Molecular Profiling of Exceptional Responders to Cancer Therapy.

BACKGROUND: The vast majority of metastatic cancers cannot be cured. Palliative treatment may relieve disease symptoms by stopping or slowing cancer growth and may prolong patients' lives, but almost all patients will inevitably develop disease progression after initial response. However, for reasons that are not fully understood, a very few patients will have extraordinary durable responses to standard anticancer treatments. MATERIALS AND METHODS: We analyzed exceptional responders treated at Fox Chase Cancer Center between September 2009 and November 2017. An exceptional response was defined as a complete response lasting more than 1 year or a partial response or stable disease for more than 2 years. Tumor samples were analyzed using an Ambry Genetics test kit with a 142-gene panel. Messenger RNA expression was evaluated using NanoString's nCounter PanCancer Pathways Panel and Immune Profiling Panel and compared with matched controls for gender, age, and cancer type. RESULTS: Twenty-six exceptional responders with metastatic bladder, kidney, breast, lung, ovarian, uterine, and colon cancers were enrolled. Mutations were identified in 45 genes. The most common mutation was an EPHA5 nonsynonymous mutation detected in 87.5% of patients. Mutations in DNA damage repair pathway genes were also frequent, suggesting increased genome instability. We also found varying expression of 73 genes in the Pathways panel and 85 genes in the Immune Profiling panel, many of them responsible for improvement in tumor recognition and antitumor immune response. CONCLUSIONS: The genomic instability detected in our exceptional responders, plus treatment with DNA damage compounds combined with favorable anticancer immunity, may have contributed to exceptional responses to standard anticancer therapies in the patients studied. IMPLICATIONS FOR PRACTICE: With recent advances in the treatment of cancer, there is increased emphasis on the importance of identifying molecular markers to predict treatment outcomes, thereby allowing precision oncology. In this study, it was hypothesized that there is a "specific biologic signature" in the biology of the cancer in long-term survivors that allows sensitivity to systemic therapy and durability of response. Results showed that DNA damage repair pathway alterations, combined with favorable anticancer immunity, may have contributed to exceptional responses. It is very likely that an in-depth examination of outlier responses will become a standard component of drug development in the future.

Nivolumab-associated acute glomerulonephritis: a case report and literature review.

BACKGROUND: Immune checkpoint inhibitors are changing the landscape of oncology treatment as they are significantly improving treatment for multiple malignancies. Nivolumab, an anti-programmed death 1 antibody, is a US Food and Drug Administration-approved treatment for melanoma, non-small cell lung cancer, and kidney cancer but can result in a spectrum of autoimmune side effects. Adverse effects can occur within any organ system in the body including the colon, lung, liver, endocrine systems, or kidneys. CASE PRESENTATION: A 70-year-old male with clear cell kidney cancer was admitted with acute kidney injury while on nivolumab. A kidney biopsy revealed diffuse tubular injury and immune complex-mediated glomerulonephritis. Electron microscopy of the specimen showed hump-like subepithelial deposits. Nivolumab was discontinued and the patient was started on a high dose of steroids. After 5 months of systemic corticosteroids and hemodialysis, the patient's kidney function improved to his baseline level. Despite a prolonged interruption to treatment, immunosuppressive therapy did not compromise the anticancer effects of nivolumab. CONCLUSION: Immune-related adverse effects in the kidney can cause autoimmune glomerulonephritis as well as tubulointerstitial injury. In the literature, immune-related nephritis generally responded well to systemic corticosteroid treatment. Based on our experience, a prolonged course of a high dose of steroids and hemodialysis may be required to achieve an adequate treatment effect.

Clinical encounter with three cancer patients affected by groundwater contamination at Camp Lejeune: a case series and review of the literature.

