies are being explored to further optimize outcomes and decrease side effects.

The addition of CDK 4/6 inhibitors to endocrine therapy has led to improved survival outcomes for patients diagnosed with advanced HR-positive-HER2-negative breast cancer. Lu and colleagues presented exploratory updated OS results among 672 patients with extended follow-up (median 53.5 months) from MONALEESA-7, which was a phase 3 randomized trial of ribociclib + endocrine therapy vs endocrine therapy alone among peri/pre-menopausal patients with HR-positive/HER2-negative advanced breast cancer. Median OS was 58.7 months vs 48.0 months for the ribociclib and placebo arms, respectively (HR 0.76), and a more pronounced benefit was seen in patients <40 years of age (median OS 51.3 months vs 40.5 months for ribociclib vs placebo arm; HR 0.65) (Lu et al). Furthermore, there was a significant delay in time to chemotherapy with ribociclib vs placebo (50.9 months vs 36.8 months; HR 0.69) which can certainly impact quality of life. A prior pooled analysis of the various MONALEESA trials demonstrated consistent PFS benefit with ribociclib across all intrinsic breast cancer subtypes, with the exception of basal-like and a more pronounced favorable impact in HER2-enriched. Future research to elucidate differences among CDK 4/6 inhibitors, influence of breast cancer subtype on their effect and how this can be translated to routine clinical practice are warranted.

Breast cancer diagnosis and treatment in young women can present unique challenges based on their life stage, including potential impact on fertility and future pregnancy. The role of GnRH analogues for ovarian protection during chemotherapy has been shown in both the POEMS-SWOG S0230 and PROMISE-GIM6 studies. Zong and colleagues conducted a phase 3 trial in China among premenopausal women with stage I-III breast cancer receiving cyclophosphamide-containing chemotherapy, with randomization to GnRHa + chemotherapy vs chemotherapy alone. Among 301 patients eligible for primary endpoint analysis, the premature ovarian insufficiency rate at 12 months was 10.3% for the GnRHa group vs 44.5% for the control group (odds ratio 0.23; P < 0.001). The rate of ovarian function recovery was also 46.4% higher in the GnRHa group. Furthermore, although survival outcomes were similar between groups, in patients <35 years of age, the tumor-free survival was higher in the GnRHa group vs control (93% vs 62%, P = 0.004) (Zong et al). These data reinforce the role of GnRHa as a means to reduce POI risk and support ovarian function recovery in young women undergoing chemotherapy for breast cancer. Measures of fertility and timing of pregnancy after breast cancer diagnosis continue to be areas of active research.

The treatment landscape for early-stage HER2-positive breast cancer continues to rapidly evolve with efforts to enhance efficacy and minimize toxicity for patients. The phase 3 KAITLIN study included 1846 patients with early-stage HER2-positive breast cancer (node-positive or node-negative, hormone receptor-negative and ≥T2 primary tumor) with randomization after surgery to adjuvant AC followed by taxane + trastuzumab + pertuzumab (AC-THP) or AC followed by T-DM1 + pertuzumab (AC-KP). In both the overall and node-positive populations, there was no significant difference in IDFS between the arms (stratified HR 0.98 and 0.97, respectively). In the overall population, the 3-year IDFS was 93.1% for AC-KP and 94.2% for AC-THP. Treatment completion rates were lower for AC-KP vs AC-THP (65.0% vs 88.4%), with T-DM1 discontinuation driven mostly by lab abnormalities (elevated liver function tests and thrombocytopenia) (Krop et al). Many patients diagnosed with early HER2-positive breast cancer (specifically those with tumors >2cm or node-positive) are treated with neoadjuvant chemotherapy + HER2-targeted therapy with subsequent tailoring of adjuvant treatment pending response, including use of T-DM1 if residual disease present. Future escalation and de-escalation strategies are being explored to further optimize outcomes and decrease side effects.

The addition of CDK 4/6 inhibitors to endocrine therapy has led to improved survival outcomes for patients diagnosed with advanced HR-positive-HER2-negative breast cancer. Lu and colleagues presented exploratory updated OS results among 672 patients with extended follow-up (median 53.5 months) from MONALEESA-7, which was a phase 3 randomized trial of ribociclib + endocrine therapy vs endocrine therapy alone among peri/pre-menopausal patients with HR-positive/HER2-negative advanced breast cancer. Median OS was 58.7 months vs 48.0 months for the ribociclib and placebo arms, respectively (HR 0.76), and a more pronounced benefit was seen in patients <40 years of age (median OS 51.3 months vs 40.5 months for ribociclib vs placebo arm; HR 0.65) (Lu et al). Furthermore, there was a significant delay in time to chemotherapy with ribociclib vs placebo (50.9 months vs 36.8 months; HR 0.69) which can certainly impact quality of life. A prior pooled analysis of the various MONALEESA trials demonstrated consistent PFS benefit with ribociclib across all intrinsic breast cancer subtypes, with the exception of basal-like and a more pronounced favorable impact in HER2-enriched. Future research to elucidate differences among CDK 4/6 inhibitors, influence of breast cancer subtype on their effect and how this can be translated to routine clinical practice are warranted.

