Commentary: Advances in HER2 advanced breast cancer, July 2023

Alterations in the PI3K/AKT/PTEN pathway are present in about half of hormone receptor–positive (HR+)/human epidermal growth factor 2–negative (HER2-) breast cancers and may mediate endocrine resistance in this population. The phase 2 BYLieve trial demonstrated activity of alpelisib + fulvestrant in patients with PIK3CA-mutated, HR+/HER2- advanced breast cancer (ABC) in the post–CDK4/6 inhibitor setting.¹ Capivasertib, an oral selective inhibitor of all three AKT isoforms, was investigated in the phase 3 CAPItello-291 trial among 708 patients with HR+/HER2- ABC who had relapsed or had disease progression on or after aromatase inhibitor therapy with or without a CDK4/6 inhibitor. The combination of capivasertib + fulvestrant led to a significant improvement in progression-free survival (PFS) vs placebo + fulvestrant both in the overall population (median PFS 7.2 mo vs 3.6 mo; hazard ratio 0.60; P < .001) and in patients with AKT pathway-altered (PIK3CA, AKT1, or PTEN) tumors (median PFS 7.3 mo vs 3.1 mo; hazard ratio 0.50; P < .001) (Turner et al). The most common grade 3 or higher adverse events were rash and diarrhea in the capivasertib + fulvestrant arm (12.1% and 9.3%, respectively), and the discontinuation rate was 13.0%. These results highlight the activity of this combination and its overall acceptable safety profile and present a potential new therapy option for patients. The selection, optimal sequencing, and combinations of new agents in the HR+/HER2 ABC space remains an area of active research.

The neoadjuvant setting provides a favorable environment to study de-escalation approaches as treatment response (via pathologic complete response [pCR] assessment) can be used as a surrogate marker for outcome. Studies have shown the effect of HER2-enriched subtype and high ERBB2 expression on pCR rates after receipt of a chemotherapy-free, dual HER2-targeted regimen.² The prospective, multicenter, neoadjuvant phase 2 WSG-TP-II trial randomly assigned 207 patients with HR+/HER2+ early breast cancer to 12 weeks of endocrine therapy (ET)–trastuzumab-pertuzumab vs paclitaxel-trastuzumab-pertuzumab. The pCR rate was inferior in the ET arm compared with the paclitaxel arm (23.7% vs 56.4%; odds ratio 0.24; 95% CI 0.12-0.46; P < .001). In addition, an immunohistochemistry ERBB2 score of 3 or higher and ERBB2-enriched subtype were predictors of higher pCR rates in both arms (Gluz et al). This study not only supports a deescalated chemotherapy neoadjuvant strategy of paclitaxel + dual HER2 blockade but also suggests that a portion of patients may potentially be spared chemotherapy with very good results. The role of biomarkers is integral to patient selection for these approaches, and the evaluation of response in real-time will allow for the tailoring of therapy to achieve the best outcome.

Systemic staging for locally advanced breast cancer (LABC) is important for informing prognosis as well as aiding in development of an appropriate treatment plan for patients. The PETABC study included 369 patients with LABC (TNM stage III or IIB [T3N0]) with random assignment to ¹⁸F-labeled fluorodeoxyglucose PET-CT or conventional staging (bone scan, CT of chest/abdomen/pelvis), and was designed to assess the rate of upstaging with each imaging modality and effect on treatment (Dayes et al). In the PET-CT group, 23% (N = 43) of patients were upstaged to stage IV compared with 11% (N = 21) in the conventional-staging group (absolute difference 12.3%; 95% CI 3.9-19.9; P = .002). Fewer patients in the PET-CT group received combined modality treatment vs those patients in the conventional staging group (81% vs 89.2%; P = .03). These results support the consideration of PET-CT as a staging tool for LABC, and this is reflected in various clinical guidelines. Furthermore, the evolving role of other imaging techniques such as ¹⁸F-fluoroestradiol (18F-FES) PET-CT in detection of metastatic lesions related to estrogen receptor–positive breast cancer³ will continue to advance the field of imaging.

