Purpose Tumor mutational burden detected by tissue next generation sequencing (NGS) correlates with checkpoint inhibitor response. However, tissue biopsy may be costly and invasive. We sought to investigate the association between hyper-mutated blood-derived circulating tumor DNA (ctDNA) and checkpoint inhibitor response. Experimental Design We assessed 69 patients with diverse malignancies who received checkpoint inhibitor-based immunotherapy and blood-derived circulating tumor DNA (ctDNA) NGS testing (54–70 genes). Rates of stable disease (SD) ≥6 months, partial and complete response (PR, CR), as well as progression-free survival (PFS) and overall survival (OS) were assessed based on total and VUS alterations. Results Statistically significant improvement in PFS was associated with high versus low alteration number in variants of unknown significance (VUS, >3 alterations versus VUS ≤3 alterations), SD≥6 months/PR/CR 45% versus 15%, respectively; p = 0.014. Similar results were seen with high versus low total alteration number (characterized plus VUS, ≥6 versus <6). Statistically significant OS improvement was also associated with high VUS alteration status. Two-month landmark analysis showed that responders versus non-responders with VUS>3 had a median PFS of 23 versus 2.3 months (p = 0.0004). Conclusion Given the association of alteration number on liquid biopsy and checkpoint inhibitor-based immunotherapy outcomes, further investigation of hyper-mutated ctDNA as a predictive biomarker is warranted.

Renal cell carcinoma (RCC) is among the most prevalent malignancies in the USA. Most RCCs are sporadic, but hereditary syndromes associated with RCC account for 2-3 % of cases and include von Hippel-Lindau, hereditary leiomyomatosis, Birt-Hogg-Dube, tuberous sclerosis, hereditary papillary RCC, and familial renal carcinoma. In the past decade, our understanding of the genetic mutations associated with sporadic forms of RCC has increased considerably, with the most common mutations in clear cell RCC seen in the VHL, PBRM1, BAP1, and SETD2 genes. Among these, BAP1 mutations are associated with aggressive disease and decreased survival. Several targeted therapies for advanced RCC have been approved and include sunitinib, sorafenib, pazopanib, axitinib (tyrosine kinase inhibitors (TKIs) with anti-vascular endothelial growth factor (VEGFR) activity), everolimus, and temsirolimus (TKIs that inhibit mTORC1, the downstream part of the PI3K/AKT/mTOR pathway). High-dose interleukin 2 (IL-2) immunotherapy and the combination of bevacizumab plus interferon-α are also approved treatments. At present, there are no predictive genetic markers to direct therapy for RCC, perhaps because the vast majority of trials have been evaluated in unselected patient populations, with advanced metastatic disease. This review will focus on our current understanding of the molecular genetics of RCC, and how this may inform therapeutics.

NCT02187302 (NIH).

Alopecia is a common side effect of chemotherapy treatments for cancer; for some individuals this results in complete hair loss. The extent of this depends on many factors including the type or combination of drugs administered, and their doses. Further, it can in some cases be lessened through use of scalp cooling techniques. This method of reducing hair loss has been available since the 1970s. However, previous evidence suggests that nurses are apathetic about its use, which in turn might mean that patients are not always offered this intervention. This small exploratory study investigated perceptions held by nurses administering chemotherapy towards alopecia and its management through scalp cooling. It entailed completion of a survey questionnaire by 13 nurses that regularly administered intravenous chemotherapy. These data were then augmented by those attained from follow-up, semi-structured interviews that were conducted with three of the sample. It determined that perceptions of scalp cooling were influenced by individuals' subjective notions of its efficacy constructed from their experiences of having administered scalp cooling. Furthermore, attempts to prevent hair loss were mediated by their cognitions of the experience of hair loss itself. This study determined that views held about scalp cooling varied considerably, and that it was unlikely to be offered to all suitable patients or administered in a systematic manner. Such variation in provision has implications both for patients wishing to access this treatment and for nurses wishing to audit its use and efficacy.

