PIK3CA mutations represent one of the most common genetic aberrations in breast cancer. They have been reported to be present in over one-third of cases, with enrichment in the luminal and in human epidermal growth factor receptor 2-positive subtypes. Substantial preclinical data on the oncogenic properties of these mutations have been reported. However, whilst the preclinical data have clearly shown an association with robust activation of the pathway and resistance to common therapies used in breast cancer, the clinical data reported up to now do not support that the PIK3CA mutated genotype is associated with high levels of pathway activation or with a poor prognosis. We speculate that this may be due to the minimal use of transgenic mice models thus far. In this review, we discuss both the preclinical and clinical data associated with PIK3CA mutations and their potential implications. Prospective clinical trials stratifying by PIK3CA genotype will be necessary to determine if the mutation also predicts for increased sensitivity to agents targeting the phosphoinositide 3-kinase pathway.

Background Trastuzumab (T) combined with chemotherapy improves survival of women with HER2-positive breast cancer. Dual therapy with T and other HER-2 targeted agents (lapatinib/pertuzumab) has demonstrated improved efficacy compared to T alone in advanced breast cancer, and is in clinical trials in early stage disease. We hypothesize that subgroups of patients with HER2-positive tumors and limited tumor burden (tumor size and no or few positive lymph nodes) have a favorable outcome and would not be candidates for dual therapy. This study will analyze the disease-free survival (DFS)and overall survival (OS) of patients with early stage breast cancer treated with chemotherapy and T in the seminal randomized studies (RCTs). Methods RCTs were identified by a Medline search from 2004-2013. Trial groups from five phase III RCTs agreed to provide data. TrialNumberEligibilityRegimenNSABP B312130T1-3; pN1, pN2a, or pN3a; M0ACx4 then Tx4 VSACx4 then THx4 then Hx40wkNCCTG N98313505T1-3; pN1-2; M0ACx4 then Tx12wk VS ACTx4 then Hx52wk VS ACx4 then Tx12wk then Hx40wkHERA5102T1-3; pN1-2; M0Any (neo)adjuvant regimen, then H q3wk x1yr VS H q3wk x 2yr VS observationFinHER232T1-4; N0-3; M0Vx3 or T*x3 then FECx3 VS Vx3 or T*x3 with Hx9wk then FECx3PACS043010(528 HER2+)T1-3; pN1-2; M0FE(100)Cx6 VSFE(100)Cx6 then Hx1yr VS T*E(75) x6 VS T*E(75) x6 then Hx1yrA, adriamycin; C, cyclophosphamide; T, paclitaxel; T*, docetaxel; H, trastuzumab; P, carboplatin; F, 5-fluorouracil; E, epirubicin; Treatment regimen also included 5 years of hormonal therapy for ER positive patients. The ER+/HER2+ and the ER-/HER2+ cohorts will be analyzed separately. Patients with tumors 3 cm or smaller (T1a, T1b, T1c and >2 cm- 3cm) and 0, 1, 2 and 3 positive lymph nodes will be included. Initially a log rank test will be used to determine if the survival results are different by study. If there is no difference across studies, Kaplan-Meier survival curves with confidence intervals will be estimated. If there is a difference between studies, individual Kaplan-Meier curves will be estimated and the mean of the curves will be estimated along with confidence intervals using the adjusted standard deviation. Estimates at 3, 5 and 8 years will be presented as well as estimates of the event rates within each subpopulation defined by tumor size, number of positive lymph nodes, and ER status. Survival endpoints of DFS, and OS as defined in the original studies will be analyzed. Results and Conclusion Data from the five trials will be analyzed and an abstract provided prior to the meeting. Subgroups of patients with a very favorable outcome when treated with adjuvant chemotherapy and T will be identified. Our survival estimates might serve as benchmarks for future trials evaluating therapy reduction. Our results will complement those of the Dana Farber single arm multicenter trial in patients with “low risk” HER2-positive disease (APT trial; NCT00542451), being submitted to SABCS 2013. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S6-03.

Background Diarrhea is the most commonly reported adverse event (AE) on pertuzumab (Ptz) in both early and metastatic breast cancer (BC) settings. We report safety analyses of diarrhea from the large adjuvant APHINTY study in HER2 positive early breast cancer (EBC). Patients and methods In this exploratory analysis, the safety population included 2364 patients in the Ptz arm and 2405 in the placebo (Pla) arm. No specific prophylaxis was mandated by the protocol, however early intervention with loperamide as well as fluid and electrolyte replacement was recommended. Diarrhea incidence, severity (NCI-CTCAE v4.0), onset and management were analyzed. Results Diarrhea was the most common AE in the Ptz arm (71.3% vs. 45.2% in the Pla arm) and the events were mostly G1. Diarrhea ≥G3 was observed in 9.8% and 3.7% in Ptz and Pla arms, respectively. The highest incidence was reported during administration of HER2 targeted therapy and taxane (61.4% vs. 33.8% with Ptz and Pla, respectively) with a marked decrease observed upon chemotherapy cessation (18.1% vs. 9.2% with Ptz and Pla, respectively). The median time from first targeted treatment to onset of diarrhea during the chemotherapy phase was 7 and 10 days (Ptz/Pla). On average, diarrhea events lasted longer in the Ptz than in the Pla arm (median 8 vs. 6 days). Diarrhea events were more frequent with the administration of docetaxel + carboplatin and targeted agents, irrespective of the severity. Detailed results are reported in Table 1. Conclusions In the curative setting, diarrhea due to Ptz was mild, generally manageable with common antidiarrheals and did not affect patients' ability to receive treatment. The APHINITY findings are consistent with the well-characterized pattern of pertuzumab-related diarrhea across the HER2 BC spectrum. Diarrhea incidence, severity (NCI-CTCAE v4.0), onset and management Ptz, n=2364Pla, n=2405Incidence and severityTotal number of patients with at least one adverse event$1685 (71.3%)1086 (45.2%)Total number of events$34151792NCI CTC AE Grade (highest grade per patient)!n1683 (71.2%)1085 (45.1%)Grade 1829 (35.1%)690 (28.7%)Grade 2622 (26.3%)305 (12.7%)Grade 3229 (9.7%)90 (3.7%)Grade 43 (0.1%)0Onset and duration$Median time (days) from 1st HER2 targeted treatment to onset (min-max)7 (1 – 358)10 (1 - 384)Median Duration (days) of each event (min-max)8 (1 - 811)6 (1 - 1022)ManagementAntidiarrheals$898 (38.0%)386 (16.0%)Dose modification* of any study drug!210 (8.9%)74 (3.1%)Dose modification* of HER2 targeted treatment!69 (2.9%)18 (0.7%)Discontinuation of any study drug!38 (1.6%)7 (0.3%)Discontinuation of HER2 Targeted treatment!20 (0.8%)2 (<0.1%)$ Based on a basket of preferred terms for diarrhea ! Based only on the preferred term diarrhea * Includes dose reductions (chemotherapy only), delays or interruptions during infusion Citation Format: Bines J, de Azambuja E, Zardavas D, Procter M, Restuccia E, Viale G, Suter T, Arahmani A, van Dooren V, Clark E, Eng-Wong J, Gelber R, Piccart M, von Minckwitz G, Baselga J. Incidence and management of diarrhea with adjuvant pertuzumab and trastuzumab in HER2-Positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-13-07.