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Mutations in PTEN, ESR1 Promote Piqray Resistance in HR-Positive Breast Cancer, Study Finds

NEW YORK – In a Phase I/II trial of Novartis' PI3 kinase inhibitor alpelisib (Piqray) combined with an aromatase inhibitor, investigators observed that only 52 percent of the 44 hormone receptor-positive breast cancer patients enrolled in the trial derived a clinical benefit from treatment. 

In a study published in Nature Cancer in March, researchers led by Pedram Razavi and Sarat Chandarlapaty of Memorial Sloan Kettering Cancer Center sought to decipher genomic alterations that might have made patients resistant to alpelisib or antiestrogen treatments, and promoted disease progression. They found that 25 percent of patients who developed resistance to treatment had loss-of-function PTEN mutations, highlighting it as a recurrent mechanism of resistance to PI3K alpha inhibition. Researchers also found that when ESR1 activating mutations were present during treatment, they were associated with resistance.

In the US, alpelisib is already approved in combination with the endocrine therapy fulvestrant as a treatment for hormone receptor-positive, HER2-negative, PIK3CA-mutated breast cancer, after progressing on an endocrine-based regimen.

To characterize the genetics involved in conferring resistance to combination hormone plus targeted therapy, the researchers conducted a longitudinal analysis of tumor and plasma circulating cell-free tumor DNA (ctDNA) of the heavily pretreated study participants who had HR-positive, non-HER-amplified metastatic breast cancer.  

A total of 51 patients were enrolled in the trial. Baseline PIK3CA mutational status of 50 patients were determined on pre-treatment tumor samples obtained for this study with either the MSK-IMPACT next-generation sequencing (NGS) assay (39 patients), Foundation Medicine NGS assay (2 patients) or Sequenom mass spectrometry genotyping (9 patients). The PIK3CA gene provides instructions for making the p110 alpha protein, which is one piece of the PI3K enzyme. Investigators also used a targeted 73-gene NGS panel to sequence ctDNA in pre-treatment, on-treatment, and post-treatment plasma samples from 47 patients.

Although patients were not required to have a baseline tumor mutation in PIK3CA, 88 percent of patients had a hotspot activating mutation in PIK3CA.

Out of those tested, 44 patients were evaluable for response, and 23 patients, or 52 percent, had either a complete response, a partial response, or stable disease greater than or equal to 16 weeks. They were defined by investigators as having a clinical benefit. Of the 44 evaluable patients, 31 had measurable disease and were used in the assessment of overall response rate, which was 19 percent. Five patients had partial responses and one had a complete response.

Clinical benefit was only observed in patients whose tumors harbored PIK3CA mutations.

When activating ESR1 mutations related to aromatase inhibitor resistance were found in the baseline tumor samples of six patients, none experienced clinical benefit. Alternatively, among the patients who did derive treatment benefit, none had ESR1 mutations.

Although previously, PIK3CA and PTEN mutations were observed to be mutually exclusive in primary breast cancer, from this trial, researchers identified two patients whose tumors harbored concurrent clonal activating PIK3CA mutations and PTEN loss-of-function mutations. Both patients had no clinical benefit from the alpelisib plus aromatase inhibitor combination and both had progressive disease on their first radiographic evaluations in week eight.

Researchers then used ctDNA samples to track PTEN mutations and copy number alterations. They identified PTEN alterations in 25 percent of patients. Out of these, three patients had loss-of-function alterations in pre-treatment samples (A126S36, R130*, and a homozygous deletion that was also confirmed in pre-treatment tumor tissue) and had rapid progression of disease upon starting alpelisib/aromatase inhibitor regimen.

Additionally, in experimental tumor xenograft models, ESR1 mutant-expressing tumors progressed more rapidly with treatment via alpelisib and estrogen deprivation. These data imply that genomic alterations promoting resistance to the hormone component of this combination therapy can significantly contribute to disease progression.

"Taken together, these data reveal that resistance to combination therapy may manifest through genomic alterations that promote resistance to either component of therapy; and sampling a single site of a highly heterogeneous disease, such as hormone receptor-positive metastatic breast cancer, may result in an inadequate biomarker that precludes more robust patient selection strategies," the authors wrote. "For instance, excluding tumors with ESR1 mutations or PTEN loss might yield meaningful improvements in the response rates observed. Patients with these specific alterations might be considered for trials of oral selective ER degraders (ESR1) and/or AKT inhibitors (PTEN)."