Anna M. Dornisch

Background: There exists an unmet clinical need to define definitive management strategies for patients with locally advanced non-melanoma skin cancers (NMSC), particularly if not amenable to surgical resection. Methods: We retrospectively reviewed a case series of locally advanced unresectable NMSC treated with induction systemic treatment followed by response-adapted consolidative radiation. Results: We identified 15 patients who met study criteria, including seven with basal cell carcinoma (BCC), six with cutaneous squamous cell carcinoma (CSCC), and two with Merkel cell carcinoma (MCC). Clinical complete response (CR) by physical examination was observed in all 15 patients. No locoregional or distant recurrences were observed in any histologic subtype after completion of radiation (median follow-up from completion of radiation: 18.1 months BCC, 22.5 months CSCC, 22.7 months MCC). The median duration of observed response (DOOR), measured from first clinical response was 26.9 months (26.2 BCC, 29.4 CSCC, 27.1 MCC). Radiation treatment volumes were response-adapted with median gross tumor volume reduction of 55.3% (15.3%–100%). Median treatment-free response was 20.5 months. No unexpected systemic therapy related toxicities were identified. Conclusions: In this single-institution retrospective case series, induction systemic therapy followed by response-adapted consolidative radiation was feasible and associated with durable disease control in selected patients with locally advanced unresectable NMSC.

Precision healthcare aims to tailor disease prevention and early detection to individual risk. Prostate cancer screening may benefit from genomics-informed approaches. We developed and validated the P-CARE model, a prostate cancer risk prediction tool combining a polygenic score, family history and genetic ancestry, using data from over 585,000 male participants in the Million Veteran Program. The model was externally validated in diverse cohorts and implemented via a blended genome–exome assay for clinical use. Here we show that the P-CARE model identifies clinically meaningful gradients of prostate cancer risk among men, with higher scores associated with increased risk of any, metastatic and fatal prostate cancer. The model is now being used in a clinical trial of precision prostate cancer screening. This work demonstrates the potential for genomics-enabled health systems to improve prostate cancer screening and prevention in men. ClinicalTrials.gov registration: NCT05926102.

Merkel cell carcinoma (MCC) is a cutaneous malignancy often treated with surgical resection followed by adjuvant radiation therapy (RT). In the node-positive setting, adjuvant RT reduces the risk of locoregional recurrence, but historical data suggest that distant failure is a persistent issue and often fatal. This has prompted new efforts to intensify treatment in these patients with the addition of neoadjuvant or adjuvant immune checkpoint inhibitor therapy. However, newer diagnostic techniques have led to stage migration in patients with previously subclinical metastatic disease; consequently, preventing locoregional recurrence may be a higher priority in node-positive MCC patients than was previously believed. Recent trials in node-positive MCC, such as ADMEC-O, have had lower rates of adjuvant RT utilization in treatment versus control arms, which may have attenuated the observed effect of adjuvant immunotherapy. The low utilization of adjuvant RT may have also resulted in a higher recurrence rate in patients who did not have a complete response to neoadjuvant immunotherapy in the CHECKMATE 358 trial. Altogether, these are important considerations for ongoing and future immunotherapy trials in MCC and may affect the interpretation of their results. Ongoing clinical trials may determine which patients are at low risk of recurrence when treated with immunotherapy and whether adjuvant RT could be omitted in select patients.