Showing papers in "JAMA Oncology in 2015"

The Global Burden of Cancer 2013

Abstract: Importance Cancer is among the leading causes of death worldwide. Current estimates of cancer burden in individual countries and regions are necessary to inform local cancer control strategies. Objective To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 28 cancers in 188 countries by sex from 1990 to 2013. Evidence Review The general methodology of the Global Burden of Disease (GBD) 2013 study was used. Cancer registries were the source for cancer incidence data as well as mortality incidence (MI) ratios. Sources for cause of death data include vital registration system data, verbal autopsy studies, and other sources. The MI ratios were used to transform incidence data to mortality estimates and cause of death estimates to incidence estimates. Cancer prevalence was estimated using MI ratios as surrogates for survival data; YLDs were calculated by multiplying prevalence estimates with disability weights, which were derived from population-based surveys; YLLs were computed by multiplying the number of estimated cancer deaths at each age with a reference life expectancy; and DALYs were calculated as the sum of YLDs and YLLs. Findings In 2013 there were 14.9 million incident cancer cases, 8.2 million deaths, and 196.3 million DALYs. Prostate cancer was the leading cause for cancer incidence (1.4 million) for men and breast cancer for women (1.8 million). Tracheal, bronchus, and lung (TBL) cancer was the leading cause for cancer death in men and women, with 1.6 million deaths. For men, TBL cancer was the leading cause of DALYs (24.9 million). For women, breast cancer was the leading cause of DALYs (13.1 million). Age-standardized incidence rates (ASIRs) per 100 000 and age-standardized death rates (ASDRs) per 100 000 for both sexes in 2013 were higher in developing vs developed countries for stomach cancer (ASIR, 17 vs 14; ASDR, 15 vs 11), liver cancer (ASIR, 15 vs 7; ASDR, 16 vs 7), esophageal cancer (ASIR, 9 vs 4; ASDR, 9 vs 4), cervical cancer (ASIR, 8 vs 5; ASDR, 4 vs 2), lip and oral cavity cancer (ASIR, 7 vs 6; ASDR, 2 vs 2), and nasopharyngeal cancer (ASIR, 1.5 vs 0.4; ASDR, 1.2 vs 0.3). Between 1990 and 2013, ASIRs for all cancers combined (except nonmelanoma skin cancer and Kaposi sarcoma) increased by more than 10% in 113 countries and decreased by more than 10% in 12 of 188 countries. Conclusions and Relevance Cancer poses a major threat to public health worldwide, and incidence rates have increased in most countries since 1990. The trend is a particular threat to developing nations with health systems that are ill-equipped to deal with complex and expensive cancer treatments. The annual update on the Global Burden of Cancer will provide all stakeholders with timely estimates to guide policy efforts in cancer prevention, screening, treatment, and palliation.

Validity and Reliability of the US National Cancer Institute’s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

Abstract: Importance To integrate the patient perspective into adverse event reporting, the National Cancer Institute developed a patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Objective To assess the construct validity, test-retest reliability, and responsiveness of PRO-CTCAE items. Design, Setting, and Participants A total of 975 adults with cancer undergoing outpatient chemotherapy and/or radiation therapy enrolled in this questionnaire-based study between January 2011 and February 2012. Eligible participants could read English and had no clinically significant cognitive impairment. They completed PRO-CTCAE items on tablet computers in clinic waiting rooms at 9 US cancer centers and community oncology practices at 2 visits 1 to 6 weeks apart. A subset completed PRO-CTCAE items during an additional visit 1 business day after the first visit. Main Outcomes and Measures Primary comparators were clinician-reported Eastern Cooperative Oncology Group Performance Status (ECOG PS) and the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30). Results A total of 940 of 975 (96.4%) and 852 of 940 (90.6%) participants completed PRO-CTCAE items at visits 1 and 2, respectively. At least 1 symptom was reported by 938 of 940 (99.8%) participants. Participants’ median age was 59 years; 57.3% were female, 32.4% had a high school education or less, and 17.1% had an ECOG PS of 2 to 4. All PRO-CTCAE items had at least 1 correlation in the expected direction with a QLQ-C30 scale (111 of 124, P P r = 0.43 [0.10-.56]; all P ≤ .006). Conclusions and Relevance Evidence demonstrates favorable validity, reliability, and responsiveness of PRO-CTCAE in a large, heterogeneous US sample of patients undergoing cancer treatment. Studies evaluating other measurement properties of PRO-CTCAE are under way to inform further development of PRO-CTCAE and its inclusion in cancer trials.

Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer

Abstract: Importance We previously showed that detection of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer (CRPC) was associated with primary resistance to enzalutamide and abiraterone therapy, but the relevance of AR-V7 status in the context of chemotherapy is unknown. Objective To investigate whether AR-V7–positive patients would retain sensitivity to taxane chemotherapy and whether AR-V7 status would have a differential impact on taxane-treated men compared with enzalutamide- or abiraterone-treated men. Design, Setting, and Participants We examined CTCs for AR-V7 mRNA using a reverse-transcription polymerase chain reaction assay. From January 2013 to July 2014, we prospectively enrolled patients with metastatic CRPC initiating taxane chemotherapy (docetaxel or cabazitaxel) at a single academic institution (Johns Hopkins). Our prespecified statistical plan required a sample size of 36 taxane-treated men. Main Outcomes and Measures We evaluated associations between AR-V7 status and prostate-specific antigen (PSA) response rates, PSA progression-free survival (PSA PFS), and clinical and/or radiographic progression-free survival (PFS). After incorporating updated data from our prior study of 62 patients treated with enzalutamide or abiraterone, we also investigated the interaction between AR-V7 status (positive or negative) and treatment type (taxane vs enzalutamide or abiraterone). Results Of 37 taxane-treated patients enrolled, 17 (46%) had detectable AR-V7 in CTCs. Prostate-specific antigen responses were achieved in both AR-V7–positive and AR-V7–negative men (41% vs 65%; P = .19). Similarly, PSA PFS (hazard ratio [HR], 1.7, 95% CI, 0.6-5.0; P = .32) and PFS (HR, 2.7, 95% CI, 0.8-8.8; P = .11) were comparable in AR-V7–positive and AR-V7–negative patients. A significant interaction was observed between AR-V7 status and treatment type ( P P P = .001; HR, 0.21 [95% CI, 0.07-0.59] for PFS, P = .003). Conclusions and Relevance Detection of AR-V7 in CTCs from men with metastatic CRPC is not associated with primary resistance to taxane chemotherapy. In AR-V7–positive men, taxanes appear to be more efficacious than enzalutamide or abiraterone therapy, whereas in AR-V7–negative men, taxanes and enzalutamide or abiraterone may have comparable efficacy. Circulating tumor cell–based AR-V7 detection may serve as a treatment selection biomarker in CRPC.

Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond

Abstract: Importance E-cadherin ( CDH1 ) is a cancer predisposition gene mutated in families meeting clinically defined hereditary diffuse gastric cancer (HDGC). Reliable estimates of cancer risk and spectrum in germline mutation carriers are essential for management. For families without CDH1 mutations, genetic-based risk stratification has not been possible, resulting in limited clinical options. Objectives To derive accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and determine if germline mutations in other genes are associated with HDGC. Design, Setting, and Participants Testing for CDH1 germline mutations was performed on 183 index cases meeting clinical criteria for HDGC. Penetrance was derived from 75 mutation-positive families from within this and other cohorts, comprising 3858 probands (353 with gastric cancer and 89 with breast cancer). Germline DNA from 144 HDGC probands lacking CDH1 mutations was screened using multiplexed targeted sequencing for 55 cancer-associated genes. Main Outcomes and Measures Accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and the relative contribution of other cancer predisposition genes in familial gastric cancers. Results Thirty-one distinct pathogenic CDH1 mutations (14 novel) were identified in 34 of 183 index cases (19%). By the age of 80 years, the cumulative incidence of gastric cancer was 70% (95% CI, 59%-80%) for males and 56% (95% CI, 44%-69%) for females, and the risk of breast cancer for females was 42% (95% CI, 23%-68%). In CDH1 mutation–negative index cases, candidate mutations were identified in 16 of 144 probands (11%), including mutations within genes of high and moderate penetrance: CTNNA1 , BRCA2 , STK11 , SDHB , PRSS1 , ATM , MSR1 , and PALB2 . Conclusions and Relevance This is the largest reported series of CDH1 mutation carriers, providing more precise estimates of age-associated risks of gastric and breast cancer that will improve counseling of unaffected carriers. In HDGC families lacking CDH1 mutations, testing of CTNNA1 and other tumor suppressor genes should be considered. Clinically defined HDGC families can harbor mutations in genes (ie, BRCA2) with different clinical ramifications from CDH1 . Therefore, we propose that HDGC syndrome may be best defined by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles.

