Intrinsic Subtypes, PIK3CA Mutation, and the Degree of Benefit From Adjuvant Trastuzumab in the NSABP B-31 Trial

Abstract

Purpose Considerable molecular heterogeneity exists among human epidermal growth factor receptor 2 (HER2) –positive breast cancer regarding gene expression and mutation profiling. Evidence from preclinical, clinical neoadjuvant, and metastatic clinical trials suggested that PIK3CA mutational status and PAM50 intrinsic subtype of a tumor were markers of response to anti-HER2 therapies. We evaluated the predictive value of these two biomarkers in the adjuvant setting using archived tumor blocks from National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31. Patients and Methods Expression data for 49 genes using the nCounter platform were used to generate PAM50 intrinsic subtypes for 1,578 archived tumor blocks from patients in the B-31 trial. Six PIK3CA hotspot mutations were examined by mass spectrometry of the primer extension products in a randomly selected subset (n = 671). We examined the heterogeneity of trastuzumab treatment effect across different subsets defined by each marker using Cox regression and disease-free survival as the end point. Results Seven hundred forty-one (47.0%) of 1,578 tumors were classified as HER2-enriched (HER2E) subtype, and 166 (24.7%) of 671 tumors had PIK3CA mutations. Hazard ratios (HRs) for trastuzumab in HER2E and other subtypes were 0.44 (95% CI, 0.34 to 0.58; P < .001) and 0.47 (95% CI, 0.35 to 0.62; P < .001), respectively (interaction P = .67). HRs for trastuzumab in PIK3CA wild-type and mutated tumors were 0.51 (95% CI, 0.37 to 0.71; P < .001) and 0.44 (95% CI, 0.24 to 0.82; P = .009), respectively (interaction P = .64). Conclusion Unlike results seen in the metastatic and neoadjuvant clinical trials, PIK3CA and PAM50 intrinsic subtypes were not predictive biomarkers for adjuvant trastuzumab in NSABP B-31. These data suggest that results from the metastatic and neoadjuvant setting may not be always applicable to the adjuvant setting.

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

“…Our present observation is in agreement with these findings. However, unlike the results observed in the neoadjuvant and metastatic settings, there is no association between the PIK3CA mutation and the degree of benefit from transtuzumab in adjuvant setting in the NSABP B-31 trial (43). Although patients with PIK3CA mutations had a slightly poorer DFS and DDFS than those with wild-type in the entire study population (n ¼ 729), the differences did not reach a significance.…”

Original paper Prognostic value of PIK3CA mutation status, PTEN and androgen receptor expression for metastasis-free survival in HER2-positive breast cancer patients treated with trastuzumab in adjuvant setting

“…We, similarly to other studies [24,26,28], did not find an association between PIK3CA mutation status and other clinical and biological parameters. However, there are reports in which the correlation between PIK3CA mutations and grade [26] or nodal status (in the ER-positive group) [27] was reported.…”

“…In our study we were able to detect 9/75 (12%) tumors with the H1047R mutation and 2/75 (2.7%) with the E545K mutation in the PIK-3CA gene. Our results are comparable to other studies, in which the mutated PIK3CA gene was found in 16%-24% of cases [22][23][24][25][26][27][28]. Comparing data with results obtained by other authors sometimes could be problematic because different mutations are investigated in groups of cancer patients with different clinical characteristics.…”

“…Some authors found that patients with tumors bearing an activating PIK-3CA mutation are characterized by shorter time to recurrence or progression [29,32], while others reported that patients with PIK3CA mutations were [23,25,31]. However, other studies did not confirm the relationship between PIK3CA mutations and patient survival (disease/progression/recurrence-free [12,17,24], or overall [22]) or reaction to trastuzumab treatment [22,30]. But, as mentioned before, the above-discussed studies included groups with different treatment schedules (neoadjuvant [23,25,31] or adjuvant [29,24,26] setting) or different clinical characteristic (metastatic breast cancer [30,32] or patients without distant metastases [25,29]).…”

“…However, other studies did not confirm the relationship between PIK3CA mutations and patient survival (disease/progression/recurrence-free [12,17,24], or overall [22]) or reaction to trastuzumab treatment [22,30]. But, as mentioned before, the above-discussed studies included groups with different treatment schedules (neoadjuvant [23,25,31] or adjuvant [29,24,26] setting) or different clinical characteristic (metastatic breast cancer [30,32] or patients without distant metastases [25,29]). It seems that PIK3CA mutation status is more valuable as a predictive factor for metastatic patients and neoadjuvant trastuzumab treatment.…”