No abstract

Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and sensitize tumors to checkpoint blockade immunotherapy. However, many POLE mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we. prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair proficient POLE-mutated solid tumors. We found that only tumors harboring selective POLE pathogenic mutations in the DNA binding or catalytic site of the exonuclease domain presented high mutational burden with specific single base substitution signature, high T-cell infiltrates, and high response rate to anti-PD1 monotherapy. This study illustrates how specific DNA repair defects can sensitize to immunotherapy, POLE proofreading deficiency representing a novel tumor agnostic biomarker for response to PD-1 checkpoint blockade therapy.

PurposeAge induces a progressive decline in functional reserve and impacts cancer treatments. Telomere attrition leads to tissue senescence. We tested the hypothesis that telomere length (TL) could predict patient vulnerability and outcome with cancer treatment.Patients and methodsAn ancillary study in the Elderly Women GINECO Trial 3 was performed to evaluate the impact of geriatric covariates on survival in elderly advanced ovarian cancer patients receiving six cycles of carboplatin. TL was estimated from peripheral blood at inclusion using standard procedures.ResultsTL (in base pairs) was estimated for 109/111 patients (median 6.1 kb; range [4.5-8.3 kb]). With a cut-off of 5.77 kb, TL discriminated two patient groups, long telomere (LT) and short telomeres (ST), with significantly different treatment completion rates of 0.80 (95%CI [0.71-0.89]) and 0.59 (95%CI [0.41-0.76]), respectively (odds ratio [OR]=2.8, p=0.02). ST patients were at higher risk of serious adverse events (SAE, OR=2.7; p=0.02) and had more unplanned hospital admissions (OR=2.1; p=0.08). After adjustment on FIGO stage, TL shorter than 6 kb was a risk factor of premature death (HR=1.57; p=0.06).ConclusionThis exploratory study identifies TL as predictive factor of decreased treatment completion, SAE risk, unplanned hospital admissions and OS after adjustment on FIGO stage.

Breast cancer (BC) is the most common female malignancy in the world and almost one third of cases occur after 70 years of age. Optimal management of BC in the elderly is a real challenge and requires a multidisciplinary approach, mainly because the elderly population is heterogeneous. In this review, we describe the various possibilities of treatment for localized or metastatic BC in an aging population. We provide an overview of the comprehensive geriatric assessment, surgery, radiotherapy, and adjuvant therapy for early localized BC and of chemotherapy and targeted therapies for metastatic BC. Finally, we attempt to put into perspective the necessary balance between the expected benefits and risks, especially in the adjuvant setting.