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BACKGROUND: The incidence of breast and colorectal cancer (CRC) in younger-than-average-age patients is rising and poorly understood. This is the largest study on patients with both cancers who are less than 60 years old and aims to characterize demographic, clinicopathologic, and genetic features and describe therapeutic dilemmas and management strategies. MATERIALS AND METHODS: This is a retrospective medical records review of patients at the University of California San Francisco with both primary breast and CRC before age 60. RESULTS: Fifty-one patients were identified; 41 had detailed medical records. Median age of diagnosis with breast cancer was 43 (range 27-59) and CRC was 50 (28-59). Most were Caucasian (38, 74.5%) and never smokers (23, 56.1%); about half were current alcohol consumers (20, 48.8%) and about one-third had sedentary jobs (14, 34.1%). Average BMI was 25.8 (range: 14-49), and 30% were overweight or obese. Breast was the first cancer diagnosed in 36 patients (70.6%) and 44 (86.3%) had a metachronous CRC diagnosis. Breast cancer was early stage (0-2) in 32 (78.0%) patients whereas CRC was split between early stage (1-2) in 14 (34.1%) and later stage (3-4) in 19 (46.2%). Ten patients (24.3%) had a known germline mutation, although 23 (56.1%) had a family history of cancer in a first-degree relative. CONCLUSION: Younger patients with both breast and CRC are a unique cohort, often without known risk factors. Alcohol consumption and sedentary jobs were the most common risk factors, and about one-quarter had a known genetic predisposition. Comanagement of both cancers requires individualized, multidisciplinary care.

ObjectivesImmunotherapy with immune checkpoint inhibitors has shown only limited success in the management of metastatic soft tissue sarcoma. Overall response rates (ORR) with single agent pembrolizumab were 18% and median PFS was 18 weeks on the clinical trial SARC028. One strategy to improve the responses to immunotherapy is with stereotactic body radiation therapy (SBRT), which can enhance the antitumor CD8 T cell response through the release of tumor-specific antigens, potentially priming a more diverse class of T cell receptors.MethodsThis is a phase 0, pilot prospective study taking place at a single center with 2 arms. In Arm A, patients are treated with pembrolizumab 400 mg IV infusion on day 1 of a 42-day cycle. Stereotactic body radiation therapy (SBRT) is delivered in 1-5 fractions starting on C1D15-28 and given every other day. In Arm B, patients who have started an immune checkpoint inhibitor within 60 days are treated with SBRT in addition to the current therapy.ResultsIn this study we outline testing the feasibility of adding SBRT to pembrolizumab.ConclusionThe ultimate goal of combination therapy is improved overall response, including tumors not treated with SBRT. This trial can be found registered online: NCT05488366.

PurposeBreast cancer (BC) is the most common secondary cancer and has poorer survival than primary BC (pBC) after any prior malignancy. For BC survivors, developing a contralateral secondary BC (CSBC) is the most frequent second-cancer event and is currently treated similarly to pBC. Identifying survival differences between pBC and CSBC could influence future counseling and treatments for patients with CSBC.MethodsWomen (≥15 years) diagnosed with pBC from 1991 to 2015 in the California Cancer Registry (n = 377,176) were compared with those with CSBC (n = 15,586) by age group (15-39 years, n = 406; 40-64 years, n = 6814; ≥ 65 years, n = 8366). Multivariable logistic regression models assessed factors associated with CSBC. Multivariable Cox proportional hazards regression models assessed BC-specific survival (BCSS), while accounting for the competing risk of death.ResultsAcross all ages, CSBC patients were more likely to have smaller tumors (T2 vs. T1a; 15-39 yeras: OR 0.25, CI 0.16-0.38; 40-64 years: OR 0.41, CI 0.37-0.45; ≥ 65 years: OR 0.46, CI 0.42-0.51) and lymph node-negative disease (positive vs. negative; 15-39 years: OR 0.86, CI 0.69-1.08; 40-64 years: OR 0.88, CI 0.83-0.93; ≥ 65 years: OR 0.89, CI 0.84-0.94). Additionally, CSBC was associated with worse survival compared with pBC across all ages (15-39 years: HR 2.73, CI 2.30-3.25; 40-64 years: HR 2.13, CI 2.01-2.26; ≥ 65 years: HR 1.52, CI 1.43-1.61).ConclusionBCSS is worse among all women diagnosed with CSBC compared with pBC, with the strongest impact seen in adolescent and young adult women. Worse survival after CSBC, despite associations with smaller tumors and lymph node negativity, suggests that CSBC may need eventual treatment reconsideration.

PurposeGenomic alterations of BRAF and NRAS are oncogenic drivers in malignant melanoma and other solid tumors. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib.MethodsThis two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics.ResultsTovorafenib was administered to 149 patients (Q2D n = 110, QW n = 39). The RP2D of tovorafenib was defined as 200 mg Q2D or 600 mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade ≥ 3 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in systemic circulation in the dose range of 400-800 mg.ConclusionsThe safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in BRAF-mutated melanoma was promising and justifies continued clinical development across multiple settings.ClinicaltrialsGov identifierNCT01425008.

