SG study underscores use of germline testing to guide cancer therapeutics

A study conducted at the Cancer Genetics Clinic of the National University Cancer Institute, Singapore underlines the use of germline genetic testing in guiding therapeutic decisions in individuals with advanced cancers.

“We conducted a retrospective review of patients who underwent germline genetic testing at our centre to determine the prevalence of actionable pathogenic germline variants (PGV) and their therapeutic applications in patients with advanced cancer,” said the researchers.

“[We found that] about one-third of cancer patients tested carried a PGV and ~80 percent were clinically actionable. About three-quarters of germline-positive advanced cancer patients received germline-directed therapies in the real world, underscoring the practical utility of germline testing to guide cancer therapeutics,” they added.

From 2000 to 2022, 3,700 individuals were referred for genetic counselling for germline testing for hereditary cancer syndrome and/or therapeutic decisions. Of the 1,154 participants who underwent germline testing (median age of testing 44 years, 84.7 percent women, 65.5 percent Chinese), 411 (35.6 percent) were germline-positive. [ESMO Open 2024;9:103482]

The most common malignancy was breast cancer (56 percent), followed by ovarian (14 percent), colon (7.6 percent), endometrial (3.9 percent), prostate (3.9 percent), and pancreatic (2.6 percent) cancers. About 12 percent had other* cancer types.

Of the 334 (81 percent) germline-positive patients with clinically actionable PGV (defined as pathogenic or likely pathogenic variants in BRCA1/2, HRR**, or MMR** genes), 274 had BRCA/HRR PGV (n=208 and 66 for BRCA and HRR, respectively) while the remaining 60 had MMR PGV.

Among patients with advanced cancers (n=426), 137 harboured a PGV (n=126 with BRCA/HRR and 11 with MMR PGV). Of the 90 BRCA/HRR PGV carriers who met the approved clinical indications for PARPi***, 69 (76.7 percent) patients received a PARPi on approved indication.

BRCA/HRR carriers: Response to platinum-based chemo

Sixty percent (n=165) of BRCA/HRR germline mutation carriers had breast cancer. Of these, half had HR+/HER2- subtype while a third had triple-negative disease. Of the 17 patients who received neoadjuvant platinum-based chemotherapy, nine (53 percent) achieved a pathologic complete response.

Of the 274 BRCA/HRR germline mutation carriers, 71 patients with advanced cancers received platinum-based chemo. The partial response (PR) and complete response (CR) rates were 73.2 percent and 18.3 percent, respectively, yielding an overall response rate of 91.5 percent. Median duration of PR and CR was 10 and 27 months, respectively.

According to the investigators, the results in the advanced (ie, metastatic) setting were durable and clinically very meaningful. “These findings support the incorporation of platinum-based chemo in the treatment armamentarium of patients with BRCA/HRR PGV and is particularly pertinent in resource-limited settings.”

Important for precision oncology

Traditionally, germline genetic testing was only utilized for identifying high-risk individuals who may benefit from enhanced cancer surveillance and/or preventive strategies. [N Engl J Med 2002;346:1616-1622; JNCI Cancer Spectr 2022;6:pkac002] The targeted approach was primarily driven by the cost and lack of therapeutic use of genetic testing in the past. [JCO Precis Oncol 2022;6:e2100516]

Today, the landscape has evolved into one that incorporates the use of genetic testing for therapeutic reasons, as germline data may be beneficial for guiding treatment, study enrolments, and patient decisions. [JAMA 2000;283:617-624; Ann Surg Oncol 2016;23:3232-3238; Cancer Genet 2022;266-267:81-85]

“Germline genetic testing now has important therapeutic implications,” said the investigators. “As the spectrum of germline-directed therapies continues to expand, future approaches looking at increasing resources for germline testing to guide precision oncology therapeutics in the real world are crucial.”