Oocyte and embryo cryopreservation are standard fertility preservation techniques, and gonadotropin-releasing hormone agonist (GnRHa) administration during chemotherapy is another strategy to preserve ovarian function. The phase 3 POEMS/S0230 study demonstrated higher pregnancy rates (5-year cumulative incidence 23.1% vs 12.2%, P = 0.03) among premenopausal patients with HR-negative early breast cancer who received GnRHa (goserelin) during chemotherapy vs chemotherapy alone. Furthermore, there was a trend towards improvement in survival outcomes with GnRHa + chemotherapy. Hypothetical concerns have existed regarding the safety of this approach, particularly in HR+ breast cancer. The PROMISE-GIM6 trial randomized 281 patients to receive chemotherapy alone or with GnRHa triptorelin (Lambertini et al) and found no difference in disease-free survival (DFS) or overall survival (OS) between GnRHa vs control groups (12-year DFS 65.7% vs 69.2%, HR 1.16; 12-year OS 81.2% vs 81.3%, HR 1.17). In patients with HR+ disease (80.4%), HR for DFS and OS was 1.02 and 1.12, respectively. The 12-year cumulative incidence of pregnancy was also higher in the GnRHa vs control group (6.5% vs 3.2%). These studies suggest no detrimental effect of GnRHa use during chemotherapy on long-term outcomes, including patients with HR+ disease, and support its role in ovarian protection.

COVID-19 has had various implications on breast cancer care, reflecting institutional policies, resources and patient preferences and potential concerns during the pandemic. A retrospective chart review of patients diagnosed at Mayo Clinic Rochester with a new breast cancer during vs pre-COVID-19, examined trends in diagnosis and treatment approaches during these times (Tonneson et al). Among 573 patients, there was no significant difference in clinical prognostic stage, although a slightly higher percentage of patients who presented with stage II-IV disease during COVID-19 vs pre-COVID-19 (29% vs 26%, P = 0.42). The use of neoadjuvant endocrine therapy (NET) significantly increased during COVID-19, and notably in patients with HR+/HER2- breast cancer (10% pre-COVID-19 vs 23% during COVID-19 (P = 0.001)) with a significant increase in stage I patients (7% vs 22%, P < 0.001). Various societies provided language to support neoadjuvant therapy as a bridge to surgical intervention during COVID-19 in the appropriate clinical scenarios. Extended follow-up of studies examining approaches utilized during the pandemic are desired to further define long-term impact on outcomes.

A pooled analysis of the PALOMA trials demonstrated progression-free survival benefit with palbociclib + endocrine therapy vs endocrine therapy alone in patients ≥65 years, and although myelosuppression was more common in patients ≥75 years, the combination remained well-tolerated. Ismail et al described real-world experience of palbociclib in older patients with advanced HR+ breast cancer. Among 598 patients, palbociclib dose reductions occurred in 33%, and those requiring a dose reduction were older vs those without dose reduction (median age 67 vs 63 years, P = 0.004). Despite higher frequency of dose reductions in older patients, this did not appear to compromise outcomes; time to next treatment was significantly longer (16.9 vs 11.6 months, P = 0.013) than younger patients but OS was similar (20.7 vs 26.7 months, P = 0.051). Although older patients may be at higher risk of toxicities due to co-morbidities or performance status limitations, palbociclib remains a valuable therapeutic option combined with endocrine therapy for advanced HR+/HER2- breast cancer.

References:

Francis PA, Pagani O, Fleming GF, et al; SOFT and TEXT Investigators and the International Breast Cancer Study Group. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379(2):122-137.

Moore HCF, Unger JM, Phillips K-A, et al. Final analysis of the prevention of early menopause study (POEMS)/SWOG Intergroup S0230. J Natl Cancer Inst. 2019;111(2):210–213.

Dietz JR, Moran MS, Isakoff SJ, et al. Recommendations for prioritization, treatment, and triage of breast cancer patients during the COVID-19 pandemic. The COVID-19 pandemic breast cancer consortium. Breast Cancer Res Treat. 2020;181(3):487–97.

Rugo HS, Turner NC, Finn RS, et al. Palbociclib plus endocrine therapy in older women with HR+/HER2- advanced breast cancer: a pooled analysis of randomised PALOMA clinical studies. Eur J Cancer. 2018;101:123e33.

Oocyte and embryo cryopreservation are standard fertility preservation techniques, and gonadotropin-releasing hormone agonist (GnRHa) administration during chemotherapy is another strategy to preserve ovarian function. The phase 3 POEMS/S0230 study demonstrated higher pregnancy rates (5-year cumulative incidence 23.1% vs 12.2%, P = 0.03) among premenopausal patients with HR-negative early breast cancer who received GnRHa (goserelin) during chemotherapy vs chemotherapy alone. Furthermore, there was a trend towards improvement in survival outcomes with GnRHa + chemotherapy. Hypothetical concerns have existed regarding the safety of this approach, particularly in HR+ breast cancer. The PROMISE-GIM6 trial randomized 281 patients to receive chemotherapy alone or with GnRHa triptorelin (Lambertini et al) and found no difference in disease-free survival (DFS) or overall survival (OS) between GnRHa vs control groups (12-year DFS 65.7% vs 69.2%, HR 1.16; 12-year OS 81.2% vs 81.3%, HR 1.17). In patients with HR+ disease (80.4%), HR for DFS and OS was 1.02 and 1.12, respectively. The 12-year cumulative incidence of pregnancy was also higher in the GnRHa vs control group (6.5% vs 3.2%). These studies suggest no detrimental effect of GnRHa use during chemotherapy on long-term outcomes, including patients with HR+ disease, and support its role in ovarian protection.