The PHQ-2 and PHQ-9 modules are an effective means of depression screening in a busy, outpatient clinic. A high prevalence of depression was reported; yet, suicidal ideation was not reported. Depression severity ranged from mild to severe. The most endorsed PHQ-9 item was fatigue, although it is uncertain if this reflects a symptom of depression, a sequela of lung cancer itself, or both. The lung cancer patients in this sample who reported depression were unlikely to receive mental health services.

Patients with a -ΔPlt were more likely to respond to TKI therapy and had longer OS. +ΔPlt above baseline had a high specificity for PD after primary TKI. Further investigation is required to determine the utility of ΔPlt.

BackgroundRadiation recall pneumonitis (RRP) is a poorly understood clinical syndrome in which patients develop radiation pneumonitis triggered by a systemic agent, often years after the completion of radiation therapy. Immune checkpoint blockade agents have only recently been posited as a trigger for RRP. Here, we present three cases of immunotherapy-induced RRP.Case PresentationOur first patient was diagnosed with primary lung adenocarcinoma, and 4.5 years after completing radiation therapy developed symptomatic RRP immediately following a second dose of nivolumab-containing immunotherapy regimen. Our second patient was diagnosed with primary bladder cancer metastatic to the mediastinum, which was treated twice with radiation therapy. He developed RRP in the days following his second course of ipilimumab-pembrolizumab which was months after his second course of radiation that he received. Our final patient was diagnosed with metastatic small cell lung cancer and received local consolidative radiation therapy in addition to whole-brain radiation. He developed RRP on the 11th day after concluding his 4th cycle of nivolumab-ipilimumab, approximately 7 months after having had completed chest radiation therapy.ConclusionsImmunotherapy-induced RRP is a rare diagnosis which can present more focally than traditional immunotherapy pneumonitis and which must be clinically differentiated from other local processes such as pneumonia. Further research should explore the mechanisms underlying these radiation recall reactions as many patients receive radiation and immunotherapy during the course of their cancer treatment.

BackgroundIn this study, we evaluated the potential of DNA polymerase epsilon (POLE) and DNA polymerase delta 1 (POLD1) as prognostic biomarkers for immune checkpoint inhibitor (ICI) treatment in patients with advanced stage non‐small cell lung cancer (NSCLC).MethodsDisease stage, PD‐L1 positivity, histological subtypes, POLE/POLD1 mutation status, tumor mutation burden (TMB), and response to ICIs in NSCLC cases were derived from AACR GENIE dataset (n = 24 120), TCGA‐Pan Lung Cancer dataset (n = 1144), AACR GENIE BPC NSCLC v2.0‐public (n = 2004), and Memorial Sloan Kettering‐Integrated Mutation Profiling of Actionable Cancer Targets dataset (n = 350). The smoking history from TCGA and AACR GENIE datasets was grouped into current, former or never‐smokers.ResultsPOLE and POLD1 genetic alterations were identified in 5% and 2.6% of NSCLC patients, respectively. Current smokers had 9% and 4% of POLE/POLD1 mutations, respectively, versus 1.7% for both POLE and POLD1 mutations prevalence in never‐smokers. POLE/POLD1 mutations were associated with elevated mutation counts than those with wild‐type (median mutation counts 16 vs. 7, p < 0.0001), more advanced disease stages (stage I disease 15.19% vs. 29.42%), more prevalent squamous histology subtype (21.69% vs. 9.05%, p = 0.0427), and a higher percentage of PD‐L1 positivity (66.67% vs. 43.87%, p < 0.001). Treatment with ICIs improved survival in patients with both POLE/POLD1 mutated and those with TMB > 18 (p < 0.001).ConclusionCurrent smokers have a five‐fold increased risk of having POLE mutations than never‐smokers. POLE/POLD1 mutation status and TMB > 18 can be a composite biomarker for selecting NSCLC patients with survival benefits to ICI treatment.