Characterizing Breast Cancer Prevalence Among Female SDHx Pathogenic Variant Carriers in a Laboratory Research...

Germline pathogenic or likely pathogenic variants (PV/LPVs) in SDHx (SDHA, SDHB, SDHC, SDHD) cause hereditary paraganglioma and pheochromocytoma (PPGL) syndromes and are linked to other tumors, such as renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GIST). As SDHx variants are increasingly identified on multigene panels, questions have arisen about a possible association with breast cancer (BC). Prior literature is mixed, underscoring the need for clearer characterization. This study assesses BC prevalence among female SDHx carriers in a large laboratory-based research registry.

We performed a retrospective cohort analysis using the Myriad Collaborative Research Registry (MCRR) v7. Females with a confirmed SDHx PV/LPV were included; those with co-occurring PV/LPVs in other cancer predisposition genes were excluded. Personal BC history was summarized overall and by gene. Indications for genetic testing were unavailable.

The MCRR includes 222,111 females with a personal history of cancer who underwent germline testing that included the SDHx genes; 135,712 (61%) had BC, with a mean diagnosis age of 57 years. Among all females tested, 508 SDHx PV/LPV carriers were identified. Of these, 286 (56.3%) had BC, including 7 with two primary BCs (293 total). Mean age at diagnosis among carriers was 57.4 years. By gene: • SDHA: 376 carriers; 218 (58%) with BC, 7 had 2 BC primaries. Mean age of diagnosis (dx): 57.4y • SDHB: 61 carriers; 32 (52.5%) with BC Mean age of dx: 55.2y • SDHC: 50 carriers; 25 (50%) with BC Mean age of dx: 58.8y • SDHD: 23 carriers; 11 (47.8%) with BC Mean age of dx: 60.5y Compared with the overall affected cohort, SDHx carriers had a lower proportion of BC (61% vs. 56.3%), with no gene specific enrichment and no evidence of earlier onset.

In a large cohort of women with cancer who underwent multigene testing, SDHx PV/LPV carriers did not show higher BC prevalence than the overall group, and age at diagnosis was similar. The proportion of breast cancer in SDHx carriers was lower, but it remains unclear whether their risk differs from the general population or if findings are incidental. Since SDHx is often found incidentally, breast care teams should prioritize surveillance for tumors known to be associated with SDHx (PPGL, RCC, and GIST) and refer patients as appropriate to genetics or specialty care. Further prospective studies with cancer-free controls are needed to define breast cancer risk in SDHx carriers and guide screening.