Harnessing the effects of hypoxia-like inhibition on homology-directed DNA repair.

Hypoxia is a hallmark feature of the tumor microenvironment which can promote mutagenesis and instability. This increase in mutational burden occurs as a result of the downregulation of DNA repair systems. Deficits in the DNA damage response can be exploited to induce cytotoxicity and treat advanced stage cancers. With the advent of precision medicine, agents such as Poly (ADP-ribose) polymerase (PARP) inhibitors have been used to achieve synthetic lethality in homology directed repair (HDR) deficient cancers. However, most cancers lack these predictive biomarkers. Treatment for the HDR proficient population represents an important unmet clinical need. There has been interest in the use of anti-angiogenic agents to promote tumor hypoxia and induce deficiency in a HDR proficient background. For example, the use of cediranib to inhibit PDGFR and downregulate enzymes of the HDR pathway can be used synergistically with a PARP inhibitor. This combination can improve therapeutic responses in HDR proficient cancers. Preclinical results and Phase II and III clinical trial data support the mechanistic rationale for the efficacy of these agents in combination. Future investigations should explore the effectiveness of cediranib and other anti-angiogenic agents with a PARP inhibitor to elicit an antitumor response and sensitize cancers to immunotherapy.

Surgical and oncologic outcomes in surgically treated women 80 years and older with endometrioid endometrial cancer as a function of their comorbidities.

Objective: To describe the surgical and oncologic outcomes in surgically treated oldest old women (≥80 years) with endometrioid endometrial cancer as a function of their comorbidities. Methods: In this retrospective cohort study, patients aged 80-99 years who underwent surgical management of stage I endometrioid endometrial cancer between 2006 and 2018 were included. Low- and high-intermediate risk disease was defined using the Gynecologic Oncology Group-99 criteria. The validated, Combined Age-Charlson Comorbidity Index (CA-CCI) was used to quantify comorbidity burden. Logistic regression was used to identify the independent predictors of various surgical and oncologic outcomes. Kaplan-Meier survival analysis was performed to compare survival distributions based on mortality cause and comorbidity status. Results: We identified 64 women who met the eligibility criteria. Median age was 84 years (IQR 80, 94 years). Among oldest old women undergoing a hysterectomy with or without lymph node dissection, women with a CA-CCI score of ≥7 had an 8 times higher risk of postoperative infections compared with oldest old women with a <7 score (95% CI 1.53-48.91, P = 0.015). Women with a CA-CCI score of ≥8 were 45% less likely to survive at 3 years (aRR 0.55, 95% CI 0.004-0.87; P = 0.039) than those with a lower CA-CCI score (three-year overall survival 73% vs 96%). Conclusion: Surgical and oncologic outcomes in oldest old women with early stage endometrioid endometrial cancer are largely determined by comorbidity status. Less comorbid women (CA-CCI score < 8) had a significantly higher five-year survival at 87% than their more comorbid counterparts. Use of age-comorbidity risk scoring such as CA-CCI, preoperative optimization, and careful selection for and counseling of patients about surgical treatment are paramount in providing optimal recovery and survival advantages in the oldest old.