Additional References

1. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021;22:489-498. doi: 10.1016/S1470-2045(21)00034-6. Erratum in: Lancet Oncol. 2021;22(5):e184. doi: 10.1016/S1470-2045(21)00194-7
2. Prat A, Pascual T, De Angelis C, et al. HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade. J Natl Cancer Inst. 2020;112:46-54. doi: 10.1093/jnci/djz042
3. Ulaner GA, Jhaveri K, Chandarlapaty S, et al. Head-to-head evaluation of ¹⁸F-FES and ¹⁸F-FDG PET/CT in metastatic invasive lobular breast cancer. J Nucl Med. 2021;62:326-331. doi: 10.2967/jnumed.120.247882

Alterations in the PI3K/AKT/PTEN pathway are present in about half of hormone receptor–positive (HR+)/human epidermal growth factor 2–negative (HER2-) breast cancers and may mediate endocrine resistance in this population. The phase 2 BYLieve trial demonstrated activity of alpelisib + fulvestrant in patients with PIK3CA-mutated, HR+/HER2- advanced breast cancer (ABC) in the post–CDK4/6 inhibitor setting.¹ Capivasertib, an oral selective inhibitor of all three AKT isoforms, was investigated in the phase 3 CAPItello-291 trial among 708 patients with HR+/HER2- ABC who had relapsed or had disease progression on or after aromatase inhibitor therapy with or without a CDK4/6 inhibitor. The combination of capivasertib + fulvestrant led to a significant improvement in progression-free survival (PFS) vs placebo + fulvestrant both in the overall population (median PFS 7.2 mo vs 3.6 mo; hazard ratio 0.60; P < .001) and in patients with AKT pathway-altered (PIK3CA, AKT1, or PTEN) tumors (median PFS 7.3 mo vs 3.1 mo; hazard ratio 0.50; P < .001) (Turner et al). The most common grade 3 or higher adverse events were rash and diarrhea in the capivasertib + fulvestrant arm (12.1% and 9.3%, respectively), and the discontinuation rate was 13.0%. These results highlight the activity of this combination and its overall acceptable safety profile and present a potential new therapy option for patients. The selection, optimal sequencing, and combinations of new agents in the HR+/HER2 ABC space remains an area of active research.

The neoadjuvant setting provides a favorable environment to study de-escalation approaches as treatment response (via pathologic complete response [pCR] assessment) can be used as a surrogate marker for outcome. Studies have shown the effect of HER2-enriched subtype and high ERBB2 expression on pCR rates after receipt of a chemotherapy-free, dual HER2-targeted regimen.² The prospective, multicenter, neoadjuvant phase 2 WSG-TP-II trial randomly assigned 207 patients with HR+/HER2+ early breast cancer to 12 weeks of endocrine therapy (ET)–trastuzumab-pertuzumab vs paclitaxel-trastuzumab-pertuzumab. The pCR rate was inferior in the ET arm compared with the paclitaxel arm (23.7% vs 56.4%; odds ratio 0.24; 95% CI 0.12-0.46; P < .001). In addition, an immunohistochemistry ERBB2 score of 3 or higher and ERBB2-enriched subtype were predictors of higher pCR rates in both arms (Gluz et al). This study not only supports a deescalated chemotherapy neoadjuvant strategy of paclitaxel + dual HER2 blockade but also suggests that a portion of patients may potentially be spared chemotherapy with very good results. The role of biomarkers is integral to patient selection for these approaches, and the evaluation of response in real-time will allow for the tailoring of therapy to achieve the best outcome.

Systemic staging for locally advanced breast cancer (LABC) is important for informing prognosis as well as aiding in development of an appropriate treatment plan for patients. The PETABC study included 369 patients with LABC (TNM stage III or IIB [T3N0]) with random assignment to ¹⁸F-labeled fluorodeoxyglucose PET-CT or conventional staging (bone scan, CT of chest/abdomen/pelvis), and was designed to assess the rate of upstaging with each imaging modality and effect on treatment (Dayes et al). In the PET-CT group, 23% (N = 43) of patients were upstaged to stage IV compared with 11% (N = 21) in the conventional-staging group (absolute difference 12.3%; 95% CI 3.9-19.9; P = .002). Fewer patients in the PET-CT group received combined modality treatment vs those patients in the conventional staging group (81% vs 89.2%; P = .03). These results support the consideration of PET-CT as a staging tool for LABC, and this is reflected in various clinical guidelines. Furthermore, the evolving role of other imaging techniques such as ¹⁸F-fluoroestradiol (18F-FES) PET-CT in detection of metastatic lesions related to estrogen receptor–positive breast cancer³ will continue to advance the field of imaging.

Additional References

1. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021;22:489-498. doi: 10.1016/S1470-2045(21)00034-6. Erratum in: Lancet Oncol. 2021;22(5):e184. doi: 10.1016/S1470-2045(21)00194-7
2. Prat A, Pascual T, De Angelis C, et al. HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade. J Natl Cancer Inst. 2020;112:46-54. doi: 10.1093/jnci/djz042
3. Ulaner GA, Jhaveri K, Chandarlapaty S, et al. Head-to-head evaluation of ¹⁸F-FES and ¹⁸F-FDG PET/CT in metastatic invasive lobular breast cancer. J Nucl Med. 2021;62:326-331. doi: 10.2967/jnumed.120.247882