COVID-19 has had various implications on breast cancer care, reflecting institutional policies, resources and patient preferences and potential concerns during the pandemic. A retrospective chart review of patients diagnosed at Mayo Clinic Rochester with a new breast cancer during vs pre-COVID-19, examined trends in diagnosis and treatment approaches during these times (Tonneson et al). Among 573 patients, there was no significant difference in clinical prognostic stage, although a slightly higher percentage of patients who presented with stage II-IV disease during COVID-19 vs pre-COVID-19 (29% vs 26%, P = 0.42). The use of neoadjuvant endocrine therapy (NET) significantly increased during COVID-19, and notably in patients with HR+/HER2- breast cancer (10% pre-COVID-19 vs 23% during COVID-19 (P = 0.001)) with a significant increase in stage I patients (7% vs 22%, P < 0.001). Various societies provided language to support neoadjuvant therapy as a bridge to surgical intervention during COVID-19 in the appropriate clinical scenarios. Extended follow-up of studies examining approaches utilized during the pandemic are desired to further define long-term impact on outcomes.

A pooled analysis of the PALOMA trials demonstrated progression-free survival benefit with palbociclib + endocrine therapy vs endocrine therapy alone in patients ≥65 years, and although myelosuppression was more common in patients ≥75 years, the combination remained well-tolerated. Ismail et al described real-world experience of palbociclib in older patients with advanced HR+ breast cancer. Among 598 patients, palbociclib dose reductions occurred in 33%, and those requiring a dose reduction were older vs those without dose reduction (median age 67 vs 63 years, P = 0.004). Despite higher frequency of dose reductions in older patients, this did not appear to compromise outcomes; time to next treatment was significantly longer (16.9 vs 11.6 months, P = 0.013) than younger patients but OS was similar (20.7 vs 26.7 months, P = 0.051). Although older patients may be at higher risk of toxicities due to co-morbidities or performance status limitations, palbociclib remains a valuable therapeutic option combined with endocrine therapy for advanced HR+/HER2- breast cancer.

References:

Francis PA, Pagani O, Fleming GF, et al; SOFT and TEXT Investigators and the International Breast Cancer Study Group. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379(2):122-137.

Moore HCF, Unger JM, Phillips K-A, et al. Final analysis of the prevention of early menopause study (POEMS)/SWOG Intergroup S0230. J Natl Cancer Inst. 2019;111(2):210–213.

Dietz JR, Moran MS, Isakoff SJ, et al. Recommendations for prioritization, treatment, and triage of breast cancer patients during the COVID-19 pandemic. The COVID-19 pandemic breast cancer consortium. Breast Cancer Res Treat. 2020;181(3):487–97.

Rugo HS, Turner NC, Finn RS, et al. Palbociclib plus endocrine therapy in older women with HR+/HER2- advanced breast cancer: a pooled analysis of randomised PALOMA clinical studies. Eur J Cancer. 2018;101:123e33.

Oocyte and embryo cryopreservation are standard fertility preservation techniques, and gonadotropin-releasing hormone agonist (GnRHa) administration during chemotherapy is another strategy to preserve ovarian function. The phase 3 POEMS/S0230 study demonstrated higher pregnancy rates (5-year cumulative incidence 23.1% vs 12.2%, P = 0.03) among premenopausal patients with HR-negative early breast cancer who received GnRHa (goserelin) during chemotherapy vs chemotherapy alone. Furthermore, there was a trend towards improvement in survival outcomes with GnRHa + chemotherapy. Hypothetical concerns have existed regarding the safety of this approach, particularly in HR+ breast cancer. The PROMISE-GIM6 trial randomized 281 patients to receive chemotherapy alone or with GnRHa triptorelin (Lambertini et al) and found no difference in disease-free survival (DFS) or overall survival (OS) between GnRHa vs control groups (12-year DFS 65.7% vs 69.2%, HR 1.16; 12-year OS 81.2% vs 81.3%, HR 1.17). In patients with HR+ disease (80.4%), HR for DFS and OS was 1.02 and 1.12, respectively. The 12-year cumulative incidence of pregnancy was also higher in the GnRHa vs control group (6.5% vs 3.2%). These studies suggest no detrimental effect of GnRHa use during chemotherapy on long-term outcomes, including patients with HR+ disease, and support its role in ovarian protection.

COVID-19 has had various implications on breast cancer care, reflecting institutional policies, resources and patient preferences and potential concerns during the pandemic. A retrospective chart review of patients diagnosed at Mayo Clinic Rochester with a new breast cancer during vs pre-COVID-19, examined trends in diagnosis and treatment approaches during these times (Tonneson et al). Among 573 patients, there was no significant difference in clinical prognostic stage, although a slightly higher percentage of patients who presented with stage II-IV disease during COVID-19 vs pre-COVID-19 (29% vs 26%, P = 0.42). The use of neoadjuvant endocrine therapy (NET) significantly increased during COVID-19, and notably in patients with HR+/HER2- breast cancer (10% pre-COVID-19 vs 23% during COVID-19 (P = 0.001)) with a significant increase in stage I patients (7% vs 22%, P < 0.001). Various societies provided language to support neoadjuvant therapy as a bridge to surgical intervention during COVID-19 in the appropriate clinical scenarios. Extended follow-up of studies examining approaches utilized during the pandemic are desired to further define long-term impact on outcomes.