Role of Local Radiation Therapy in Cancer Immunotherapy

Abstract: The recent success of cancer immunotherapy has demonstrated the power of the immune system to clear tumors, generating renewed enthusiasm for identifying ways to induce antitumor immune responses in patients. Natural antitumor immune responses are detectable in a fraction of patients across multiple malignant neoplasms and can be reactivated by targeting rate-limiting immunosuppressive mechanisms. In most patients, however, interventions to induce a de novo antitumor immune response are necessary. We review growing evidence that radiation therapy targeted to the tumor can convert it into an in situ tumor vaccine by inducing release of antigens during cancer cell death in association with proinflammatory signals that trigger the innate immune system to activate tumor-specific T cells. In addition, radiation’s effects on the tumor microenvironment enhance infiltration of activated T cells and can overcome some of the barriers to tumor rejection. Thus, the complementary effects of radiation on priming and effector phases of antitumor immunity make it an appealing strategy to generate immunity against a patient’s own individual tumor, that through immunological memory, can result in long-lasting systemic responses. Several anecdotal cases have demonstrated the efficacy of combining radiation with available immunotherapies, and results of prospective trials are forthcoming.

Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia

Abstract: Importance The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in patients with chronic lymphocytic leukemia (CLL). Reasons for discontinuing therapy with this drug and outcomes following discontinuation have not been evaluated outside of clinical trials with relatively short follow-up. Objective To determine features associated with discontinuation of ibrutinib therapy and outcomes. Design, Setting, and Participants A total of 308 patients participating in 4 sequential trials of ibrutinib at The Ohio State University Comprehensive Cancer Center were included. These clinical trials accrued patients included in this analysis from May 2010 until April 2014, and data were locked in June 2014. Main Outcomes and Measures Patients were evaluated for time to therapy discontinuation, reasons for discontinuation, and survival following discontinuation. For patients who discontinued therapy because of disease progression, targeted deep sequencing was performed in samples at baseline and time of relapse. Results With a median follow-up of 20 months, 232 patients remained on therapy, 31 had discontinued because of disease progression, and 45 had discontinued for other reasons. Disease progression includes Richter’s transformation (RT) or progressive CLL. Richter’s transformation appeared to occur early and CLL progressions later (cumulative incidence at 12 months, 4.5% [95% CI, 2.0%-7.0%] and 0.3% [95% CI, 0%-1.0%], respectively). Median survival following RT was 3.5 months (95% CI, 0.3-6.0 months) and 17.6 months (95% CI, 4.7 months–“not reached”) following CLL progression. Sequencing on peripheral blood from 8 patients with RT revealed 2 with mutations in BTK , and a lymph node sample showed no mutations in BTK or PLCG2 . Deep sequencing on 11 patients with CLL progression revealed BTK or PLCG2 mutations in all. These mutations were not identified before treatment in any patient. Conclusions and Relevance This single-institution experience with ibrutinib confirms it to be an effective therapy and identifies, for the first time, baseline factors associated with ibrutinib therapy discontinuation. Outcomes data show poor prognosis after discontinuation, especially for those patients with RT. Finally, sequencing data confirm initial reports associating mutations in BTK and PLCG2 with progression and clearly show that CLL progressions are associated with these mutations, while RT is likely not. Trial Registrations clinicaltrials.gov Identifiers:NCT01105247,NCT01217749,NCT01589302, andNCT01578707

Association of Polymerase e–Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1

Abstract: Importance Immune checkpoint inhibitor therapy has shown benefit in various cancers, but their potential in endometrial cancer (EC) is unknown. Observations Prediction of neoantigen load was performed using sequencing data from the Cancer Genome Atlas data set. Evaluation of tumor-infiltrating lymphocytes (TILs) and PD-1 and PD-L1 expression was performed in 63 patients with EC referred to our institution. The predicted median (range) neoantigen load (predicted neoepitopes per sample) was proportional to the mutational load: highest in ultramutated polymerase e (POLE) tumors (8342 [628-20 440]), less in hypermutated MSI (541 [146-8063]; P P + (44.5 vs 21.8; P = .001) and CD8 + (32.8 vs 13.5; P P P P = .02). Conclusions and Relevance Polymerase e–mutated and MSI ECs are associated with high neoantigen loads and number of TILs, which is counterbalanced by overexpression of PD-1 and PD-L1. Polymerase e–mutated and MSI EC tumors may be excellent candidates for PD-1–targeted immunotherapies.

Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab A Secondary Analysis of the NeoALTTO Trial

Abstract: Importance The presence of tumor-infiltrating lymphocytes (TILs) is associated with improved outcomes in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer treated with adjuvant trastuzumab and chemotherapy. The prognostic associations in the neoadjuvant setting of other anti-HER2 agents and combinations are unknown. Objective To determine associations between presence of TILs, pathological complete response (pCR), and event-free survival (EFS) end points in patients with early breast cancer treated with trastuzumab, lapatinib, or the combination. Design, Setting, and Participants The NeoALTTO trial (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) randomly assigned 455 women with HER2-positive early-stage breast cancer between January 5, 2008, and May 27, 2010, to 1 of 3 neoadjuvant treatment arms: trastuzumab, lapatinib, or the combination for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide after surgery. The primary end point used in this study was pCR in the breast and lymph nodes, with a secondary end point of EFS. We evaluated levels of percentage of TILs using hematoxylin-eosin–stained core biopsy sections taken at diagnosis (prior to treatment) in a prospectively defined retrospective analysis. Main Outcomes and Measures Levels of TILs were examined for their associations with efficacy end points adjusted for prognostic clinicopathological factors including PIK3CA genotype. Results Of the 455 patients, 387 (85.1%) tumor samples were used for the present analysis. The median (interquartile range [IQR]) level of TILs was 12.5% (5.0%-30.0%), with levels lower in hormone receptor–positive (10.0% [5.0%-22.5%]) vs hormone receptor–negative (12.5% [3.0%-35.0%]) samples ( P = .02). For the pCR end point, levels of TILs greater than 5% were associated with higher pCR rates independent of treatment group (adjusted odds ratio, 2.60 [95% CI, 1.26-5.39]; P = .01). With a median (IQR) follow-up time of 3.77 (3.50-4.22) years, every 1% increase in TILs was associated with a 3% decrease in the rate of an event (adjusted hazard ratio, 0.97 [95% CI, 0.95-0.99]; P = .002) across all treatment groups. Conclusions and Relevance The presence of TILs at diagnosis is an independent, positive, prognostic marker in HER2-positive early breast cancer treated with neoadjuvant anti-HER2 agents and chemotherapy for both pCR and EFS end points. Trial Registration clinicaltrials.gov Identifier: NCT00553358

Breast Cancer Mortality After a Diagnosis of Ductal Carcinoma In Situ

Abstract: Importance Women with ductal carcinoma in situ (DCIS), or stage 0 breast cancer, often experience a second primary breast cancer (DCIS or invasive), and some ultimately die of breast cancer. Objective To estimate the 10- and 20-year mortality from breast cancer following a diagnosis of DCIS and to establish whether the mortality rate is influenced by age at diagnosis, ethnicity, and initial treatment received. Design, Setting, and Participants Observational study of women who received a diagnosis of DCIS from 1988 to 2011 in the Surveillance, Epidemiology, and End Results (SEER) 18 registries database. Age at diagnosis, race/ethnicity, pathologic features, date of second primary breast cancer, cause of death, and survival were abstracted for 108 196 women. Their risk of dying of breast cancer was compared with that of women in the general population. Cox proportional hazards analysis was performed to estimate the hazard ratio (HR) for death from DCIS by age at diagnosis, clinical features, ethnicity, and treatment. Main Outcomes and Measures Ten- and 20-year breast cancer–specific mortality. Results Among the 108 196 women with DCIS, the mean (range) age at diagnosis of DCIS was 53.8 (15-69) years and the mean (range) duration of follow-up was 7.5 (0-23.9) years. At 20 years, the breast cancer–specific mortality was 3.3% (95% CI, 3.0%-3.6%) overall and was higher for women who received a diagnosis before age 35 years compared with older women (7.8% vs 3.2%; HR, 2.58 [95% CI, 1.85-3.60];P Conclusions and Relevance Important risk factors for death from breast cancer following a DCIS diagnosis include age at diagnosis and black ethnicity. The risk of death increases after a diagnosis of an ipsilateral second primary invasive breast cancer, but prevention of these recurrences by radiotherapy does not diminish breast cancer mortality at 10 years.

Overweight, Obesity, and Postmenopausal Invasive Breast Cancer Risk: A Secondary Analysis of the Women’s Health Initiative Randomized Clinical Trials

Abstract: Importance More than two-thirds of US women are overweight or obese, placing them at increased risk for postmenopausal breast cancer. Objective To investigate in this secondary analysis the associations of overweight and obesity with risk of postmenopausal invasive breast cancer after extended follow-up in the Women’s Health Initiative (WHI) clinical trials. Design, Setting, and Participants The WHI clinical trial protocol incorporated measured height and weight, baseline and annual or biennial mammography, and adjudicated breast cancer end points in 67 142 postmenopausal women ages 50 to 79 years at 40 US clinical centers. The women were enrolled from 1993 to 1998 with a median of 13 years of follow-up through 2010; 3388 invasive breast cancers were observed. Main Outcomes and Measures Height and weight were measured at baseline, and weight was measured annually thereafter. Data were collected on demographic characteristics, personal and family medical history, and personal habits (smoking, physical activity). Women underwent annual or biennial mammograms. Breast cancers were verified by medical records reviewed by physician adjudicators. Results Women who were overweight and obese had an increased invasive breast cancer risk vs women of normal weight. Risk was greatest for obesity grade 2 plus 3 (body mass index [BMI], calculated as weight in kilograms divided by height in meters squared, >35.0) (hazard ratio [HR] for invasive breast cancer, 1.58; 95% CI, 1.40-1.79). A BMI of 35.0 or higher was strongly associated with risk for estrogen receptor–positive and progesterone receptor–positive breast cancers (HR, 1.86; 95% CI, 1.60-2.17) but was not associated with estrogen receptor–negative cancers. Obesity grade 2 plus 3 was also associated with advanced disease, including larger tumor size (HR, 2.12; 95% CI, 1.67-2.69; P = .02), positive lymph nodes (HR, 1.89; 95% CI, 1.46-2.45; P = .06), regional and/or distant stage (HR, 1.94; 95% CI, 1.52-2.47; P = .05), and deaths after breast cancer (HR, 2.11; 95% CI, 1.57-2.84; P Conclusions and Relevance Obesity is associated with increased invasive breast cancer risk in postmenopausal women. These clinically meaningful findings should motivate programs for obesity prevention. Trial Registration clinicaltrials.gov Identifier:NCT00000611

Fusobacterium nucleatum and T Cells in Colorectal Carcinoma.

Abstract: Importance Evidence indicates a complex link between gut microbiome, immunity, and intestinal tumorigenesis. To target the microbiota and immunity for colorectal cancer prevention and therapy, a better understanding of the relationship between microorganisms and immune cells in the tumor microenvironment is needed. Experimental evidence suggests thatFusobacterium nucleatummay promote colonic neoplasia development by downregulating antitumor T cell–mediated adaptive immunity. Objective To test the hypothesis that a greater amount ofF nucleatumin colorectal carcinoma tissue is associated with a lower density of T cells in tumor tissue. Design, Setting, and Participants A cross-sectional analysis was conducted on 598 rectal and colon carcinoma cases in 2 US nationwide prospective cohort studies with follow-up through 2006, the Nurses’ Health Study (participants enrolled in 1976) and the Health Professionals Follow-up Study (participants enrolled in 1986). Tissue collection and processing were performed from 2002 through 2008, and immunity assessment, 2008 through 2009. From 2013 through 2014, the amount ofF nucleatumin colorectal carcinoma tissue was measured by quantitative polymerase chain reaction assay; we equally dichotomized positive cases (high vs low). Multivariable ordinal logistic regression analysis was conducted in 2014 to assess associations of the amount ofF nucleatumwith densities (quartiles) of T cells in tumor tissue, controlling for clinical and tumor molecular features, including microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 (LINE-1) methylation, andKRAS,BRAF, andPIK3CAmutation status. We adjusted the 2-sided α level to .013 for multiple hypothesis testing. Main Outcomes and Measures Densities of CD3+, CD8+, CD45RO (protein tyrosine phosphatase receptor type C [PTPRC])+, and FOXP3+T cells in tumor tissue, determined by means of tissue microarray immunohistochemical analysis and computer-assisted image analysis. Results F nucleatumwas detected in colorectal carcinoma tissue in 76 (13%) of 598 cases. Compared withF nucleatum–negative cases,F nucleatum–high cases were inversely associated with the density of CD3+T cells (for a unit increase in quartile categories of CD3+T cells as an outcome: multivariable odds ratio, 0.47 [95% CI, 0.26-0.87];Pfor trend = .006). The amount ofF nucleatumwas not significantly associated with the density of CD8+, CD45RO+, or FOXP3+T cells (P fortrend = .24, .88, and .014, respectively). Conclusions and Relevance The amount of tissueF nucleatumis inversely associated with CD3+T-cell density in colorectal carcinoma tissue. On validation, our human population data may provide an impetus for further investigations on potential interactive roles ofFusobacteriumand host immunity in colon carcinogenesis.

Chemotherapy Use, Performance Status, and Quality of Life at the End of Life

Abstract: Importance Although many patients with end-stage cancer are offered chemotherapy to improve quality of life (QOL), the association between chemotherapy and QOL amid progressive metastatic disease has not been well-studied. American Society for Clinical Oncology guidelines recommend palliative chemotherapy only for solid tumor patients with good performance status. Objective To evaluate the association between chemotherapy use and QOL near death (QOD) as a function of patients’ performance status. Design, Setting, and Participants A multi-institutional, longitudinal cohort study of patients with end-stage cancer recruited between September 2002 and February 2008. Chemotherapy use (n = 158 [50.6%]) and Eastern Cooperative Oncology Group (ECOG) performance status were assessed at baseline (median = 3.8 months before death) and patients with progressive metastatic cancer (N = 312) following at least 1 chemotherapy regimen were followed prospectively until death at 6 outpatient oncology clinics in the United States. Main Outcomes and Measures Patient QOD was determined using validated caregiver ratings of patients’ physical and mental distress in their final week. Results Chemotherapy use was not associated with patient survival controlling for clinical setting and patients’ performance status. Among patients with good (ECOG score = 1) baseline performance status, chemotherapy use compared with nonuse was associated with worse QOD (odds ratio [OR], 0.35; 95% CI, 0.17-0.75;P = .01). Baseline chemotherapy use was not associated with QOD among patients with moderate (ECOG score = 2) baseline performance status (OR, 1.06; 95% CI, 0.51-2.21;P = .87) or poor (ECOG score = 3) baseline performance status (OR, 1.34; 95% CI, 0.46-3.89;P = .59). Conclusions and Relevance Although palliative chemotherapy is used to improve QOL for patients with end-stage cancer, its use did not improve QOD for patients with moderate or poor performance status and worsened QOD for patients with good performance status. The QOD in patients with end-stage cancer is not improved, and can be harmed, by chemotherapy use near death, even in patients with good performance status.

Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial.

Abstract: Importance Myelofibrosis (MF) is a BCR-ABL –negative myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib, a JAK2-selective inhibitor, previously demonstrated clinically beneficial activity in patients with MF in early-phase trials. Objective To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post–polycythemia vera or post–essential thrombocythemia) MF. Design, Setting, and Participants Double-blind, randomized, placebo-controlled phase 3 study in 94 sites in 24 countries in which 289 adult patients (≥18 years of age) with intermediate-2 or high-risk primary MF, post–polycythemia vera MF, or post–essential thrombocythemia MF were randomly assigned between December 2011 and September 2012 to once-daily oral fedratinib, at a dose of 400 mg or 500 mg, or placebo, for at least 6 consecutive 4-week cycles. Main Outcomes and Measures The primary end point was spleen response (≥35% reduction in spleen volume from baseline as determined by magnetic resonance imaging or computed tomography) at week 24 and confirmed 4 weeks later. The main secondary end point was symptom response (≥50% reduction in total symptom score, assessed using the modified Myelofibrosis Symptom Assessment Form). Results The primary end point was achieved by 35 of 96 (36% [95% CI, 27%-46%]) and 39 of 97 (40% [95% CI, 30%-50%]) patients in the fedratinib 400-mg and 500-mg groups, vs 1 of 96 (1% [95% CI, 0%-3%]) in the placebo group ( P P Conclusions and Relevance Fedratinib therapy significantly reduced splenomegaly and symptom burden in patients with MF. These benefits were accompanied by toxic effects in some patients, the most important being encephalopathy of unknown mechanism. Clinical development of fedratinib was subsequently discontinued. Trial Registration clinicaltrials.gov identifier:NCT01437787

Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment.

Abstract: Importance The practice of genetic testing for hereditary breast and/or ovarian cancer (HBOC) is rapidly evolving owing to the recent introduction of multigene panels. While these tests may identify 40% to 50% more individuals with hereditary cancer gene mutations than does testing for BRCA1/2 alone, whether finding such mutations will alter clinical management is unknown. Objective To define the potential clinical effect of multigene panel testing for HBOC in a clinically representative cohort. Design, setting, and participants Observational study of patients seen between 2001 and 2014 in 3 large academic medical centers. We prospectively enrolled 1046 individuals who were appropriate candidates for HBOC evaluation and who lacked BRCA1/2 mutations. Interventions We carried out multigene panel testing on all participants, then determined the clinical actionability, if any, of finding non-BRCA1/2 mutations in these and additional comparable individuals. Main outcomes and measures We evaluated the likelihood of (1) a posttest management change and (2) an indication for additional familial testing, considering gene-specific consensus management guidelines, gene-associated cancer risks, and personal and family history. Results Among 1046 study participants, 40 BRCA1/2-negative patients (3.8%; 95% CI, 2.8%-5.2%) harbored deleterious mutations, most commonly in moderate-risk breast and ovarian cancer genes (CHEK2, ATM, and PALB2) and Lynch syndrome genes. Among these and an additional 23 mutation-positive individuals enrolled from our clinics, most of the mutations (92%) were consistent with the spectrum of cancer(s) observed in the patient or family, suggesting that these results are clinically significant. Among all 63 mutation-positive patients, additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone would be considered for most (33 [52%] of 63; 95% CI, 40.3%-64.2%). Furthermore, additional familial testing would be considered for those with first-degree relatives (42 [72%] of 58; 95% CI, 59.8%-82.2%) based on potential management changes for mutation-positive relatives. This clinical effect was not restricted to a few of the tested genes because most identified genes could change clinical management for some patients. Conclusions and relevance In a clinically representative cohort, multigene panel testing for HBOC risk assessment yielded findings likely to change clinical management for substantially more patients than does BRCA1/2 testing alone. Multigene testing in this setting is likely to alter near-term cancer risk assessment and management recommendations for mutation-affected individuals across a broad spectrum of cancer predisposition genes.

Disparities by Race, Age, and Sex in the Improvement of Survival for Major Cancers: Results From the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program in the United States, 1990 to 2010.

Abstract: Importance Substantial progress has been made in cancer diagnosis and treatment, resulting in a steady improvement in cancer survival. The degree of improvement by age, race, and sex remains unclear. Objective To quantify the degree of survival improvement over time by age, race, and sex in the United States. Design, Setting, and Participants Longitudinal analyses of cancer follow-up data from 1990 to 2010, from 1.02 million patients who had been diagnosed as having cancer of the colon or rectum, breast, prostate, lung, liver, pancreas, or ovary from 1990 to 2009 and who were included in 1 of 9 population-based registries of the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program. Main Outcomes and Measures Hazard ratios (HRs) and 95% CIs for cancer-specific death were estimated for patients diagnosed as having any of these cancers during 1995 to 1999, 2000 to 2004, and 2005 to 2009, compared with those diagnosed in 1990 to 1994. Results Significant improvements in survival were found for cancers of the colon or rectum, breast, prostate, lung, and liver. Improvements were more pronounced for younger patients. For patients aged 50 to 64 years and diagnosed from 2005 to 2009, adjusted HRs (95% CIs) were 0.57 (95% CI, 0.55-0.60), 0.48 (95% CI, 0.45-0.51), 0.61 (95% CI, 0.57-0.69), and 0.32 (95% CI, 0.30-0.36), for cancer of the colon or rectum, breast, liver, and prostate, respectively, compared with the same age groups of patients diagnosed during 1990 to 1994. However, the corresponding HRs (95% CIs) for elderly patients (those 75-85 years old) were only 0.88 (95% CI, 0.84-0.92), 0.88 (95% CI, 0.82-0.95), 0.76 (95% CI, 0.69-0.84), and 0.65 (95% CI, 0.61-0.70), for the same 4 cancer sites, respectively. A similar, although weaker, age-related period effect was observed for lung and pancreatic cancers. The adjusted HRs (95% CIs) for lung cancer were 0.75 (95% CI, 0.73-0.77) and 0.84 (95% CI, 0.81-0.86), respectively, for patients aged 50 to 64 years and 75 to 85 years diagnosed between 2005 and 2009, compared with the same age groups of patients diagnosed between 1990 and 1994 (0.73 [95% CI, 0.69-0.77] and 0.90 [95% CI, 0.85-0.95], respectively. Compared with whites or Asians, African Americans experienced greater improvement in prostate cancer survival. From 1990 to 2009, ovarian cancer survival declined among African Americans but improved among whites. No apparent sex difference in the degree of improvement for any non–sex-specific cancer was noted. Conclusions and Relevance Younger patients experienced greater benefit from recent oncology advances than elderly patients. African Americans experienced poorer survival than whites for all cancers, and the racial difference decreased for prostate cancer but increased for ovarian cancer. Identifying factors associated with varied improvement in cancer survival can inform future improvements in cancer care for all.

Whole-Exome Sequencing of Metastatic Cancer and Biomarkers of Treatment Response.

Abstract: Importance Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low-frequency mutations. We describe a whole-exome sequencing (WES) precision medicine trial focused on patients with advanced cancer. Objective To understand how WES data affect therapeutic decision making in patients with advanced cancer and to identify novel biomarkers of response. Design, Setting, and Patients Patients with metastatic and treatment-resistant cancer were prospectively enrolled at a single academic center for paired metastatic tumor and normal tissue WES during a 19-month period (February 2013 through September 2014). A comprehensive computational pipeline was used to detect point mutations, indels, and copy number alterations. Mutations were categorized as category 1, 2, or 3 on the basis of actionability; clinical reports were generated and discussed in precision tumor board. Patients were observed for 7 to 25 months for correlation of molecular information with clinical response. Main Outcomes and Measures Feasibility, use of WES for decision making, and identification of novel biomarkers. Results A total of 154 tumor-normal pairs from 97 patients with a range of metastatic cancers were sequenced, with a mean coverage of 95X and 16 somatic alterations detected per patient. In total, 16 mutations were category 1 (targeted therapy available), 98 were category 2 (biologically relevant), and 1474 were category 3 (unknown significance). Overall, WES provided informative results in 91 cases (94%), including alterations for which there is an approved drug, there are therapies in clinical or preclinical development, or they are considered drivers and potentially actionable (category 1-2); however, treatment was guided in only 5 patients (5%) on the basis of these recommendations because of access to clinical trials and/or off-label use of drugs. Among unexpected findings, a patient with prostate cancer with exceptional response to treatment was identified who harbored a somatic hemizygous deletion of the DNA repair gene FANCA and putative partial loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response. Conclusions and Relevance The majority of advanced, treatment-resistant tumors across tumor types harbor biologically informative alterations. The establishment of a clinical trial for WES of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response.

Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma.

Abstract: Importance Carfilzomib-lenalidomide-dexamethasone therapy yields deep responses in patients with newly diagnosed multiple myeloma (NDMM). It is important to gain an understanding of this combination’s tolerability and impact on minimal residual disease (MRD) negativity because this end point has been associated with improved survival. Objective To assess the safety and efficacy of carfilzomib-lenalidomide-dexamethasone therapy in NDMM and high-risk smoldering multiple myeloma (SMM). Design, Setting, and Participants Clinical and correlative pilot study at the National Institutes of Health Clinical Center. Patients with NDMM or high-risk SMM were enrolled between July 11, 2011, and October 9, 2013. Median follow-up was 17.3 (NDMM) and 15.9 months (SMM). Interventions Eight 28-day cycles were composed of carfilzomib 20/36 mg/m2on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on days 1 through 21; and dexamethasone 20/10 mg (cycles 1-4/5-8) on days 1, 2, 8, 9, 15, 16, 22, and 23. Patients who achieved at least stable disease subsequently received 24 cycles of lenalidomide extended dosing. Main Outcomes and Measures Primary end points were neuropathy of grade 3 or greater (NDMM) and at least very good partial response rates (SMM). Minimal residual disease was also assessed. Results Of 45 patients with NDMM, none had neuropathy of grade 3 or greater. Of 12 patients with high-risk SMM, the most common of any-grade adverse events were lymphopenia (12 [100%]) and gastrointestinal disorders (11 [92%]). All patients with SMM achieved at least a very good partial response during the study period. Among the 28 patients with NDMM and the 12 with SMM achieving at least a near-complete response, MRD negativity was found in 28 of 28 (100% [95% CI, 88%-100%]), 11 of 12 (92% [95% CI, 62%-100%]) (multiparametric flow cytometry), 14 of 21 (67% [95% CI, 43%-85%]), and 9 of 12 (75% [95% CI, 43%-94%]) (next-generation sequencing), respectively. In patients with NDMM, 12-month progression-free survival for MRD-negative vs MRD-positive status by flow cytometry and next-generation sequencing was 100% vs 79% (95% CI, 47%-94%;P Conclusions and Relevance Carfilzomib-lenalidomide-dexamethasone therapy is tolerable and demonstrates high rates of MRD negativity in NDMM, translating into longer progression-free survival in patients achieving MRD negativity. Carfilzomib-lenalidomide-dexamethasone therapy also demonstrates efficacy in high-risk SMM.

Myeloproliferative Neoplasms: A Contemporary Review.

Abstract: Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) constitute the BCR-ABL1-negative myeloproliferative neoplasms and are characterized by mutually exclusive Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) mutations; respective frequencies of these mutations are approximately 95%, 0%, and 0% in PV, 60%, 20%, and 3% in ET, and 60%, 25%, and 7% in PMF. These mutations might be accompanied by other mutations that are less specific to myeloproliferative neoplasms but are prognostically relevant, such as additional sex combs-like 1 (ASXL1). Characteristic bone marrow morphology is required for World Health Organization-compliant diagnosis, especially in distinguishing ET from prefibrotic PMF and masked PV. Survival is the longest in ET, although still inferior to that of the age- and sex-matched control population; median survivals for patients younger than 60 years are approximately 33 years for ET, 24 for PV, and 15 for PMF. Major disease complications include thrombosis and leukemic or fibrotic transformation. In PV and ET, risk factors for survival include older age, leukocytosis, and thrombosis, whereas JAK2 mutation in ET is associated with increased risk of thrombosis. In PMF, type 1 or type 1-like CALR mutations are associated with superior and ASXL1 with inferior survival. Prevention of thrombosis in PV is secured by phlebotomy (hematocrit target <45%) and in both PV and ET by low-dose aspirin therapy; high-risk patients derive additional antithrombotic benefit from cytoreductive therapy with hydroxyurea as first-line and interferon-alfa and busulfan as second-line drugs of choice. Although the JAK inhibitor ruxolitinib was recently approved for use in hydroxyurea-resistant PV, its role in routine clinical practice remains debatable. In myelofibrosis, stem cell transplant is the current treatment of choice for genetically or clinically high-risk disease; for all other patients requiring treatment, participation in clinical trials may be preferred because currently available drugs, including JAK inhibitors, are palliative and not shown to be disease modifying.

Five Years of Cancer Drug Approvals: Innovation, Efficacy, and Costs

Abstract: Five Years of Cancer Drug Approvals: Innovation, Efficacy, and Costs The price of cancer drugs has risen, drawing criticism from leading academics.1,2 The annual cost of a new cancer medication now routinely exceeds $100 000, and medical bills have become the single largest cause of personal bankruptcy.2 Although some contend that the high cost of drugs is required to support re-search and development efforts,3 the fact remains that when costs and revenues are balanced, the pharmaceutical industry generates high profit margins.4 High profits may be justified if novel products offer significant benefits to patients (thus producing indirect economic value through the patients’ restored health) or if they represent significant pharmacologic advances over their predecessors—offering new mechanisms of actions and emblematic of high-risk research. We investigated whether novelty of medications or their relative benefits affected drug pricing.

Association of EGFR L858R Mutation in Circulating Free DNA With Survival in the EURTAC Trial.

Abstract: Importance The EURTAC trial demonstrated the greater efficacy of erlotinib compared with chemotherapy for the first-line treatment of European patients with advanced non–small-cell lung cancer (NSCLC) harboring oncogenic epidermal growth factor receptor ( EGFR ) mutations (exon 19 deletion or L858R mutation in exon 21) in tumor tissue. Objective To assess the feasibility of using circulating free DNA (cfDNA) from blood samples as a surrogate for tumor biopsy for determining EGFR mutation status and to correlate EGFR mutations in cfDNA with outcome. Design, Setting, and Participants This prespecified analysis was a secondary objective of the EURTAC trial using patients included in the EURTAC trial from 2007 to 2011 with available baseline serum or plasma samples. Patients had advanced NSCLC, oncogenic EGFR mutations in the tumor, and no prior chemotherapy for metastatic disease and were treated with erlotinib or chemotherapy. EGFR mutations were examined in cfDNA isolated from 97 baseline blood samples by our novel peptide nucleic acid–mediated 5´ nuclease real-time polymerase chain reaction (TaqMan) assay. Main Outcomes and Measures Overall survival (OS), progression-free survival (PFS), and response to therapy were correlated with type of EGFR mutations in cfDNA. Results In samples from 76 of 97 (78%) patients with usable blood samples, EGFR mutations in cfDNA were detected. Median OS was shorter in patients with the L858R mutation in cfDNA than in those with the exon 19 deletion (13.7 [95% CI, 7.1-17.7] vs 30.0 [95% CI, 19.3-37.7] months; P EGFR mutations in cfDNA identified the L858R mutation in tumor tissue or in cfDNA as a marker of shorter OS (hazard ratio [HR], 2.70 [95% CI, 1.60-4.56]; P P = .008). For patients with the L858R mutation in tissue, median OS was 13.7 (95% CI, 7.1-17.7) months for patients with the L858R mutation in cfDNA and 27.7 (95% CI, 16.1-46.2) months for those in whom the mutation was not detected in cfDNA (HR, 2.22 [95% CI, 1.09-4.52]; P = .03). In the multivariate analysis of the 76 patients with EGFR mutations in cfDNA, only erlotinib treatment remained an independent predictor of longer PFS (HR, 0.41 [95% CI, 0.23-0.74]; P = .003). Conclusions and Relevance The peptide nucleic acid–mediated 5´ nuclease real-time polymerase chain reaction (TaqMan) assay used in this study can be used to efficiently assess EGFR mutations in cfDNA. The L858R mutation in cfDNA may be a novel surrogate prognostic marker. Trial Registration clinicaltrials.gov Identifier:NCT00446225

Acute and short-term toxic effects of conventionally fractionated vs hypofractionated whole-breast irradiation: A randomized clinical trial

Abstract: Importance The most appropriate dose fractionation for whole-breast irradiation (WBI) remains uncertain. Objective To assess acute and 6-month toxic effects and quality of life (QOL) with conventionally fractionated WBI (CF-WBI) vs hypofractionated WBI (HF-WBI). Design, Setting, and Participants Unblinded randomized trial of CF-WBI (n = 149; 50.00 Gy/25 fractions + boost [10.00-14.00 Gy/5-7 fractions]) vs HF-WBI (n = 138; 42.56 Gy/16 fractions + boost [10.00-12.50 Gy/4-5 fractions]) following breast-conserving surgery administered in community-based and academic cancer centers to 287 women 40 years or older with stage 0 to II breast cancer for whom WBI without addition of a third field was recommended; 76% of study participants (n = 217) were overweight or obese. Patients were enrolled from February 2011 through February 2014 and observed for a minimum of 6 months. Interventions Administration of CF-WBI or HF-WBI. Main Outcomes and Measures Physician-reported acute and 6-month toxic effects using National Cancer Institute Common Toxicity Criteria, and patient-reported QOL using the Functional Assessment of Cancer Therapy for Patients with Breast Cancer (FACT-B). All analyses were intention to treat, with outcomes compared using the χ 2 test, Cochran-Armitage test, and ordinal logistic regression. Results Of 287 participants, 149 were randomized to CF-WBI and 138 to HF-WBI. Treatment arms were well matched for baseline characteristics, including FACT-B total score (HF-WBI, 120.1 vs CF-WBI, 118.8; P = .46) and individual QOL items such as somewhat or more lack of energy (HF-WBI, 38% vs CF-WBI, 39%; P = .86) and somewhat or more trouble meeting family needs (HF-WBI, 10% vs CF-WBI, 14%; P = .54). Maximum physician-reported acute dermatitis (36% vs 69%; P P P = .001), hyperpigmentation (9% vs 20%; P = .002), and fatigue (9% vs 17%; P = .02) during irradiation were lower in patients randomized to HF-WBI. The rate of overall grade 2 or higher acute toxic effects was less with HF-WBI than with CF-WBI (47% vs 78%; P P = .01), and patients randomized to HF-WBI reported less lack of energy (23% vs 39%; P P = .01). Multivariable regression confirmed the superiority of HF-WBI in terms of patient-reported lack of energy (odds ratio [OR], 0.39; 95% CI, 0.24-0.63) and trouble meeting family needs (OR, 0.34; 95% CI, 0.16-0.75). Conclusions and Relevance Treatment with HF-WBI appears to yield lower rates of acute toxic effects than CF-WBI as well as less fatigue and less trouble meeting family needs 6 months after completing radiation therapy. These findings should be communicated to patients as part of shared decision making. Trial Registration clinicaltrials.gov Identifier:NCT01266642

Acquired Resistance of EGFR-Mutant Lung Cancer to a T790M-Specific EGFR Inhibitor: Emergence of a Third Mutation (C797S) in the EGFR Tyrosine Kinase Domain

Abstract: EGFR-mutant lung cancers represent a paradigm for the use of tyrosine kinase inhibitors (TKIs) to treat molecular subsets of cancer, with randomized trials demonstrating the efficacy of first-generation, reversible epidermal growth factor receptor (EGFR) TKIs. However, acquired resistance invariably develops, and rebiopsy of patients with clinical progression has elucidated EGFR T790M mutation as the major resistance mechanism.1 To address this clinical challenge, third-generation pyrimidine-based EGFR TKIs have been designed to have selectivity for EGFR T790M over wild-type EGFR.2 They form a covalent bond with cysteine 797 in the adenosine triphosphate–binding cleft. Early-phase clinical trials have demonstrated their efficacy in patients with double-mutant tumors (EGFR L858R/T790M and ex19del/T790M) and acquired resistance to first-generation EGFR inhibitors.3 Specificity for EGFR T790M may be the result of hydrophobic interactions between the bulky methionine moiety of EGFR T790M and these pyrimidine-based drugs. Mechanisms of resistance to these third-generation EGFR TKIs have been identified in preclinical in vitro models, but none have so far been identified in patients. Mutations at the EGFR C797 codon, located within the kinase-binding site, are a predicted resistance mechanism to irreversible EGFR inhibitors also confirmed in vitro.4 Loss of the potential for covalent bond formation at position 797 by the missense mutation C797S results in a markedly reduced cellular potency of this class of TKIs.5 Interestingly, an analogous cysteine-to-serine mutation is a mechanism of resistance to the irreversible Bruton tyrosine kinase inhibitor ibrutinib in patients with chronic lymphocytic leukemia.6

Efficacy and Safety of Nivolumab in Patients With BRAF V600 Mutant and BRAF Wild-Type Advanced Melanoma: A Pooled Analysis of 4 Clinical Trials

Abstract: Importance The anti–PD-1 therapeutic antibody, nivolumab, has demonstrated clinical activity in patients with advanced melanoma. The activity of nivolumab in subgroups of patients with tumors which have wild-type BRAF kinase vs patients with tumors having mutant BRAF has not systematically been explored in a large dataset. Objective To evaluate the efficacy and safety of nivolumab in patients with wild-type BRAF and mutant BRAF metastatic melanoma. Design, Setting, and Participants This was a retrospective analysis of data pooled from 4 clinical trials of nivolumab in 440 adult patients with unresectable stage III or stage IV melanoma, who had been tested for BRAF mutational status while participating in one of the studies. Intervention The investigational drug, nivolumab, was administered intravenously to study participants over a 60-minute period, at doses of 0.1, 0.3, 1.0, 3.0, or 10.0 mg/kg every 2 weeks until disease progression, discontinuation owing to adverse events, withdrawal, or end of study. Most patients (83%) received nivolumab at a dosage of 3 mg/kg. Main Outcome and Measure Best overall response by modified World Health Organization or Response Evaluation Criteria In Solid Tumors criteria and safety profile. Results Of a total of 440 patients from 4 nivolumab clinical trials included in the analysis, 334 were BRAF wild-type and 106 were positive for BRAF V600 mutation. With the exception of prior BRAF inhibitor therapy, the demographics were well balanced between the 2 cohorts. In patients evaluable for response, the objective response rates were 34.6% (95% CI, 28.3-41.3) for the 217 patients with wild-type BRAF status and 29.7% (95% CI, 19.7-41.5) for the 74 with mutant BRAF status. The objective response rates did not seem to be affected by prior BRAF inhibitor therapy, prior ipilimumab therapy, or PD-L1 status of the tumor. The median duration of objective response was 14.8 months (95% CI, 11.1-24.0 months) for wild-type BRAF and 11.2 months (95% CI, 7.3-22.9 months) for mutant BRAF . Median time to objective response was 2.2 months in both patient groups. The incidence of treatment-related adverse events of any grade was 68.3% in the wild-type BRAF group and 58.5% in the mutant BRAF group, with grade 3 or 4 adverse events in 11.7% and 2.8% of patients, respectively. Treatment-related AEs of any grade that occurred in at least 5% of patients in either group were fatigue, pruritus, rash, and diarrhea. Conclusions and Relevance The results of this retrospective analysis suggest that nivolumab has similar efficacy and safety outcomes in patients with wild-type or mutant BRAF , regardless of prior BRAF inhibitor or ipilimumab treatment.

Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Site: New Routes to Targeted Therapies.

Abstract: Importance For carcinoma of unknown primary site (CUP), determining the primary tumor site may be uninformative and often does not improve outcome. Objective To discover opportunities for targeted therapies in patients with CUP not currently searched for in routine practice. Design, Setting, and Participants Comprehensive genomic profiling on 200 CUP formalin-fixed paraffin-embedded specimens (mean, 756× coverage) using the hybrid-capture–based FoundationOne assay at academic and community oncology clinics. Main Outcomes and Measures Presence of targetable genomic alterations (GAs) in CUP and responses to targeted therapies. Results There were 125 adenocarcinomas of unknown primary site (ACUPs) and 75 carcinomas of unknown primary site without features of adenocarcinoma (non-ACUPs). At least 1 GA was found in 192 (96%) of CUP specimens, with a mean (SD) of 4.2 (2.8) GAs per tumor. The most frequent GAs were in TP53 (110 [55%]), KRAS (40 [20%]), CDKN2A (37 [19%]), MYC (23 [12%]), ARID1A (21 [11%]), MCL1 (19 [10%]), PIK3CA (17 [9%]), ERBB2 (16 [8%]), PTEN (14 [7%]), EGFR (12 [6%]) , SMAD4 (13 [7%]), STK11 (13 [7%]), SMARCA4 (12 [6%]), RB1 (12 [6%]), RICTOR (12 [6%]), MLL2 (12 [6%]), BRAF (11 [6%]), and BRCA2 (11 [6%]). One or more potentially targetable GAs were identified in 169 of 200 (85%) CUP specimens. Mutations or amplifications of ERBB2 were more frequent in ACUPs (13 [10%]) than in non-ACUPs (3 [4%]). Alterations of EGFR (10 [8%] vs 2 [3%]) and BRAF (8 [6%] vs 3 [4%]) were more common in ACUPs than in non-ACUPs. Strikingly, clinically relevant alterations in the receptor tyrosine kinase (RTK)/Ras signaling pathway including alterations in ALK , ARAF , BRAF , EGFR , FGFR1 , FGFR2 , KIT , KRAS , MAP2K1 , MET , NF1 , NF2 , NRAS , RAF1 , RET , and ROS1 were found in 90 (72%) ACUPs but in only 29 (39%) non-ACUPs ( P .001). Conclusions and Relevance Almost all CUP samples harbored at least 1 clinically relevant GA with potential to influence and personalize therapy. The ACUP tumors were more frequently driven by GAs in the highly druggable RTK/Ras/mitogen-activated protein kinase (MAPK) signaling pathway than the non-ACUP tumors. Comprehensive genomic profiling can identify novel treatment paradigms to address the limited options and poor prognoses of patients with CUP.

Breast Cancer After Use of Estrogen Plus Progestin and Estrogen Alone: Analyses of Data From 2 Women’s Health Initiative Randomized Clinical Trials

Abstract: Importance The use of menopausal hormone therapy (HT) continues in clinical practice, but reports are conflicting concerning the longer-term breast cancer effects of relatively short-term use. Objective To report the longer-term influence of menopausal HT on breast cancer incidence in the 2 Women’s Health Initiative (WHI) randomized clinical trials. Design, Setting, and Participants A total of 27 347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers from 1993 to 1998 and followed up for a median of 13 years through September 2010. Interventions A total of 16 608 women with a uterus were randomized to conjugated equine estrogens (0.625 mg/d [estrogen]) plus medroxyprogesterone acetate (2.5 mg/d [progestin]) (E + P) or placebo with a median intervention duration of 5.6 years, and 10 739 women with prior hysterectomy were randomized to conjugated equine estrogens alone (0.625 mg/d) or placebo with a median intervention duration of 7.2 years. Main Outcomes and Measures Time-specific invasive breast cancer incidence rates and exploratory analyses of breast cancer characteristics by intervention and postintervention phases in the 2 HT trials. Results In the E + P trial, hazard ratios (HRs) for the influence of combined HT on breast cancer were lower than 1 for 2 years (HR, 0.71; 95% CI, 0.47-1.08) and steadily increased throughout intervention, becoming significantly increased for the entire intervention phase (HR, 1.24; 95% CI, 1.01-1.53). In the early postintervention phase (within 2.75 years from intervention), there was a sharp decrease in breast cancer incidence in the combined HT group, though the HR remained higher than 1 (HR, 1.23; 95% CI, 0.90-1.70). During the late postintervention phase (requiring patient re-consent), the HR for breast cancer risk remained higher than 1 through 5.5 years (median) of additional follow-up (HR, 1.37; 95% CI, 1.06-1.77). In the estrogen alone trial, the HR for invasive breast cancer risk was lower than 1 throughout the intervention phase (HR, 0.79; 95% CI, 0.61-1.02) and remained lower than 1 in the early postintervention phase (HR, 0.55; 95% CI, 0.34-0.89), but risk reduction was not observed during the late postintervention follow-up (HR, 1.17; 95% CI, 0.73-1.87). Characteristics of breast cancers diagnosed during early and late postintervention phases differed in both trials. Conclusions and Relevance In the E + P trial, the higher breast cancer risk seen during intervention was followed by a substantial drop in risk in the early postintervention phase, but a higher breast cancer risk remained during the late postintervention follow-up. In the estrogen alone trial, the lower breast cancer risk seen during intervention was sustained in the early postintervention phase but was not evident during the late postintervention follow-up.

Stereotactic Radiosurgery With or Without Whole-Brain Radiotherapy for Brain Metastases: Secondary Analysis of the JROSG 99-1 Randomized Clinical Trial

Abstract: Importance It remains uncertain whether treatment with stereotactic radiosurgery (SRS) alone can be safely applied to all patient populations with 1 to 4 brain metastases (BMs) exhibiting heterogeneous prognoses. Objective To investigate the feasibility of SRS alone for patients with different prognoses determined by the diagnosis-specific Graded Prognostic Assessment (DS-GPA). Design, Setting, and Participants A secondary analysis (performed in September 2014) of the Japanese Radiation Oncology Study Group (JROSG) 99-1, a phase 3 randomized trial, comparing SRS alone and whole-brain radiotherapy (WBRT) + SRS conducted in 1999 to 2003. Among a total of 132 patients, 88 with non–small-cell lung cancer (NSCLC) and 1 to 4 BMs were included and poststratified by DS-GPA scores to avoid potential bias from BMs from different primary cancer types. The median follow-up time was 8.05 months. Interventions The WBRT schedule was 30 Gy in 10 fractions over 2 to 2.5 weeks. The mean SRS dose was 21.9 Gy in SRS alone and 16.6 Gy in WBRT + SRS. Main Outcomes and Measures The primary end point was overall survival (OS), and the secondary end points included brain tumor recurrence (BTR), salvage treatment, and radiation toxic effects. Results Forty-seven patients had a favorable prognosis, with DS-GPA scores of 2.5 to 4.0 (26 SRS-alone and 21 WBRT + SRS [DS-GPA 2.5-4.0 group]), and 41 had an unfavorable prognosis, with DS-GPA scores of 0.5 to 2.0 (19 SRS-alone and 22 WBRT + SRS [DS-GPA 0.5-2.0 group]). Significantly better OS was observed in the DS-GPA 2.5-4.0 group in WBRT + SRS vs the SRS alone, with a median survival time of 16.7 (95% CI, 7.5-72.9) months vs 10.6 (95% CI, 7.7-15.5) months ( P = .04) (hazard ratio [HR], 1.92; 95% CI, 1.01-3.78). However, no such difference was observed in the DS-GPA 0.5-2.0 group (HR, 1.05; 95% CI, 0.55-1.99) ( P = .86). This benefit could be explained by the differing BTR rates, in that the prevention against BTR by WBRT had a more significant impact in the DS-GPA 2.5-4.0 group (HR, 8.31; 95% CI, 3.05-29.13) ( P P = .04). Conclusions and Relevance Despite the current trend of using SRS alone, the important role of WBRT for patients with BMs from NSCLC with a favorable prognosis should be considered. Our findings should be validated through appropriately designed prospective studies. Trial Registration umin.ac.jp/ctr Identifier:C000000412

