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Tristan Manalac, 11 Jul 2018
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MK-2206 unlikely to add to anastrozole efficacy in PIK3CA-mutant ER+ breast cancer

05 Dec 2017

Using MK-2206 as an adjunct to anastrozole has been ineffective at inducing pathologic complete response (pCR) in patients with PIK3CA-mutant oestrogen receptor–positive (ER+) breast cancer and should not be studied further in the target patient population, according to a team of US-based investigators.

In the phase II trial of neoadjuvant MK-2206, 16 stage II/III ER+ breast cancer patients with PIK3CA-mutant tumours received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 and started MK-2206 (150 mg orally weekly, with prophylactic prednisone) at cycle 1 (C1) day 2. All patients received a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1 days 1 and 7.

Of the patients, only 13 completed neoadjuvant therapy, with three discontinuing treatment due to the presence of Ki67 >10 percent (n=2) and toxicity (n=1).

No pCRs were reported with MK-2206. The agent failed to further supress cell proliferation and induce apoptosis, as indicated on biopsies. Rash was commonly observed in treated patients.

Furthermore, although there was a decrease in AKT phosphorylation, PRAS40 phosphorylation persisted at C1 day 17 after MK-2206 treatment. ESR1 mutation was detected in one patient during surgery.

Researchers pointed out that although the sample size was small, the proof of concept study design definitively showed that an MK-2206-anastrozole combination should not be further pursued in early stage ER+ HER2-PIK3CA mutant breast cancer.

“The frequent dose-limiting toxicity of skin rash despite prophylactic prednisone is also an issue with further development of this combination. Aspects of this investigation, including sequential biopsies, careful patient selection and pharmacodynamic biomarker analysis could be considered when investigating other endocrine therapy combinations with signal transduction inhibitors to avoid accrual to larger studies of combinations that ultimately prove ineffective,” they said.

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Most Read Articles
Tristan Manalac, 11 Jul 2018
Gestational exposure to grain products fortified with folic acid appears to be linked to a lower risk of psychosis in offspring, according to a recent study.
Pearl Toh, 10 Jul 2018
A dual-hormone artificial pancreas (DAP) with a rapid delivery of insulin and pramlintide in a fixed ratio improves glycaemic control and reduces glucose variability in adults with type 1 diabetes (T1D) compared with first-generation artificial pancreas delivering insulin alone, according to a study presented at ADA 2018.
4 days ago
Chocolate consumption is not associated with risk of coronary heart disease (CHD), stroke or both combined in postmenopausal women free of pre-existing major chronic disease, a study suggests.
Pearl Toh, 5 days ago
More intensive lowering of LDL-C levels was associated with a progressively greater survival benefit than less intensive approach, when the baseline LDL-C levels were ≥100 mg/dL, reveals a meta-analysis of 34 randomized trials.