Alterations in PTEN and ESR1 promote clinical resistance to alpelisib plus aromatase inhibitors in patients with hormone receptor–positive metastatic breast cancer.
Pedram Razavi, MD, PhD
Alterations in PTEN and ESR1 promote clinical resistance to alpelisib (Piqray) plus aromatase inhibitors in patients with hormone receptor (HR)—positive metastatic breast cancer, according to results of a longitudinal analysis of tumor and plasma circulating tumor DNA (ctDNA) from a phase I/II study published in Nature Cancer.1
Results from the analysis showed that the Guardant360 (Guardant Health) liquid biopsy used in the study effectively identified patients with PIK3CA mutations, as well as other mutations that correlate with resistance to treatment. The test also detected significantly more potential resistance alterations versus standard tissue biopsy, according to a press release on the research.2
Among 44 evaluable patients, the observed clinical benefit rate with alpelisib was 52%. When investigators correlated genetic alterations with outcome, they observed loss-of-function PTEN mutations in 25% of patients with resistance. Additionally, ESR1 activating mutations, which were also found to increase in number and allele fraction during treatment, were also associated with resistance. These data suggest that genomic alterations that mediate resistance to alpelisib or antiestrogen, may encourage disease progression; they also highlight PTEN loss as a recurrent mechanism of resistance to PI3Kα inhibition.
“While the introduction of PI3K inhibitors in combination with endocrine therapy has made a significant difference in improving progression-free survival, the findings of this new study indicate the need for more comprehensive genomic profiling in [patients with] HR-positive metastatic breast cancer,” lead investigator, Pedram Razavi, MD, PhD, of Memorial Sloan Kettering Cancer Center, stated in the press release. “Testing more broadly beyond PIK3CA can help identify potential mechanisms of resistance to therapy and determine those patients most likely to respond to a PI3K inhibitor.”
The purpose of the phase I trial (NCT01870505) was to evaluate the safety of alpelisib at different dose levels and to determine the impact the agent had on patients with breast cancer. In the trial, alpelisib was given with either letrozole or exemestane to patients with HR-positive locally advanced or metastatic breast cancer.3 The objective of the longitudinal analysis was to evaluate the tumor and plasma ctDNA of pre- and post-treatment samples collected from patients on the trial and identify possible mechanisms of resistance to treatment.
A total of 51 patients were enrolled between June 2013 and September 2015 and split into 4 arms: arm A (n = 7), B (n = 7), C (n = 12), and D (n = 25). At the data cutoff, which was April 30, 2018, the median age of the cohort was 58 years (range, 28-83). Overall, 69% of patients had visceral disease and 31% had bone-only disease. Eighty-eight percent of patients were previously exposed to ≥1 line of endocrine therapy (median 2 lines; range, 0-6) and 51% were previously exposed to ≥1 line of chemotherapy for metastatic disease (median 1 line; range, 0-9).
Baseline PIK3CA mutational status of 50 patients were determined on pre-treatment tumor samples obtained utilizing the MSK-IMPACT next-generation sequencing (NGS) assay (n = 39 patients), Foundation Medicine NGS assay (n = 2), or Sequenom mass spectrometry genotyping (n = 9).
ctDNA sequencing was also performed utilizing a targeted 73-gene panel NGS panel on pre-, on- and post-treatment plasma samples collected from 47 patients (n = 90 samples). A total of 88% of patients were selected based on having a hotspot activating mutation in PIK3CA at baseline. The most common mutations were in the kinase domain or helical domain.
The median time to treatment failure for all 51 patients was 14 weeks (range, 2-169) and the median time to treatment failure by arm was: 21 weeks in arm A, 8 weeks in arm B; 12 weeks in arm C, and 17 weeks in arm D. In 41 patients, the reason cited for study discontinuation was disease progression (arm A, n = 4; arm B, n = 5; arm C, n = 11; arm D, n = 21); 7 patients cited toxicity (arm A, n = 1; arm B, n = 2; arm C, n = 1; arm D, n = 3) and 3 patients cited withdrawal of consent unrelated to toxicity (arm A, n = 2 and arm D, n = 1).
Forty-four patients were determined to be evaluable for response per protocol in that they received ≥1 week of therapy and had on-study imaging and were included in the assessment of clinical benefit rate. The overall clinical benefit rate was 52% (95% CI, 37%-68%). Of the 44 evaluable patients, 31 had measurable disease and were included in the assessment of overall response rate (ORR). The ORR was 19% (95% CI, 7%-37%), with 5 PRs (arm A, n = 1 and arm D, n = 4) and 1 CR (arm D).
Clinical benefit was only observed in patients whose tumors harbored PIK3CA mutations (57.5%; 95% CI, 41%-73%), with none of the patients with wild-type PIK3CA demonstrating clinical benefit (95% CI, 0-46%; P =.025).
Regarding safety, the most common AEs observed with the treatment was hyperglycemia (78%), fatigue (65%), mucositis (55%), QTc prolongation (55%), diarrhea (55%), nausea/ vomiting (53%) and maculopapular rash (43%). The majority of AEs were grade 1 or 2; however, maculopapular rash was the most commonly observed grade 3 event and it occurred in 33% of patients. Toxicities that led to study discontinuation included maculopapular rash in 5 patients% of patients, grade 1 pneumonitis in 1 patient, and grade 3 hypotension in 1 patient. No grade 4 toxicities were observed, and no deaths were deemed to be related to the drug.
In the analysis, investigators set out to evaluate whether any co-occurring alterations were linked with either clinical benefit or intrinsic resistance. Activating ESR1 mutations known to confer aromatase inhibitor resistance (D538G, n = 3; Y537S, n = 3) were found in the baseline tumor samples of 6 patients. Additionally, no clinical benefit was observed in the patients with these mutations and these mutations were not identified in any of the patients who experienced clinical benefit from treatment. As such, ESR1 mutations were determined to be significantly associated with lack of clinical benefit (P =.0067).
Previously, investigators identified a patient in whom distinct PTEN loss-of-function mutations were linked with progression on alpelisib monotherapy. In this trial, 2 patients whose tumors harbored concurrent clonal activating PIK3CA mutations and PTEN loss were identified and they were not found to experience clinical benefit from alpelisib plus an aromatase inhibitor. In fact, both patients experienced disease progression on their first radiographic evaluations in week 8.
To better understand whether de novo or acquired PTEN loss might contribute to the development of resistance to alpelisib in combination with an aromatase inhibitor, investigators turned to ctDNA samples. PTEN alterations were found in 25% of patients (n = 8/32); 3 of these patients had loss-of-function alterations in pre-treatment samples and experienced rapid disease progression following treatment with the alpelisib combination. These mutations were also detected in post-treatment specimens collected from 5 patients; notably, all of these patients did not exhibit any evidence of these alterations in their pre-treatment specimens.
“These data reveal that genomic alterations causing loss of PTEN function may be identified in the population of HR-positive PIK3CA-mutant patients receiving alpelisib therapy,” the investigators wrote.
To evaluate whether certain mutant alleles could play a role in the development of resistance to therapy, investigators compared variant allele frequencies (VAFs) in both pre- and post-treatment specimens. Here, investigators observed an enrichment in VAFs of mutant PTEN as well as a significant increase in the VAFs of hotspot, activating ESR1 mutations. Considered collectively, PTEN loss and ESR1 activating mutations were found to be present in nearly half of the patients on the study and their presence was linked with progression on therapy.
“Going forward in HR-positive metastatic breast cancer, deployment of biomarkers and therapeutic strategies taking into consideration heterogeneity and evolvability are likely to be essential tools for ultimately overcoming drug resistance,” the investigators concluded.