The Prognostic Significance of Homologous Recombination Repair Pathway Alterations in Metastatic Hormone Sensitive Prostate Cancer.

INTRODUCTION: The homologous recombination repair (HRR) pathway is a frequently mutated pathway in advanced prostate cancer. The clinical course of patients with HRR gene alterations who have metastatic hormone sensitive prostate cancer (mHSPC) has not been fully characterized. Here, we examine the outcomes of men with mHSPC with HRR alterations. METHODS: We conducted a single-center retrospective analysis of men with mHSPC who underwent next generation sequencing. The primary objective was to assess the time from diagnosis of mHSPC to metastatic castrate resistance prostate cancer (mCRPC) in patients with pathogenic HRR alterations compared to individuals lacking these alterations. Key secondary objectives included time to mCRPC in prespecified cohorts, PSA response, and overall survival. RESULTS: 151 men with mHSPC were identified for the study. 24% (N = 37) had pathogenic HRR gene alterations detected with the most common alterations found in BRCA2 (n = 15), ATM (n = 10), and CDK12 (n = 7). Time to mCRPC was significantly decreased in patients with HRR gene alterations versus those without such alterations (12.7 vs. 16.1 months, HR 1.95, P = .02). In multivariate analysis, the effect of HRR gene alterations on time to CRPC remained significant when adjusting for age, mHSPC therapy, the volume of disease, the presence of visceral metastases, and PSA (adjusted HR 1.69, P = .02). Stratified by specific HRR gene alteration, patients with BRCA2 or CDK12 had significantly decreased time to mCRPC compared to other HRR alterations. CONCLUSION: HRR gene alterations are associated with the worse outcomes in mHSPC with significantly shorter time to mCRPC. Given the established role of Poly (ADP-ribose) Polymerase (PARP) inhibitors in mCRPC, these data highlight an opportunity to examine PARP inhibitors earlier in the clinical course for prostate cancer patients. Ongoing prospective studies will further validate the role of PARP inhibitors in mHSPC patients.

Germline alterations among Hispanic men with prostate cancer.

BACKGROUND: Little is known about the true rate of pathogenic (P)/likely pathogenic (LP) germline alterations in Hispanic men with prostate cancer as most studies analyzing the prevalence of P/LP germline alterations were performed in a largely non-Hispanic white population (NHW). METHODS: We performed a retrospective analysis of two separate cohorts of men with prostate cancer: (1) a multicenter cohort of 17,256 men who underwent germline testing in a CLIA-certified laboratory and (2) a single-center cohort of all men eligible for germline testing between 2018 and 2020. The proportions of P/LP alterations and variants of uncertain significance (VUS) were computed. Fisher's exact test was used to compare germline alteration rates for significance. A multivariate logistic regression was performed adjusting for demographic and clinical factors to examine factors associated with germline testing. RESULTS: In the multicenter cohort, the rate of P/LP germline alterations among self-reported Hispanic men was 7.1%, which was lower than self-reported NHW men (9.7% vs. 7.1%, p = 0.058), but was not statistically significant. The VUS rate was significantly higher among the Hispanic cohort (21.5% vs. 16.6%, p = 0.005). In the single-center cohort, 136 Hispanic patients were eligible for testing of which 34 underwent germline testing (26.1%, N = 34/136). Of all prostate cancer patients in the single-center cohort undergoing germline testing (n = 173), the rate of P/LP alterations in Hispanic patients was not significantly different compared to NHW patients (14.7% vs. 12.2%, p = 0.77). The rate of VUS in Hispanic patients was significantly higher than that of NHW patients (20.6% vs. 7.2%, p = 0.047). CONCLUSION: The P/LP germline alteration rate in our cohorts was similar between Hispanic and NHW men. The rate of VUS was significantly higher in Hispanic men, a consequence of undertesting in minority populations. These data support that Hispanic men with prostate cancer should be screened for germline testing similar to NHW men.

Radiation Recall Pneumonitis After Treatment With Checkpoint Blockade Immunotherapy: A Case Series and Review of Literature.

BACKGROUND: Radiation 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 PRESENTATION: Our 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. CONCLUSIONS: Immunotherapy-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.

Combined Androgen Blockade in Localized Prostate Cancer Treated With Definitive Radiation Therapy.

BACKGROUND: The addition of androgen deprivation therapy to radiation therapy (RT) improves survival in patients with intermediate- and high-risk prostate cancer (PCa), but it is not known whether combined androgen blockade (CAB) with a gonadotropin-releasing hormone agonist (GnRH-A) and a nonsteroidal antiandrogen improves survival over GnRH-A monotherapy. METHODS: This study evaluated patients with intermediate- and high-risk PCa diagnosed in 2001 through 2015 who underwent RT with either GnRH-A alone or CAB using the Veterans Affairs Informatics and Computing Infrastructure. Associations between CAB and prostate cancer-specific mortality (PCSM) and overall survival (OS) were determined using multivariable regression with Fine-Gray and multivariable Cox proportional hazards models, respectively. For a positive control, the effect of long-term versus short-term GnRH-A therapy was tested. RESULTS: The cohort included 8,423 men (GnRH-A, 4,529; CAB, 3,894) with a median follow-up of 5.9 years. There were 1,861 deaths, including 349 resulting from PCa. The unadjusted cumulative incidences of PCSM at 10 years were 5.9% and 6.9% for those receiving GnRH-A and CAB, respectively (P=.16). Compared with GnRH-A alone, CAB was not associated with a significant difference in covariate-adjusted PCSM (subdistribution hazard ratio [SHR], 1.05; 95% CI, 0.85-1.30) or OS (hazard ratio, 1.02; 95% CI, 0.93-1.12). For high-risk patients, long-term versus short-term GnRH-A therapy was associated with improved PCSM (SHR, 0.74; 95% CI, 0.57-0.95) and OS (SHR, 0.82; 95% CI, 0.73-0.93). CONCLUSIONS: In men receiving definitive RT for intermediate- or high-risk PCa, CAB was not associated with improved PCSM or OS compared with GnRH alone.

