Li-Fraumeni syndrome (LFS) was first described in 1969 as a highly penetrant cancer-prone syndrome.¹ Formal diagnostic criteria for LFS have subsequently been developed, based on a family or a personal history of a broad spectrum of early-onset cancers, including sarcoma, breast cancer, adrenocortical carcinoma, and brain tumors, often with more than 1 cancer per affected individual.^2-5 Quiz Ref ID Lifetime cancer risks are reported to approach 100% for both sexes in cases identified by family history.^6-8 The exceedingly high cancer risk in LFS often confers a high psychological and medical burden.⁹ Pathogenic variants in the tumor suppressor gene, TP53 (NCBI Entrez Gene 7157), were first identified and subsequently found to cause about 70% of classic LFS in 1990.^10-13 Identification of germline TP53 mutation carriers has been augmented by increased with increased sequencing of germline and somatic DNA using gene panels and whole-exome and whole-genome testing, owing in part to the influence of precision medicine initiatives.

In a trial of patients with high grade serous ovarian cancer (HGSOC), addition of the ATR inhibitor berzosertib to gemcitabine improved progression free survival (PFS) compared to gemcitabine alone but biomarkers predictive of treatment are lacking. Here we report a candidate biomarker of response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in HGSOC ovarian cancer. Patients with replication stress (RS)-high tumors (n = 27), defined as harboring at least one genomic RS alteration related to loss of RB pathway regulation and/or oncogene-induced replication stress achieve significantly prolonged PFS (HR = 0.38, 90% CI, 0.17–0.86) on gemcitabine monotherapy compared to those with tumors without such alterations (defined as RS-low, n = 30). However, addition of berzosertib to gemcitabine benefits only patients with RS-low tumors (gemcitabine/berzosertib HR 0.34, 90% CI, 0.13–0.86) and not patients with RS-high tumors (HR 1.11, 90% CI, 0.47–2.62). Our findings support the notion that the exacerbation of RS by gemcitabine monotherapy is adequate for lethality in RS-high tumors. Conversely, for RS-low tumors addition of berzosertib-mediated ATR inhibition to gemcitabine is necessary for lethality to occur. Independent prospective validation of this biomarker is required.