Alterations in the PI3K/AKT/PTEN pathway are present in about half of hormone receptor–positive (HR+)/human epidermal growth factor 2–negative (HER2-) breast cancers and may mediate endocrine resistance in this population. The phase 2 BYLieve trial demonstrated activity of alpelisib + fulvestrant in patients with PIK3CA-mutated, HR+/HER2- advanced breast cancer (ABC) in the post–CDK4/6 inhibitor setting.¹ Capivasertib, an oral selective inhibitor of all three AKT isoforms, was investigated in the phase 3 CAPItello-291 trial among 708 patients with HR+/HER2- ABC who had relapsed or had disease progression on or after aromatase inhibitor therapy with or without a CDK4/6 inhibitor. The combination of capivasertib + fulvestrant led to a significant improvement in progression-free survival (PFS) vs placebo + fulvestrant both in the overall population (median PFS 7.2 mo vs 3.6 mo; hazard ratio 0.60; P < .001) and in patients with AKT pathway-altered (PIK3CA, AKT1, or PTEN) tumors (median PFS 7.3 mo vs 3.1 mo; hazard ratio 0.50; P < .001) (Turner et al). The most common grade 3 or higher adverse events were rash and diarrhea in the capivasertib + fulvestrant arm (12.1% and 9.3%, respectively), and the discontinuation rate was 13.0%. These results highlight the activity of this combination and its overall acceptable safety profile and present a potential new therapy option for patients. The selection, optimal sequencing, and combinations of new agents in the HR+/HER2 ABC space remains an area of active research.

The neoadjuvant setting provides a favorable environment to study de-escalation approaches as treatment response (via pathologic complete response [pCR] assessment) can be used as a surrogate marker for outcome. Studies have shown the effect of HER2-enriched subtype and high ERBB2 expression on pCR rates after receipt of a chemotherapy-free, dual HER2-targeted regimen.² The prospective, multicenter, neoadjuvant phase 2 WSG-TP-II trial randomly assigned 207 patients with HR+/HER2+ early breast cancer to 12 weeks of endocrine therapy (ET)–trastuzumab-pertuzumab vs paclitaxel-trastuzumab-pertuzumab. The pCR rate was inferior in the ET arm compared with the paclitaxel arm (23.7% vs 56.4%; odds ratio 0.24; 95% CI 0.12-0.46; P < .001). In addition, an immunohistochemistry ERBB2 score of 3 or higher and ERBB2-enriched subtype were predictors of higher pCR rates in both arms (Gluz et al). This study not only supports a deescalated chemotherapy neoadjuvant strategy of paclitaxel + dual HER2 blockade but also suggests that a portion of patients may potentially be spared chemotherapy with very good results. The role of biomarkers is integral to patient selection for these approaches, and the evaluation of response in real-time will allow for the tailoring of therapy to achieve the best outcome.

Systemic staging for locally advanced breast cancer (LABC) is important for informing prognosis as well as aiding in development of an appropriate treatment plan for patients. The PETABC study included 369 patients with LABC (TNM stage III or IIB [T3N0]) with random assignment to ¹⁸F-labeled fluorodeoxyglucose PET-CT or conventional staging (bone scan, CT of chest/abdomen/pelvis), and was designed to assess the rate of upstaging with each imaging modality and effect on treatment (Dayes et al). In the PET-CT group, 23% (N = 43) of patients were upstaged to stage IV compared with 11% (N = 21) in the conventional-staging group (absolute difference 12.3%; 95% CI 3.9-19.9; P = .002). Fewer patients in the PET-CT group received combined modality treatment vs those patients in the conventional staging group (81% vs 89.2%; P = .03). These results support the consideration of PET-CT as a staging tool for LABC, and this is reflected in various clinical guidelines. Furthermore, the evolving role of other imaging techniques such as ¹⁸F-fluoroestradiol (18F-FES) PET-CT in detection of metastatic lesions related to estrogen receptor–positive breast cancer³ will continue to advance the field of imaging.

Additional References

1. Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): One cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 2021;22:489-498. doi: 10.1016/S1470-2045(21)00034-6. Erratum in: Lancet Oncol. 2021;22(5):e184. doi: 10.1016/S1470-2045(21)00194-7
2. Prat A, Pascual T, De Angelis C, et al. HER2-enriched subtype and ERBB2 expression in HER2-positive breast cancer treated with dual HER2 blockade. J Natl Cancer Inst. 2020;112:46-54. doi: 10.1093/jnci/djz042
3. Ulaner GA, Jhaveri K, Chandarlapaty S, et al. Head-to-head evaluation of ¹⁸F-FES and ¹⁸F-FDG PET/CT in metastatic invasive lobular breast cancer. J Nucl Med. 2021;62:326-331. doi: 10.2967/jnumed.120.247882