PIK3CA Mutations Are Associated With Decreased Benefit to Neoadjuvant Human Epidermal Growth Factor Receptor 2–Targeted Therapies in Breast Cancer

Abstract

A B S T R A C T PurposeWe investigated whether mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) correlates with response to neoadjuvant human epidermal growth factor receptor 2 (HER2) -targeted therapies in patients with breast cancer. Patients and MethodsBaseline tissue biopsies were available from patients with HER2-positive early breast cancer who were enrolled onto the Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial (NeoALTTO). Activating mutations in PIK3CA were identified using mass spectrometry-based genotyping. ResultsPIK3CA mutations were identified in 23% of HER2-positive breast tumors, and these mutations were associated with poorer outcome in all of the treatment arms. Patients treated with a combination of trastuzumab and lapatinib who had wild-type PIK3CA obtained a total pathologic complete response (pCR) rate of 53.1%, which decreased to 28.6% in patients with tumors that carried PIK3CA activating mutations (P ϭ .012). ConclusionActivating mutations in PIK3CA predicted poor pCR in patients with HER2-positive breast cancer treated with neoadjuvant therapies that target HER2. Consequently, the combination of anti-HER2 agents and PI3K inhibitors is being investigated.

Integrated Analysis of PTEN and p4EBP1 Protein Expression as Predictors for pCR in HER2-Positive Breast Cancer

“…The NeoALTTO trial showed that PTEN alone is not predictive of response to HER2-targeted agents (34). PIK3CA mutations were found in 21.7% of samples with a similar distribution in HR-positive or -negative tumors, which confirms results from the previous studies (32). Reduced PTEN expression was found in 80% of tumors.…”

“…Sueta and colleagues recently reported a correlation between PIK3CA mutation or low PTEN and poorer response to trastuzumab (26). Several studies investigating the role of PIK3CA mutation in neoadjuvant anti-HER2 therapy in combination with chemotherapy revealed a significantly lower pCR rate in tumors with a PIK3CA mutation after dual anti-HER2 therapy with lapatinib and trastuzumab and only a trend for lower pCR in tumors with a PIK3CA mutation after single anti-HER2 therapy (21,31,32). PIK3CA was not predictive of pCR also in patients receiving neoadjuvant chemotherapy with double anti-HER2 treatment (pertuzumab plus trastuzumab) within the TRYPHAENA study (33).…”

Association of PIK3CA Mutation Status before and after Neoadjuvant Chemotherapy with Response to Chemotherapy in Women with Breast Cancer

“…In contrast, the HER2 þ patients treated with neoadjuvant chemotherapy in combination with trastuzumab, we found that patients with PIK3CA mutations had a lower pCR rate than those with wild-type. Interestingly, two recent studies have demonstrated that HER2 þ breast cancer patients with PIK3CA mutations are less likely to achieve a pCR compared with those with wild-type when the patients treated with neoadjuvant chemotherapy plus anti-HER2 therapies in the GeparQuattro, GeparQuinto, and GeparSixto trials (19) and the NeoATTO trial (35). Similarly, PIK3CA mutation is associated with a shorter progression-free survival in HER2 þ metastatic breast cancer treated with HER2-targeted therapies in the CLEOPATRA trial (42).…”

“…However, few studies have investigated the association between PIK3CA mutations and the response to neoadjuvant chemotherapy in breast cancer (19,34,35). Therefore, whether breast cancer patients with PIK3CA mutations are sensitive to neoadjuvant chemotherapy is not fully determined.…”

General St. Gallen-2015 guidelines for the treatment of early breast cancer (adapted by the experts of the Russian Society of Breast Oncologists)

“…Частота pCR была выше у пациентов, в опухолях которых отмечалась лимфоцитарная инфильтра-ция, или трижды негативный, или HER-2-позитивный РМЖ, получавших лечение карбоплатином [77,78]. В нескольких исследованиях неоадъювантной терапии было показано, что у пациентов с мутацией PIK3CA, получавших анти-HER-2-терапию, отмечалась более низкая частота pCR [82][83][84]. Неоадъювантная эндокринотерапия, как правило, требует больше времени для достижения ответа опухоли; лечение может быть продолжено до достижения максимального ответа [85].…”