Does timing of targeted therapy for metastatic renal cell carcinoma impact treatment toxicity and surgical complications? A comparison of primary and adjuvant approaches.

INTRODUCTION: To compare surgical complications and tyrosine kinase inhibitor (TKI)-toxicities in patients who underwent primary cytoreductive nephrectomy (CN) followed by adjuvant TKI therapy versus those who underwent neoadjuvant TKI therapy prior to planned CN for metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: Two-center retrospective analysis. Sixty-one mRCC patients underwent TKI therapy with sunitinib between July 2007 to January 2014. Patients were divided into three groups: primary CN followed by adjuvant TKI (n = 27, Group 1), neoadjuvant TKI prior to CN (n = 21, Group 2), and primary TKI alone (no surgery, n = 13, Group 3). Primary outcome was frequency and severity of surgical complications (Clavien). Secondary outcome was frequency and severity of TKI-related toxicities (NIH Common Toxicity Criteria). Multivariable analysis was carried out for factors associated with complications. RESULTS: There were no significant differences in demographics, ECOG status, and median number TKI cycles (p = 0.337). Mean tumor size (cm) was larger in Group 3 (12.8) than Group 2 (8.9) and Group 1 (9.3), p = 0.014. TKI-related toxicities occurred in 100%, 90.5%, and 88.9% in Group 3, Group 2, and Group 1 (p = 0.469). There was no difference in incidence of high grade (p = 0.967) and low grade (p = 0.380) TKI-toxicities. Overall surgical complication rate was similar between Group 2 (47.6%) and Group 1 (33.3%), p = 0.380. Group 2 had more high grade surgical complications (28.6%) than Group 1 (0%), p = 0.004. Multivariable analysis demonstrated increasing age was independently associated with development of surgical complications (HR 1.059, p = 0.040). CONCLUSION: Patients receiving neoadjuvant TKI therapy prior to CN experienced more high grade surgical complications than patients who underwent primary CN. Potential for increased high grade surgical complications requires further investigation and may impact pretreatment counseling.

Molecular aberrations, targeted therapy, and renal cell carcinoma: current state-of-the-art.

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.

Hypersensitivity reactions to carboplatin and cisplatin in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) treatment has changed in the past ten years due to the acceptance of platinum-based adjuvant chemotherapy. In the event of relapse, patients are often retreated with platinum agents. Hypersensitivity reactions to carboplatin are well documented among gynecologic oncology patients. Now that adjuvant chemotherapy is a component of NSCLC treatment, platinum hypersensitivity is also a concern in the lung cancer population. A 74-year-old male developed relapsed NSCLC two years after a lobectomy and adjuvant chemotherapy including carboplatin. He was treated with a carboplatin containing regimen, and experienced hypersensitivity during his 2(nd) cycle (post-relapse). We briefly report four additional cases of platinum sensitivity in NSCLC patients, to highlight the increasing likelihood of platinum hypersensitivity in this "at risk" group. Hypersensitivity reactions to platinum chemotherapeutics occur in NSCLC patients, and patients and treating medical staff should be aware of this serious, treatment-related complication.

Clinic-based depression screening in lung cancer patients using the PHQ-2 and PHQ-9 depression questionnaires: a pilot study.

OBJECTIVES: This study aims to validate the ability to perform depression screening with the patient health questionnaire (PHQ)-2 and PHQ-9 depression modules in a busy, outpatient practice, and to evaluate the prevalence of depression among lung cancer outpatients at our institution. METHODS: In 2010, 64 patients in a thoracic malignancy clinic completed the Patient Health Questionnaire-2. Patients endorsing either one or both items were then given the Patient Health Questionnaire-9, a nine-item depression assessment tool. Patients with mild or worse depression were offered a referral to a mental health care provider. RESULTS: Eighteen of 64 patients (28 %) endorsed one or both items on the PHQ-2. Thirteen of 18 patients with a positive PHQ-2 screen completed the PHQ-9, with mean score of 10.2 (SD 3.91), suggesting moderate depression. PHQ-9 item 4, evaluating fatigue, was positive in 12 patients, and PHQ-9 item 9, evaluating suicidal ideation, was never reported. Only 1 of 18 patients with a positive PHQ-2 screen was being followed by a psychiatrist, and no patient accepted a new referral to a mental health provider. CONCLUSIONS: 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.