BACKGROUND: Advanced understanding of tumor biology has recently revealed the complexity of cancer genetics, intra/inter-tumor heterogeneity, and diverse mechanisms of resistance to cancer treatment. In turn, there has been a growing interest in cancer prevention and minimizing exposure to potential environmental carcinogens that surround us. In the 1980s, several chemical carcinogens, including perchloroethylene (PCE), trichloroethylene (TCE), and benzene, were detected in water systems supplying Camp Lejeune, a US Marine Corps Base Camp located in North Carolina. CASE PRESENTATION: This article presents three cases of cancer patients who have lived at Camp Lejeune, and, decades later, came to our clinic located 1000 miles from the original exposure site. The first patient is a young Caucasian man who was diagnosed with T cell acute lymphoblastic leukemia at the age of 37, and the second patient is a Caucasian man who had multiple types of cancer in the prostate, lung, and colon as well as chronic lymphocytic leukemia in his 60s and 70s. The third patient is another Caucasian man who had recurrent skin cancers of different histology, namely basal cell carcinomas, squamous cell carcinomas, and melanoma, from his 50s to 70s. CONCLUSIONS: The US Congress passed the Honoring America's Veterans and Caring for Camp Lejeune Families Act in 2012, which covers appropriate medical care for the people affected by the contamination. We hope that this article raises awareness about the history of Camp Lejeune's water contamination among cancer care providers, so the affected patients can receive appropriate medical coverage and cancer screening across the country.

Squamous cell carcinoma of head and neck: what internists should know.

Squamous cell carcinoma of head and neck (SCCHN) is a group of cancer arising from mucosal surfaces of the head and neck. Optimal management of SCCHN requires a multidisciplinary team of surgical oncologists, radiation oncologists, medical oncologists, nutritionist, and speech-language pathologists, due to the complexity of anatomical structure and importance of functional outcome. Human papilloma virus (HPV)-related SCCHN represents a distinct subset from HPV negative SCCHN which is associated with carcinogen exposure such as cigarette smoking, betel nut use and alcohol. HPV related SCCHN responds better to concurrent chemoradiation and has better overall prognosis, compared to HPV negative SCCHN. Radiation therapy has been introduced to the treatment of SCCHN, administered concurrently with systemic chemotherapy for locoregional SCCHN, as well as a palliative measure for recurrent and/or metastatic (R/M) SCCHN. Recently, immune checkpoint inhibitors have been shown to improve overall survival in R/M-SCCHN and have been incorporated into the standard of care. Combination approaches with immune therapy and targeted therapy for biomarker enriched population based on genomics are being actively investigated and will shape the future of SCCHN treatment.

Targeting phosphoinositide 3-kinase (PI3K) in head and neck squamous cell carcinoma (HNSCC).

The landscape of head and neck squamous cell carcinoma (HNSCC) has been changing rapidly due to growing proportion of HPV-related disease and development of new therapeutic agents. At the same time, there has been a constant need for individually tailored treatment based on genetic biomarkers in order to optimize patient survival and alleviate treatment-related toxicities. In this regard, aberrations of PI3K pathway have important clinical implications in the treatment of HNSCC. They frequently constitute 'gain of function' mutations which trigger oncogenesis, and PI3K mutations can also lead to emergence of drug resistance after treatment with EGFR inhibitors. In this article, we review PI3K pathway as a target of treatment for HNSCC and summarize PI3K/mTOR inhibitors that are currently under clinical trials. In light of recent advancement of immune checkpoint inhibitors, consideration of PI3K inhibitors as potential immune modulators is also suggested.

Androgen deprivation therapy is associated with decreased second primary lung cancer risk in the United States veterans with prostate cancer.

OBJECTIVES: We investigated whether androgen deprivation therapy (ADT) in prostate cancer patients was associated with a decreased risk for second primary lung cancer in US veterans. METHODS: Prostate cancer diagnoses in the US Veterans Affairs Cancer Registry between 1999 and 2008 were identified. Use of hormonal therapy and diagnoses of second primary lung cancer were determined from the registry. Synchronous prostate and lung cancers, defined as 2 diagnoses made within 1 year, were excluded from the analysis. Cancer-free survival was estimated using the Kaplan-Meier method and hazard ratios were estimated using Cox proportional hazard models. RESULTS: Among the 63,141 identified patients with prostate cancer, 18,707 subjects were eligible for the study. Hormonal therapy was used in 38% of patients and the median follow-up period was 28 months. ADT use was associated with longer lung cancer-free survival in prostate cancer patients (log-rank p=0.01). After adjusting for age, race, smoking and prostate cancer stage, ADT use was associated with decreased lung cancer risk by 15, 21, and 24% after 1, 2, and 3 years, respectively. CONCLUSIONS: ADT in prostate cancer patients may be associated with decreased second primary lung cancer risk among US veterans.