A pooled analysis of the PALOMA trials demonstrated progression-free survival benefit with palbociclib + endocrine therapy vs endocrine therapy alone in patients ≥65 years, and although myelosuppression was more common in patients ≥75 years, the combination remained well-tolerated. Ismail et al described real-world experience of palbociclib in older patients with advanced HR+ breast cancer. Among 598 patients, palbociclib dose reductions occurred in 33%, and those requiring a dose reduction were older vs those without dose reduction (median age 67 vs 63 years, P = 0.004). Despite higher frequency of dose reductions in older patients, this did not appear to compromise outcomes; time to next treatment was significantly longer (16.9 vs 11.6 months, P = 0.013) than younger patients but OS was similar (20.7 vs 26.7 months, P = 0.051). Although older patients may be at higher risk of toxicities due to co-morbidities or performance status limitations, palbociclib remains a valuable therapeutic option combined with endocrine therapy for advanced HR+/HER2- breast cancer.

References:

Francis PA, Pagani O, Fleming GF, et al; SOFT and TEXT Investigators and the International Breast Cancer Study Group. Tailoring adjuvant endocrine therapy for premenopausal breast cancer. N Engl J Med. 2018;379(2):122-137.

Moore HCF, Unger JM, Phillips K-A, et al. Final analysis of the prevention of early menopause study (POEMS)/SWOG Intergroup S0230. J Natl Cancer Inst. 2019;111(2):210–213.

Dietz JR, Moran MS, Isakoff SJ, et al. Recommendations for prioritization, treatment, and triage of breast cancer patients during the COVID-19 pandemic. The COVID-19 pandemic breast cancer consortium. Breast Cancer Res Treat. 2020;181(3):487–97.

Rugo HS, Turner NC, Finn RS, et al. Palbociclib plus endocrine therapy in older women with HR+/HER2- advanced breast cancer: a pooled analysis of randomised PALOMA clinical studies. Eur J Cancer. 2018;101:123e33.

Metastatic triple-negative breast cancer (TNBC) is a heterogeneous, biologically complex subtype, with continuing efforts to identify therapeutic targets. The PI3K/AKT signaling pathway plays a key role in cell proliferation, survival, invasion, and metabolism. In the phase II LOTUS trial (Dent et al) including 124 patients with advanced TNBC (no prior therapy for advanced disease), addition of the oral AKT inhibitor, ipatasertib, to paclitaxel led to a numerical improvement in OS that was not statistically significant. The median OS was 25.8 vs 16.9 months for the ipatasertib-paclitaxel vs placebo-paclitaxel, respectively (HR 0.80, 95% CI 0.50-1.28). Findings from cohort A of the phase III IPATunity130 trial showed that ipatasertib-paclitaxel did not lead to a statistically significant improvement in PFS vs placebo-paclitaxel in patients with PIK3CA/AKT1/PTEN-altered advanced TNBC in the first-line metastatic setting (mPFS 7.4 vs 6.1 months, respectively; HR 1.02, p=0.9237). These findings support further investigation into predictors of response and other molecular markers that may play a role in the diversity of mTNBC. 

Endocrine therapy resistance remains a significant challenge in advanced HR+/HER2- breast cancer, and initial studies with the oral histone deacetylase inhibitor, etinostat, showed promise in this space. Unfortunately, these findings were not upheld in the phase III E2112 trial (Connolly et al), which failed to show an improvement in PFS or OS with exemestane-etinostat (EE) compared to exemestane-placebo (EP) among patients who had progressed on prior non-steroidal AI. Median PFS was 3.3 vs 3.1 months (HR 0.87; p=0.30) and median OS was 23.4 vs 21.7 months (HR 0.99; p=0.94) for the EE vs EP arms, respectively. The combination of an alternative HDAC inhibitor, tucidinostat, has been approved in China in combination with exemestane based on PFS benefit (3.6 months) in the phase III ACE trial. There are notable difference between E2112 and ACE trials, including patient population and design, and importantly OS has not been reported for the latter. The relatively short mPFS and low response rate (5-6%) in E2112 argues for more efficacious therapeutics. There is also value in correlative studies to help further elucidate if there is a role for HDAC inhibitors in this space.

Although adjuvant endocrine therapy has had a significantly beneficial effect on outcomes in early-stage HR+ breast cancer, late recurrences are characteristic of the luminal subtype, and have led to trials investigating extended adjuvant endocrine therapy. The phase III SALSA trial included 3484 women with early HR+ breast cancer who had received 5 years of adjuvant endocrine therapy with randomization to anastrozole for an additional 2 vs 5 years (comparing total of 7 vs 10 years). There was no significant difference in disease-free survival (DFS) at 8 years (73.6% vs 73.9% in the 2 vs 5-year groups, respectively; HR 0.99, p=0.90). Additionally, there was a lower risk of bone fracture in the 2 vs 5-year group (4.7% vs 6.3%; HR 1.35). It is essential to balance modest benefits with toxicities of prolonged AI use, and valuable to identify high-risk patients who may benefit from extended adjuvant endocrine therapy.

References:

Chan A, Moy B, Mansi J, et al; ExteNET Study Group. Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin Breast Cancer. 2021;21(1):80-91.e7.

von Minckwitz G, Huang CS, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628.

Dent R, Kim SB, Oliveira M, et al. Double-blind placebo-controlled randomized phase III trial evaluating first-line ipatasertib combined with paclitaxel for PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer: primary results from IPATunity130 cohort A. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Oral GS3-04.

Jiang Z, Li W, Hu X, et al. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(6):806-815.

Mamounas EP, Bandos H, Lembersky BC, et al. Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(1):88-99.

Metastatic triple-negative breast cancer (TNBC) is a heterogeneous, biologically complex subtype, with continuing efforts to identify therapeutic targets. The PI3K/AKT signaling pathway plays a key role in cell proliferation, survival, invasion, and metabolism. In the phase II LOTUS trial (Dent et al) including 124 patients with advanced TNBC (no prior therapy for advanced disease), addition of the oral AKT inhibitor, ipatasertib, to paclitaxel led to a numerical improvement in OS that was not statistically significant. The median OS was 25.8 vs 16.9 months for the ipatasertib-paclitaxel vs placebo-paclitaxel, respectively (HR 0.80, 95% CI 0.50-1.28). Findings from cohort A of the phase III IPATunity130 trial showed that ipatasertib-paclitaxel did not lead to a statistically significant improvement in PFS vs placebo-paclitaxel in patients with PIK3CA/AKT1/PTEN-altered advanced TNBC in the first-line metastatic setting (mPFS 7.4 vs 6.1 months, respectively; HR 1.02, p=0.9237). These findings support further investigation into predictors of response and other molecular markers that may play a role in the diversity of mTNBC. 

Endocrine therapy resistance remains a significant challenge in advanced HR+/HER2- breast cancer, and initial studies with the oral histone deacetylase inhibitor, etinostat, showed promise in this space. Unfortunately, these findings were not upheld in the phase III E2112 trial (Connolly et al), which failed to show an improvement in PFS or OS with exemestane-etinostat (EE) compared to exemestane-placebo (EP) among patients who had progressed on prior non-steroidal AI. Median PFS was 3.3 vs 3.1 months (HR 0.87; p=0.30) and median OS was 23.4 vs 21.7 months (HR 0.99; p=0.94) for the EE vs EP arms, respectively. The combination of an alternative HDAC inhibitor, tucidinostat, has been approved in China in combination with exemestane based on PFS benefit (3.6 months) in the phase III ACE trial. There are notable difference between E2112 and ACE trials, including patient population and design, and importantly OS has not been reported for the latter. The relatively short mPFS and low response rate (5-6%) in E2112 argues for more efficacious therapeutics. There is also value in correlative studies to help further elucidate if there is a role for HDAC inhibitors in this space.

Although adjuvant endocrine therapy has had a significantly beneficial effect on outcomes in early-stage HR+ breast cancer, late recurrences are characteristic of the luminal subtype, and have led to trials investigating extended adjuvant endocrine therapy. The phase III SALSA trial included 3484 women with early HR+ breast cancer who had received 5 years of adjuvant endocrine therapy with randomization to anastrozole for an additional 2 vs 5 years (comparing total of 7 vs 10 years). There was no significant difference in disease-free survival (DFS) at 8 years (73.6% vs 73.9% in the 2 vs 5-year groups, respectively; HR 0.99, p=0.90). Additionally, there was a lower risk of bone fracture in the 2 vs 5-year group (4.7% vs 6.3%; HR 1.35). It is essential to balance modest benefits with toxicities of prolonged AI use, and valuable to identify high-risk patients who may benefit from extended adjuvant endocrine therapy.

References:

Chan A, Moy B, Mansi J, et al; ExteNET Study Group. Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin Breast Cancer. 2021;21(1):80-91.e7.

von Minckwitz G, Huang CS, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628.

Dent R, Kim SB, Oliveira M, et al. Double-blind placebo-controlled randomized phase III trial evaluating first-line ipatasertib combined with paclitaxel for PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer: primary results from IPATunity130 cohort A. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Oral GS3-04.

Jiang Z, Li W, Hu X, et al. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(6):806-815.

Mamounas EP, Bandos H, Lembersky BC, et al. Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(1):88-99.

Metastatic triple-negative breast cancer (TNBC) is a heterogeneous, biologically complex subtype, with continuing efforts to identify therapeutic targets. The PI3K/AKT signaling pathway plays a key role in cell proliferation, survival, invasion, and metabolism. In the phase II LOTUS trial (Dent et al) including 124 patients with advanced TNBC (no prior therapy for advanced disease), addition of the oral AKT inhibitor, ipatasertib, to paclitaxel led to a numerical improvement in OS that was not statistically significant. The median OS was 25.8 vs 16.9 months for the ipatasertib-paclitaxel vs placebo-paclitaxel, respectively (HR 0.80, 95% CI 0.50-1.28). Findings from cohort A of the phase III IPATunity130 trial showed that ipatasertib-paclitaxel did not lead to a statistically significant improvement in PFS vs placebo-paclitaxel in patients with PIK3CA/AKT1/PTEN-altered advanced TNBC in the first-line metastatic setting (mPFS 7.4 vs 6.1 months, respectively; HR 1.02, p=0.9237). These findings support further investigation into predictors of response and other molecular markers that may play a role in the diversity of mTNBC. 

