PracticeUpdate: Haematology & Oncology

CONFERENCE COVERAGE 30

PIK3CAmutation testing fromctDNAmay potentiallybeusedas a surrogate forunknownor wild-typemutationstatuswhen tissue isunavailable

Based on circulating tumour DNA analysis (n=60), 13 patients (21.7%) harboured mutations in both ESR1 and PIK3CA. Twenty-one patients (35.0%) were classified as mutation not detected for both genes, eight (13.3%) harboured ESR1 mutations and PIK3CA mutation not detected, and 18 (30.0%), ESR1 mutation not detected and PIK3CA mutations. In patients with measurable disease at baseline, confirmed responses (all partial) were: • PIK3CA mutation, 38.1% (8 of 21) • PIK3CA mutation not detected, 8.7% (2 of 23) • All patients, 22.7% (10/44). Clinical benefit rates were: • PIK3CA mutation, 42.9% • PIK3CA mutation not detected, 17.4% • All patients, 29.5%. Objective response and clinical benefit rates from circulating tumour DNA analyses were similar to archival tumour tissue data. Dr Dickler concluded that circulating tumour DNA analysis identified PIK3CA mutations in patients with metastatic breast cancer with previously unknown or wild type mutation status from archival tumour tissue. Objective response and clinical benefit rates were similar to those from archival tumour tissue, suggesting that PIK3CA mutation testing from circulating tumour DNA may potentially be used as a surrogate when tissue is unavailable. A total of 21.7% of patients harboured mutations in both ESR1 and PIK3CA genes. Dr Dickler said, “We found that PIK3CA mutations could be found in circulating tumour DNA in several patients with either wild type or unknown status in tumour tissue, making liquid biopsies a useful alternative to tumour tissue for detecting these mutations.” She added, “We also determined that PIK3CA and ESR1 mutations were both present in almost 22% of patients. Circulating tumour DNA analysis should be incorporated into future prospective trials as a less invasive and potentially more informative test for acquiring genomic data.”

C irculating tumour DNA anal- ysis has identified PIK3CA mutations in patients with metastatic breast cancer with previ- ously unknown or wild-type mutation status from archival tumour tissue. Objective response rate and clinical benefit rate were similar to those from archival tumour tissue, suggesting that PIK3CA mutation testing from circulating tumour DNA may potentially be used as a surrogate when tissue is unavailable, finds a phase 2, open-label, single-arm study. Maura N. Dickler, MD, of Memorial Sloan Kettering Cancer Center, New York, explained that the phosphatidylinositol 3-kinase (PI3K) pathway is frequently dysregulated in hormone receptor-positive breast cancer, with activating mutations of PIK3CA detected in approximately 35–45% of patients. Acquired mutations of the ESR1 gene, which encodes oestrogen receptor α , may be associated with resistance to aromatase inhibitor therapy. Taselisib is a potent and selective PI3K inhibitor, with greater selectivity against mutant PI3K α isoforms than wild-type via a unique mechanism. In phase 1 studies, taselisib plus fulvestrant exerted clinical activity and manageable tolerability in patients with hormone receptor- positive breast cancer. Dr Dickler reported on exploratory analyses of PIK3CA and ESR1 from circulating tumour DNA of patients with metastatic breast cancer. Dr Dickler said, “This study is a phase 2 evaluation of fulvestrant in combination with taselisib, a P13K inhibitor, in postmenopausal women with oestrogen receptor-positive breast cancer. The study was designed to get a signal of activity in a PIK3CA- mutant and nonmutant population. “We’re presenting circulating tumour DNA data showing efficacy in patients based on mutation status, and comparing rates of mutation detection to that in tumour tissue.”

Participating patients were post- menopausal with human epidermal receptor 2-negative, hormone recep- tor-positive locally advanced or metastatic breast cancer and progres- sion or nonresponse to at least one prior endocrine therapy in the adju- vant or metastatic setting. They received taselisib (one 6 mg capsule orally a day) plus fulvestrant (500 mg given intramuscularly on days 1 and 15 of cycle 1, then on day 1 of each 28-day cycle) until disease progression or unacceptable toxicity. PIK3CA mutation testing on archival tumour tissue used the cobas ® PIK3CA Mutation Test. The Sysmex Inostics BEAMing Digital Polymerase Chain Reaction platform was used for circulating tumour DNA analysis of ESR1 and PIK3CA mutations (predose on day 1 of cycle 1). Primary endpoints were objective response rate and clinical benefit rate in all patients and those with PIK3CA mutations. Objective response rate was confirmed complete response and confirmed partial response. Clinical benefit rate was confirmed complete response, confirmed partial response, or stable disease for ≥ 6 months. Secondary endpoints included safety, efficacy, pharmacokinetics, and exploratory biomarker analysis. Sixty patients were enrolled. Median age was 61.5 (range 31–82) years. In the metastatic setting, patients had received prior chemotherapy (21.7%) and prior hormonal therapy (50.0%). A total of 86.7% of patients had received prior treatment with an aromatase inhibitor. Forty-five patients were screened for PIK3CA mutation status based on archival tumour tissue and circulating tumour DNA testing; concordance was 86.7% (39/45). Circulating tumour DNA analysis, versus archival tumour tissue testing, identified four and nine patients with PIK3CA mutations from patients with wild type and unknown PIK3CA mutation status, respectively.

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PracticeUpdate Editorial Team

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY