ctDNA Informs Targeted Therapy Choice for Breast Cancer

Patients with metastatic breast cancer who carry rare mutations identified by circulating tumor DNA (ctDNA) responded to matched targeted therapies, according to results of the plasmaMATCH trial (NCT03182634) presented during the 2019 San Antonio Breast Cancer Symposium.¹ Specifically, patients with HER2 mutations responded to neratinib (Nerlynx) and patients with AKT1 mutations responded to capivasertib.

The benefit of ctDNA is its ability to provide tumor genotyping information in a noninvasive, simple, and efficient method that can aid making a diagnosis and prognosis and guide treatment.² Using ctDNA may provide a more current assessment of the genetic profile of advanced breast cancer compared with analysis of the primary tumor. Historically, ctDNA has been used in solid malignancies to detect actionable driver mutations, monitor treatment response, detect recurrence, identify resistance mechanisms, and prognosticate outcome.

The study’s lead author, Nicholas Turner, PhD, MA, MRCP, of The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, both in London, England, said during the presentation that the plasmaMATCH trial was designed to assess the clinical utility of using ctDNA testing to select patients for targeted therapies.

“Our team wanted to solve the issue of genotyping breast cancer tumors without having to perform multiple biopsies,” Turner said in a statement.3 Because mutations can change after treatment or when cancer metastasizes, it is important to develop methods to easily identify genetic mutations. Further, it is not always possible to take additional biopsies from patients with advanced disease.

Between December 2016 and April 2019, 1044 patients with metastatic or locally recurrent breast cancer were registered for the trial. Of 1033 patients screened, 142 entered into 4 parallel treatment cohorts with therapies matched to mutations that were identified through ctDNA testing.

The investigators reported that ctDNA testing was conducted prospectively using digital droplet polymerase chain reaction (ddPCR) in all patients. Guardant360 was used prospectively for error-corrected sequencing during recruitment. Sequencing from an advanced disease biopsy was conducted retrospectively and did not influence cohort entry, according to investigators.

At baseline, median age at registration was 56 years (range, 49-65) and 146 patients (14%) had metastatic disease at diagnosis. Thirty-six percent (n = 382) of patients had received ≥2 lines of chemotherapy; 8% (n = 89), a CDK4/6 inhibitor; 65% (n = 685), endocrine therapy; and 69% (n = 727), chemotherapy.

Mutation frequencies were reported using ddPCR as follows: ESR1, 27.7%; HER2, 2.7%; AKT1, 4.2%. Patients in cohort A had the ESR1 mutation; all were hormone receptor (HR)– positive and 3 (4%) were HER2-positive. In cohort B, patients had the HER2 mutation, with 86% HR-positive and 14% HER2-positive. For cohort C, patients had the AKT1 mutation with estrogen receptor (ER)–positive breast cancer; all were HR positive and 1 (6%) was also HER2-positive. In cohort D, patients had the AKT1 mutation in ER-negative breast cancer or the PTEN-inactivating mutation; 13 (68%) were HR-positive, and all patients were HER2- negative (TABLE 1).¹ Results for cohort E, which was designated for patients with no actionable mutations and triple-negative breast cancer, will be reported separately, Turner said.

Cohort A (n = 74) received fulvestrant 500 mg intramuscularly on days 1, 8, and 15 of cycle 1 and days 1 and 15 of cycle 2. Patients in cohort B (n = 20) received neratinib 240 mg orally on a continuous schedule starting day 1 of cycle 1, and patients with ER-positive breast cancer received fulvestrant 500 mg intramuscularly on days 1 and 15 of cycle 1 and in cycle 2 onward after day 1. Patients in cohort C (n = 18) received capivasertib 400 mg orally twice a day on a 7-day schedule of 4 days on treatment followed by 3 days off and fulvestrant 500 mg intramuscularly during days 1 and 15 of cycle 1 and in cycle 2 onward after day 1. Patients in cohort D (n = 19) received capivasertib 480 mg orally twice a day on a 7-day schedule of 4 days on treatment followed by 3 days off. In cohort E, patients received capivasertib 160 mg once daily on days 1 to 7 of each cycle and olaparib (Lynparza) 300 mg twice daily on a continuous schedule starting with cycle 1 on day 1.

The primary end point for cohorts A through D was confirmed objective response rate by RECIST 1.1. Secondary end points included clinical benefit rate, progression-free survival (PFS), and safety and frequency of mutations identified in ctDNA screening.

The investigators reported a high level of individual gene-level agreement between ctDNA digital PCR and sequencing results (95.5%-99.4%; κ = 0.89-0.93). When comparing the patients’ tumor samples with the findings from ctDNA testing, the investigators found that the ctDNA assay had an overall sensitivity of 93%.

The investigators noted that Guardant360 identified over 35% more PIK3CA mutations that can be targeted by therapies approved by the FDA. The assay also detected significantly more ESR1 mutations and found previously undetected microsatellite instability and ERBB2 mutations.

Predefined efficacy criteria were met in cohorts B (neratinib for HER2 mutations) and C (capivasertib for AKT mutations), with exploratory analysis of cohort D identifying activity of capivasertib in AKT1 mutations (TABLE 2). Efficacy criteria were not met in cohort A (extended-dose fulvestrant for ESR1 mutations).

Specifically, patients in cohort A had an 8.1% response, which was below the threshold for inferred efficacy. In cohort B, patients with the HER2 mutation had a response rate of 25.0%, demonstrating inferred efficacy. In cohort C, 22.2% of patients demonstrated a response; in D, 10.5% had a response, which was below the efficacy threshold. In this cohort, an exploratory analysis of patients with an AKT1 mutation had a response rate of 33.3% (2 of 6 patients), which did meet efficacy levels.

Adverse events were consistent with prior reports, with extended-dose fulvestrant well tolerated, according to the investigators. “This is a huge step in terms of making decisions in the clinic, particularly for those women with advanced breast cancer who could quickly be put on new targeted treatments matched to their cancer if [the disease] evolves to become drug resistant,” Turner said.

The investigators say the results suggest a robust way of identifying rare subtypes of breast cancer and could replace the more invasive methods of analyzing breast tumors.

“We have now confirmed that blood tests can quickly give us a bigger picture of the mutations that are present within multiple tumors throughout the study,” concluded Turner.

_References:

_{1. Turner N, Kingston B, Kilburn L, et al. Results from the plasmaMATCH trial: a multiple parallel cohort, multi-centre clinical trial of circulating tumour DNA testing to direct targeted therapies in patients with advanced breast cancer (CRUK/15/010). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract GS3-06.}

_{2. Han X, Wang J, Sun Y. Circulating tumor DNA as biomarkers for cancer detection. Genomics Proteomics Bioinformatics. 2017;15(2):59–72. doi: 10.1016/j.gpb.2016.12.004.}

_{3. Blood Test Can Quickly Match Advanced Breast Cancer Patients to Targeted Treatments. The Institute of Cancer Research website. bit. ly/2NMn3Oy. Published December 12, 2019. Accessed January 10, 2020.}