Endocrine therapy resistance remains a significant challenge in advanced HR+/HER2- breast cancer, and initial studies with the oral histone deacetylase inhibitor, etinostat, showed promise in this space. Unfortunately, these findings were not upheld in the phase III E2112 trial (Connolly et al), which failed to show an improvement in PFS or OS with exemestane-etinostat (EE) compared to exemestane-placebo (EP) among patients who had progressed on prior non-steroidal AI. Median PFS was 3.3 vs 3.1 months (HR 0.87; p=0.30) and median OS was 23.4 vs 21.7 months (HR 0.99; p=0.94) for the EE vs EP arms, respectively. The combination of an alternative HDAC inhibitor, tucidinostat, has been approved in China in combination with exemestane based on PFS benefit (3.6 months) in the phase III ACE trial. There are notable difference between E2112 and ACE trials, including patient population and design, and importantly OS has not been reported for the latter. The relatively short mPFS and low response rate (5-6%) in E2112 argues for more efficacious therapeutics. There is also value in correlative studies to help further elucidate if there is a role for HDAC inhibitors in this space.

Although adjuvant endocrine therapy has had a significantly beneficial effect on outcomes in early-stage HR+ breast cancer, late recurrences are characteristic of the luminal subtype, and have led to trials investigating extended adjuvant endocrine therapy. The phase III SALSA trial included 3484 women with early HR+ breast cancer who had received 5 years of adjuvant endocrine therapy with randomization to anastrozole for an additional 2 vs 5 years (comparing total of 7 vs 10 years). There was no significant difference in disease-free survival (DFS) at 8 years (73.6% vs 73.9% in the 2 vs 5-year groups, respectively; HR 0.99, p=0.90). Additionally, there was a lower risk of bone fracture in the 2 vs 5-year group (4.7% vs 6.3%; HR 1.35). It is essential to balance modest benefits with toxicities of prolonged AI use, and valuable to identify high-risk patients who may benefit from extended adjuvant endocrine therapy.

References:

Chan A, Moy B, Mansi J, et al; ExteNET Study Group. Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin Breast Cancer. 2021;21(1):80-91.e7.

von Minckwitz G, Huang CS, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628.

Dent R, Kim SB, Oliveira M, et al. Double-blind placebo-controlled randomized phase III trial evaluating first-line ipatasertib combined with paclitaxel for PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer: primary results from IPATunity130 cohort A. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Oral GS3-04.

Jiang Z, Li W, Hu X, et al. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(6):806-815.

Mamounas EP, Bandos H, Lembersky BC, et al. Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(1):88-99.

Program death-ligand 1 (PD-L1) inhibition suppresses tumor activity via modulation of immune and tumor cell interaction. TNBC is characterized by higher PD-L1 expression and increased immune infiltration, compared to other subtypes. In the randomized, phase 3 IMpassion130 trial, among 902 patients who were treatment naïve in the metastatic TNBC setting, an exploratory analysis in the PD-L1-positive population demonstrated a clinically meaningful OS benefit with atezolizumab + nab-paclitaxel compared to placebo + nab-paclitaxel (25.4 vs 17.9 months; HR 0.67) (Emens et al). Additionally, the phase 3 KEYNOTE-355 trial demonstrated PFS benefit among patients with mTNBC with combined positive score (CPS) ≥10 with pembrolizumab + chemotherapy (nab-paclitaxel, paclitaxel or gemcitabine/carboplatin) versus placebo + chemotherapy (mPFS 9.7 vs 5.6 months; HR 0.65, 95% CI 0.49-0.86). These results are in contrast to the phase 3 IMpassion131 trial which found no statistically significant difference in PFS or OS among 651 patients with mTNBC randomized to atezolizumab + paclitaxel vs placebo + paclitaxel (PD-L1-positive population: PFS 6.0 vs 5.7 months, HR 0.82, 95% CI 0.60-1.12; OS 22.1 vs 28.3 months, HR 1.11, 95% CI 0.76-1.62) (Miles et al). The reasons underlying these differences remain unclear and warrant further investigation. Some thoughts raised include lack of information on BRCA status (which may serve as prognostic factor) in IMpassion131, concomitant use of steroids with paclitaxel, and allowance of sufficient long-term follow-up for generation of events. Regardless, these studies suggest chemotherapy backbone is relevant and the regimens utilized in IMpassion130 and KEYNOTE-355 have gained FDA approval in the first-line mTNBC setting.