Presymptomatic Identification of Cancers in Pregnant Women During Noninvasive Prenatal Testing

Abstract: Importance Noninvasive prenatal testing (NIPT) for fetal aneuploidy by scanning cell-free fetal DNA in maternal plasma is rapidly becoming a major prenatal genetic test. Similar to placental DNA, tumor DNA can be detected in the plasma, and analysis of cell-free tumor DNA can be used to characterize and monitor cancers. We show that plasma DNA profiling allows for presymptomatic detection of tumors in pregnant women undergoing routine NIPT. Observations During NIPT in over 4000 prospective pregnancies by parallel sequencing of maternal plasma cell-free DNA, 3 aberrant genome representation (GR) profiles were observed that could not be attributed to the maternal or fetal genomic constitution. A maternal cancer was suspected, and those 3 patients were referred for whole-body diffusion-weighted magnetic resonance imaging, which uncovered an ovarian carcinoma, a follicular lymphoma, and a Hodgkin lymphoma, each confirmed by subsequent pathologic and genetic investigations. The copy number variations in the subsequent tumor biopsies were concordant with the NIPT plasma GR profiles. Conclusions and Relevance We show that maternal plasma cell-free DNA sequencing for noninvasive prenatal testing also may enable accurate presymptomatic detection of maternal tumors and treatment during pregnancy.

Correlation of Smoking-Associated DNA Methylation Changes in Buccal Cells With DNA Methylation Changes in Epithelial Cancer.

Abstract: Importance The utility of buccal cells as an epithelial source tissue for epigenome-wide association studies (EWASs) remains to be demonstrated. Given the direct exposure of buccal cells to potent carcinogens such as smoke, epigenetic changes in these cells may provide insights into the development of smoke-related cancers. Objective To perform an EWAS in buccal and blood cells to assess the relative effect of smoking on the DNA methylation (DNAme) patterns in these cell types and to test whether these DNAme changes are also seen in epithelial cancer. Design, Setting, and Participants In 2013, we measured DNAme at more than 480 000 CpG sites in buccal samples provided in 1999 by 790 women (all aged 53 years in 1999) from the United Kingdom Medical Research Council National Survey of Health and Development. This included matched blood samples from 152 women. We constructed a DNAme-based smoking index and tested its sensitivity and specificity to discriminate normal from cancer tissue in more than 5000 samples. Main Outcomes and Measures CpG sites whose DNAme level correlates with smoking pack-years, and construction of an associated sample-specific smoking index, which measures the mean deviation of DNAme at smoking-associated CpG sites from a normal reference. Results In a discovery set of 400 women, we identified 1501 smoking-associated CpG sites at a genome-wide significance level of P −7 , which were validated in an independent set of 390 women. This represented a 40-fold increase of differentially methylated sites in buccal cells compared with matched blood samples. Hypermethylated sites were enriched for bivalently marked genes and binding sites of transcription factors implicated in DNA repair and chromatin architecture ( P −10 ). A smoking index constructed from the DNAme changes in buccal cells was able to discriminate normal tissue from cancer tissue with a mean receiver operating characteristic area under the curve of 0.99 (range, 0.99-1.00) for lung cancers and of 0.91 (range, 0.71-1.00) for 13 other organs. The corresponding area under the curve of a smoking signature derived from blood cells was lower than that derived from buccal cells in 14 of 15 cancer types (Wilcoxon signed rank test, P = .001). Conclusions and Relevance These data point toward buccal cells as being a more appropriate source of tissue than blood to conduct EWASs for smoking-related epithelial cancers.

Association of Actual and Preferred Decision Roles With Patient-Reported Quality of Care: Shared Decision Making in Cancer Care

Abstract: Importance Shared decision making is associated with improved patient-reported outcomes of cancer treatment, but not all patients prefer to participate in medical decisions. Results from studies of the effect of matching between actual and preferred medical decision roles on patients’ perceptions of care quality have been conflicting. Objectives To determine whether shared decision making was associated with patient ratings of care quality and physician communication and whether patients’ preferred decision roles modified those associations. Design, Setting, and Participants We performed a population- and health system–based survey of participants in the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) study diagnosed with lung and/or colorectal cancer between 2003 and 2005 (56% with colorectal cancer, 40% with non–small-cell lung cancer, and 5% with small-cell lung cancer). The CanCORS study included 9737 patients (cooperation rate among patients contacted, 59.9%) treated in integrated care delivery systems, academic institutions, private offices, and Veterans Affairs hospitals. The medical records were abstracted between October 11, 2005, and April 30, 2009; all analyses were conducted between 2013 and 2014. Interventions We surveyed patients specifically about their preferred roles in cancer treatment decisions and their actual roles in decisions about surgery, chemotherapy, and radiation therapy. We analyzed the responses of 5315 patients who completed baseline surveys and reported decision roles for a total of 10 817 treatment decisions and assessed associations of patients’ decision roles with patient-reported quality of care and physician communication. Main Outcomes and Measures The outcomes (identified before data collection) included patient-reported excellent quality of care and top ratings (highest score) on a physician communication scale. Results After adjustment, patients describing physician-controlled (vs shared) decisions were less likely to report excellent quality of care (odds ratio [OR], 0.64; 95% CI, 0.54-0.75; P P = .29 for the interaction). Patients describing either actual or preferred physician-controlled (vs shared) roles were less likely to provide a top rating of physician communication (OR, 0.55; 95% CI, 0.45-0.66; P P = .002, respectively). The preferred role did not modify the effect of the actual role ( P = .76 for interaction). Conclusions and Relevance Physician-controlled decisions regarding lung or colorectal cancer treatment were associated with lower ratings of care quality and physician communication. These effects were independent of patients’ preferred decision roles, underscoring the importance of seeking to involve all patients in decision making about their treatment.

Contemporary Occupational Carcinogen Exposure and Bladder Cancer: A Systematic Review and Meta-analysis

Abstract: Importance Bladder cancer (BC) is a common disease. Despite manufacturing and legislative changes to workplace hygiene, many BCs still arise through occupational carcinogen exposure. Objective To profile contemporary risks of occupational BC. Data Sources A systematic review using PubMed, Medline, Embase, and Web of Science was performed in October 2012 (initial review) and May 2014 (final review) and was updated in June 2015. Study Selection We identified 263 eligible articles. We excluded reports in which BC or occupation were not the main focus, and those with insufficient case, risk, or confidence interval data. We selected the most recent data from populations with multiple reports. Data Extraction and Synthesis Reports were selected by 2 of us independently. We combined odds ratios and risk ratios (RRs) to provide pooled RRs, using maximally adjusted RRs in a random effects model. Heterogeneity and publication bias were assessed using I 2 and Begg and Egger tests. Risk estimates were annotated by occupational class using Nordisk Yrkesklassificering, or Nordic Occupational Classification, and International Standard Classifications of Occupations (NYK and ISCO-1958) Codes. Main Outcomes and Measures Occupations were profiled by BC incidence and mortality risk over time. After data collection, we detected a sex difference in these profiles and recorded this as a secondary outcome. Results Meta-analysis revealed increased BC incidence in 42 of 61 occupational classes and increased BC-specific mortality in 16 of 40 occupational classes. Reduced incidence and mortality were seen in 6 of 61 and 2 of 40 classes, respectively. Risk varied with sex and was greatest in men (standardized incidence ratio, 1.03 [95% CI, 1.02-1.03]; P Conclusions and Relevance The profile of contemporary occupations with increased BC risk is broad and differs for incidence and mortality. Currently the incidence seems to be increasing, and this increase is occurring faster in women than men. Improved detection mechanisms and screening are possible reasons for this. Workers with aromatic amine exposure have the highest incidence, while those exposed to polycyclic aromatic hydrocarbons and heavy metals have the greatest mortality.