PI3K pathway (PI3Kp) dysregulation and response to pan-PI3K/AKT/mTOR/dual PI3K-mTOR inhibitors (PI3Kpi) in metastatic breast cancer (MBC) patients (pts).

Abstract

509 Background: The role of PI3Kp dysregulation as a predictor of sensitivity to PI3Kpi is unclear. We aimed to evaluate the efficacy of PI3Kpi in two cohorts of MBC pts with assessable PI3Kp status. Methods: MBC pts treated in ≥3rd line with PI3Kpi were reviewed. PI3Kp status: (a) No dysregulation: PIK3CA wt and PTEN normal; (b) PI3Kp dysregulation: PIK3CA mutation (PIK3CAmut) or PTEN low (HScore≤50). Cohort A: pts treated with single agent PI3Kpi. Cohort B: pts treated with PI3Kpi in combination with hormonal therapy (HT), chemotherapy (CT) and/or trastuzumab (T). Results: Out of 232 MBC pts screened for PI3Kp alterations from Sep09 to Sep11, 32 were treated with PI3Kpi. Cohort A (n=17): HR+/HER2- 88%, HER2+ 6%, triple negative 6%; median age 43, median MBC lines 4 (2-9); PIK3CAmut in 10/17 (58.8%; 6 exon9, 4 exon20), PTEN low 3/17 (17.6%), 1 pt both; PI3Kp dysregulation 12/17 pts. Cohort B (n=15): HR+/HER2- 40%, HER2+ 60%; median age 49, median MBC lines 4 (2-13); PIK3CAmut 3/13 assessable (23.1%; all exon20), PTEN low 6/15 (40%), 1 pt both; PI3Kp dysregulation 8/15 pts. Time to progression to PI3Kpi (TTP), overall survival from MBC diagnosis (OSMBC) and OS from PI3Kpi beginning (OSPI3Kpi), according to PIK3CA status and PI3Kp dysregulation, are shown. No differences were found according to PTEN status. Conclusions: These results suggest that the best outcomes with PI3Kpi in PIK3CAmut MBC pts occur when they are used in combination with HT/CT/T. Activity of non selective PI3Kpi used as single agents seems to be limited, making results from prospective trials with selective PI3Kα inhibitors and PI3Kpi in combinations eagerly awaited. [Table: see text]

The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers

“…A retrospective review of patients with metastatic breast cancer treated with inhibitors of the PI3K/Akt/mTOR pathway reported that patients with PIK3CA mutations treated with a single agent did not have an increased TTP; however, when PI3K/Akt/mTOR inhibitors were combined with endocrine therapy, HER2-directed therapy or chemotherapy, the presence of PIK3CA mutations correlated with increased TTP compared with patients with wild type tumors [Oliveira et al 2012]. In the same analysis, the PTEN status did not seem to have any correlation with clinical outcome, which seems to confirm the results reported by Weigelt and colleagues.…”

Advances in Breast Cancer – Looking Back over the Year

“…All studies published so far still have a very small number of cases and the results are suggestive at best. It has been shown, for instance, that a mutation in PI3KCA was associated with a poorer prognosis among patients receiving PI3K inhibition as monotherapy, while it was associated with a better prognosis among combination treatments with anti-hormonal therapy or chemotherapy [28].…”

“…In each case of response to therapy or stability, treatment was either continued until progression or chemotherapy discontinued and bevacizumab continued as maintenance treatment. Neither nab-paclitaxel nor ixabepilone exhibited an improvement in Prognose bei Patientinnen mit einer PI3K-Inhibition als Monotherapie, aber mit einer besseren Prognose bei Kombinationsbehandlungen mit Antihormontherapie oder Chemotherapie verbunden war [28]. In der FinHER-Studie wurden auch somatische Genmutationen in PI3K mit der Prognose und dem Therapieansprechen entsprechend dem Trasuzumab-Behandlungsstatus verglichen, jedoch konnte kein Zusammenhang mit der Prognose oder der Trastuzumab-Wirksamkeit gesehen werden [29].…”