The phase 3 CLEOPATRA trial has established the regimen of docetaxel + trastuzumab + pertuzumab as standard of care in the first-line setting for metastatic HER2-positive breast cancer with an OS benefit of 16 months compared to docetaxel + trastuzumab + placebo (57.1 vs 40.8 months; HR 0.69, 95% CI 0.58-0.82) with over 8 years of follow-up. PERUSE was a single-arm phase 3b study that investigated the safety and efficacy of trastuzumab + pertuzumab combined with various taxanes (docetaxel, paclitaxel or nab-paclitaxel) among 1426 patients with HER2+ mBC (Miles et al). In the overall population at follow-up of 5.7 years, median PFS and OS were 20.7 and 65.3 months, respectively, and were similar regardless of taxane backbone. Docetaxel was associated with higher incidences of neutropenia and febrile neutropenia. These results support consideration of an alternative taxane combined with trastuzumab + pertuzumab in this setting (for example paclitaxel) in patients who may not be ideal candidates for docetaxel.

In the second-line treatment setting for HER2+ mBC with prior exposure to trastuzumab and taxane, the phase 3 EMILIA study showed improvement in OS with T-DM1 vs capecitabine + lapatinib (mOS 29.9 vs 25.9 months, HR 0.75, 95% CI 0.64-0.88). Ethier et al explored real-world application and outcomes associated with pertuzumab and T-DM1 in the first- and second-line settings respectively, in a population-based, retrospective cohort study in Ontario, Canada. In the pertuzumab cohort, median OS and time on treatment were 43 and 4 months, respectively. In the T-DM1 cohort, median OS and time on treatment were 15 months and 4 months, respectively. Additionally, patients in the T-DM1 cohort who were pertuzumab-naïve appeared to do better, potentially suggesting less responsiveness to subsequent HER2-targeted treatment in the real world setting among those who received prior pertuzumab. Findings from this population study demonstrate inferior outcomes when compared to the pivotal CLEOPATRA and EMILIA trials, and highlight a gap between clinical trial and real-world observations (described by authors as efficacy-effectiveness gap). Potential etiologies for these differences include patient factors, prior therapies and delivery of care models, and convey the importance of recognizing this gap exists and optimizing any modifiable factors as trial data and novel therapies are applied to routine clinical practice.

References:

Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2(4):361-70.

Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828.

Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530.

Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732-742.

Program death-ligand 1 (PD-L1) inhibition suppresses tumor activity via modulation of immune and tumor cell interaction. TNBC is characterized by higher PD-L1 expression and increased immune infiltration, compared to other subtypes. In the randomized, phase 3 IMpassion130 trial, among 902 patients who were treatment naïve in the metastatic TNBC setting, an exploratory analysis in the PD-L1-positive population demonstrated a clinically meaningful OS benefit with atezolizumab + nab-paclitaxel compared to placebo + nab-paclitaxel (25.4 vs 17.9 months; HR 0.67) (Emens et al). Additionally, the phase 3 KEYNOTE-355 trial demonstrated PFS benefit among patients with mTNBC with combined positive score (CPS) ≥10 with pembrolizumab + chemotherapy (nab-paclitaxel, paclitaxel or gemcitabine/carboplatin) versus placebo + chemotherapy (mPFS 9.7 vs 5.6 months; HR 0.65, 95% CI 0.49-0.86). These results are in contrast to the phase 3 IMpassion131 trial which found no statistically significant difference in PFS or OS among 651 patients with mTNBC randomized to atezolizumab + paclitaxel vs placebo + paclitaxel (PD-L1-positive population: PFS 6.0 vs 5.7 months, HR 0.82, 95% CI 0.60-1.12; OS 22.1 vs 28.3 months, HR 1.11, 95% CI 0.76-1.62) (Miles et al). The reasons underlying these differences remain unclear and warrant further investigation. Some thoughts raised include lack of information on BRCA status (which may serve as prognostic factor) in IMpassion131, concomitant use of steroids with paclitaxel, and allowance of sufficient long-term follow-up for generation of events. Regardless, these studies suggest chemotherapy backbone is relevant and the regimens utilized in IMpassion130 and KEYNOTE-355 have gained FDA approval in the first-line mTNBC setting.

The phase 3 CLEOPATRA trial has established the regimen of docetaxel + trastuzumab + pertuzumab as standard of care in the first-line setting for metastatic HER2-positive breast cancer with an OS benefit of 16 months compared to docetaxel + trastuzumab + placebo (57.1 vs 40.8 months; HR 0.69, 95% CI 0.58-0.82) with over 8 years of follow-up. PERUSE was a single-arm phase 3b study that investigated the safety and efficacy of trastuzumab + pertuzumab combined with various taxanes (docetaxel, paclitaxel or nab-paclitaxel) among 1426 patients with HER2+ mBC (Miles et al). In the overall population at follow-up of 5.7 years, median PFS and OS were 20.7 and 65.3 months, respectively, and were similar regardless of taxane backbone. Docetaxel was associated with higher incidences of neutropenia and febrile neutropenia. These results support consideration of an alternative taxane combined with trastuzumab + pertuzumab in this setting (for example paclitaxel) in patients who may not be ideal candidates for docetaxel.