BRCA2, EGFR, and NTRK mutations in mismatch repair-deficient colorectal cancers with MSH2 or MLH1 mutations.

Deficient mismatch repair (MMR) and microsatellite instability (MSI) contribute to ~15% of colorectal cancer (CRCs). We hypothesized MSI leads to mutations in DNA repair proteins including BRCA2 and cancer drivers including EGFR. We analyzed mutations among a discovery cohort of 26 MSI-High (MSI-H) and 558 non-MSI-H CRCs profiled at Caris Life Sciences. Caris-profiled MSI-H CRCs had high mutation rates (50% vs 14% in non-MSI-H, P < 0.0001) in BRCA2. Of 1104 profiled CRCs from a second cohort (COSMIC), MSH2/MLH1-mutant CRCs showed higher mutation rates in BRCA2 compared to non-MSH2/MLH1-mutant tumors (38% vs 6%, P < 0.0000001). BRCA2 mutations in MSH2/MLH1-mutant CRCs included 75 unique mutations not known to occur in breast or pancreatic cancer per COSMIC v73. Only 5 deleterious BRCA2 mutations in CRC were previously reported in the BIC database as germ-line mutations in breast cancer. Some BRCA2 mutations were predicted to disrupt interactions with partner proteins DSS1 and RAD51. Some CRCs harbored multiple BRCA2 mutations. EGFR was mutated in 45.5% of MSH2/MLH1-mutant and 6.5% of non-MSH2/MLH1-mutant tumors (P < 0.0000001). Approximately 15% of EGFR mutations found may be actionable through TKI therapy, including N700D, G719D, T725M, T790M, and E884K. NTRK gene mutations were identified in MSH2/MLH1-mutant CRC including NTRK1 I699V, NTRK2 P716S, and NTRK3 R745L. Our findings have clinical relevance regarding therapeutic targeting of BRCA2 vulnerabilities, EGFR mutations or other identified oncogenic drivers such as NTRK in MSH2/MLH1-mutant CRCs or other tumors with mismatch repair deficiency.

Small-Cell Carcinoma of the Bladder: 20-Year Single-Institution Retrospective Review.

INTRODUCTION: Small-cell carcinoma of the bladder is a poorly differentiated neoplasm with aggressive behavior. We analyzed clinical outcomes of patients who were treated at our institution to identify an optimal treatment strategy. MATERIALS AND METHODS: Retrospective chart analysis was performed for patients who were treated for small-cell carcinoma of the bladder at Fox Chase Cancer Center between 1995 and 2015. Survival was compared between different treatment periods (before January 2010 vs. after January 2010) and different treatment modalities (surgery vs. neoadjuvant chemotherapy vs. radiation). RESULTS: Thirty-eight patients were treated for small-cell carcinoma of the bladder at our institution during the 20-year study period. Median survival was 11.8 months and overall survival rates after 1, 3, and 5 years were 46.6%, 26.2%, and 14%, respectively. Survival analysis adjusted for age, histology, and stage showed that no single treatment strategy was significantly superior (95% confidence interval [CI], 0.26-3.03; P = .860 for surgery; 95% CI, 0.31-2.87; P = .928 for neoadjuvant chemotherapy; 95% CI, 0.65-5.49; P = .238 for radiation). In separate analyses of long-term survivors, we found that most received platinum-based neoadjuvant chemotherapy followed by radical cystectomy. Among the 20 patients who received neoadjuvant chemotherapy, downstaging occurred in 9 (45%). CONCLUSION: Although none of the treatment options were found to be significantly superior with respect to survival, neoadjuvant chemotherapy might halt the progression of the disease until cystectomy and lead to downstaging. At our institution, the best outcomes were observed in patients who received neoadjuvant platinum-based chemotherapy combined with radical cystectomy.