In the second-line treatment setting for HER2+ mBC with prior exposure to trastuzumab and taxane, the phase 3 EMILIA study showed improvement in OS with T-DM1 vs capecitabine + lapatinib (mOS 29.9 vs 25.9 months, HR 0.75, 95% CI 0.64-0.88). Ethier et al explored real-world application and outcomes associated with pertuzumab and T-DM1 in the first- and second-line settings respectively, in a population-based, retrospective cohort study in Ontario, Canada. In the pertuzumab cohort, median OS and time on treatment were 43 and 4 months, respectively. In the T-DM1 cohort, median OS and time on treatment were 15 months and 4 months, respectively. Additionally, patients in the T-DM1 cohort who were pertuzumab-naïve appeared to do better, potentially suggesting less responsiveness to subsequent HER2-targeted treatment in the real world setting among those who received prior pertuzumab. Findings from this population study demonstrate inferior outcomes when compared to the pivotal CLEOPATRA and EMILIA trials, and highlight a gap between clinical trial and real-world observations (described by authors as efficacy-effectiveness gap). Potential etiologies for these differences include patient factors, prior therapies and delivery of care models, and convey the importance of recognizing this gap exists and optimizing any modifiable factors as trial data and novel therapies are applied to routine clinical practice.

References:

Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2(4):361-70.

Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828.

Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530.

Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732-742.

Program death-ligand 1 (PD-L1) inhibition suppresses tumor activity via modulation of immune and tumor cell interaction. TNBC is characterized by higher PD-L1 expression and increased immune infiltration, compared to other subtypes. In the randomized, phase 3 IMpassion130 trial, among 902 patients who were treatment naïve in the metastatic TNBC setting, an exploratory analysis in the PD-L1-positive population demonstrated a clinically meaningful OS benefit with atezolizumab + nab-paclitaxel compared to placebo + nab-paclitaxel (25.4 vs 17.9 months; HR 0.67) (Emens et al). Additionally, the phase 3 KEYNOTE-355 trial demonstrated PFS benefit among patients with mTNBC with combined positive score (CPS) ≥10 with pembrolizumab + chemotherapy (nab-paclitaxel, paclitaxel or gemcitabine/carboplatin) versus placebo + chemotherapy (mPFS 9.7 vs 5.6 months; HR 0.65, 95% CI 0.49-0.86). These results are in contrast to the phase 3 IMpassion131 trial which found no statistically significant difference in PFS or OS among 651 patients with mTNBC randomized to atezolizumab + paclitaxel vs placebo + paclitaxel (PD-L1-positive population: PFS 6.0 vs 5.7 months, HR 0.82, 95% CI 0.60-1.12; OS 22.1 vs 28.3 months, HR 1.11, 95% CI 0.76-1.62) (Miles et al). The reasons underlying these differences remain unclear and warrant further investigation. Some thoughts raised include lack of information on BRCA status (which may serve as prognostic factor) in IMpassion131, concomitant use of steroids with paclitaxel, and allowance of sufficient long-term follow-up for generation of events. Regardless, these studies suggest chemotherapy backbone is relevant and the regimens utilized in IMpassion130 and KEYNOTE-355 have gained FDA approval in the first-line mTNBC setting.

The phase 3 CLEOPATRA trial has established the regimen of docetaxel + trastuzumab + pertuzumab as standard of care in the first-line setting for metastatic HER2-positive breast cancer with an OS benefit of 16 months compared to docetaxel + trastuzumab + placebo (57.1 vs 40.8 months; HR 0.69, 95% CI 0.58-0.82) with over 8 years of follow-up. PERUSE was a single-arm phase 3b study that investigated the safety and efficacy of trastuzumab + pertuzumab combined with various taxanes (docetaxel, paclitaxel or nab-paclitaxel) among 1426 patients with HER2+ mBC (Miles et al). In the overall population at follow-up of 5.7 years, median PFS and OS were 20.7 and 65.3 months, respectively, and were similar regardless of taxane backbone. Docetaxel was associated with higher incidences of neutropenia and febrile neutropenia. These results support consideration of an alternative taxane combined with trastuzumab + pertuzumab in this setting (for example paclitaxel) in patients who may not be ideal candidates for docetaxel.

In the second-line treatment setting for HER2+ mBC with prior exposure to trastuzumab and taxane, the phase 3 EMILIA study showed improvement in OS with T-DM1 vs capecitabine + lapatinib (mOS 29.9 vs 25.9 months, HR 0.75, 95% CI 0.64-0.88). Ethier et al explored real-world application and outcomes associated with pertuzumab and T-DM1 in the first- and second-line settings respectively, in a population-based, retrospective cohort study in Ontario, Canada. In the pertuzumab cohort, median OS and time on treatment were 43 and 4 months, respectively. In the T-DM1 cohort, median OS and time on treatment were 15 months and 4 months, respectively. Additionally, patients in the T-DM1 cohort who were pertuzumab-naïve appeared to do better, potentially suggesting less responsiveness to subsequent HER2-targeted treatment in the real world setting among those who received prior pertuzumab. Findings from this population study demonstrate inferior outcomes when compared to the pivotal CLEOPATRA and EMILIA trials, and highlight a gap between clinical trial and real-world observations (described by authors as efficacy-effectiveness gap). Potential etiologies for these differences include patient factors, prior therapies and delivery of care models, and convey the importance of recognizing this gap exists and optimizing any modifiable factors as trial data and novel therapies are applied to routine clinical practice.

References:

Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2(4):361-70.

Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828.

Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530.

Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732-742.