Patients with prior colorectal polyps are at high risk for metachronous colorectal neoplasia, especially in the presence of obesity. We assessed the impact of 2 common bariatric surgeries, vertical sleeve gastrectomy and roux-n-Y gastric bypass, on the risk of colorectal neoplasia recurrence. This nationally representative analysis included 1183 postbariatric adults and 3193 propensity score-matched controls, who all had prior colonoscopy with polyps and polypectomy. Colorectal polyps reoccurred in 63.8% of bariatric surgery patients and 71.7% of controls at a mean follow-up of 53.1 months from prior colonoscopy. There was a reduced odds of colorectal polyp recurrence after bariatric surgery compared with controls (odds ratio [OR] = 0.70, 95% confidence interval [CI] = 0.58 to 0.83). This effect was most pronounced in men (OR = 0.58, 95% CI = 0.42 to 0.79), and post roux-n-Y gastric bypass (OR = 0.57, 95% CI = 0.41 to 0.79). However, the risk of rectal polyps or colorectal cancer remained consistent between groups. This study is the first to our knowledge to show a reduction in risk of polyp recurrence following bariatric surgery.

Antisense RNAs are ubiquitous in human cells, yet their role is largely unexplored. Here we profiled antisense RNAs in the MDA-MB-231 breast cancer cell line and its highly lung metastatic derivative. We identified one antisense RNA that drives cancer progression by upregulating the redox enzyme NADPH quinone dehydrogenase 1 (NQO1), and named it NQO1-AS. Knockdown of either NQO1 or NQO1-AS reduced lung colonization in a mouse model, and investigation into the role of NQO1 indicated that it is broadly protective against oxidative damage and ferroptosis. Breast cancer cells in the lung are dependent on this pathway, and this dependence can be exploited therapeutically by inducing ferroptosis while inhibiting NQO1. Together, our findings establish a role for NQO1-AS in the progression of breast cancer by regulating its sense mRNA post-transcriptionally. Because breast cancer predominantly affects females, the disease models used in this study are of female origin and the results are primarily applicable to females.

PURPOSE: To report the incidence and risk factors for secondary neoplasm after transplantation for sickle cell disease. METHODS: Included are 1,096 transplants for sickle cell disease between 1991 and 2016. There were 22 secondary neoplasms. Types included leukemia/myelodysplastic syndrome (MDS; n = 15) and solid tumor (n = 7). Fine-Gray regression models examined for risk factors for leukemia/MDS and any secondary neoplasm. RESULTS: The 10-year incidence of leukemia/MDS was 1.7% (95% CI, 0.90 to 2.9) and of any secondary neoplasm was 2.4% (95% CI, 1.4 to 3.8). After adjusting for other risk factors, risks for leukemia/MDS (hazard ratio, 22.69; 95% CI, 4.34 to 118.66; P = .0002) or any secondary neoplasm (hazard ratio, 7.78; 95% CI, 2.20 to 27.53; P = .0015) were higher with low-intensity (nonmyeloablative) regimens compared with more intense regimens. All low-intensity regimens included total-body irradiation (TBI 300 or 400 cGy with alemtuzumab, TBI 300 or 400 cGy with cyclophosphamide, TBI 200, 300, or 400 cGy with cyclophosphamide and fludarabine, or TBI 200 cGy with fludarabine). None of the patients receiving myeloablative and only 23% of those receiving reduced-intensity regimens received TBI. CONCLUSION: Low-intensity regimens rely on tolerance induction and establishment of mixed-donor chimerism. Persistence of host cells exposed to low-dose radiation triggering myeloid malignancy is one plausible etiology. Pre-existing myeloid mutations and prior inflammation may also contribute but could not be studied using our data source. Choosing conditioning regimens likely to result in full-donor chimerism may in part mitigate the higher risk for leukemia/MDS.

BackgroundTargeting programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase (IDO1) pathways is an appealing option for cancer treatment.MethodsThe open-label, phase 1/2 ECHO-203 study evaluated the safety, tolerability, and efficacy of the IDO1 inhibitor epacadostat in combination with durvalumab, a human anti-PD-L1 monoclonal antibody in adult patients with advanced solid tumors.ResultsThe most common treatment-related adverse events were fatigue (30.7%), nausea (21.0%), decreased appetite (13.1%), pruritus (12.5%), maculopapular rash (10.8%), and diarrhea (10.2%). Objective response rate (ORR) in the overall phase 2 population was 12.0%. Higher ORR was observed in immune checkpoint inhibitor (CPI)-naïve patients (16.1%) compared with patients who had received previous CPI (4.1%). Epacadostat pharmacodynamics were evaluated by comparing baseline kynurenine levels with those on therapy at various time points. Only the 300-mg epacadostat dose showed evidence of kynurenine modulation, albeit unsustained.ConclusionsEpacadostat plus durvalumab was generally well tolerated in patients with advanced solid tumors. ORR was low, and evaluation of kynurenine concentration from baseline to cycle 2, day 1, and cycle 5, day 1, suggested >300 mg epacadostat twice daily is needed to ensure sufficient drug effect.Clinical trial informationA study of epacadostat (INCB024360) in combination with durvalumab (MEDI4736) in subjects with selected advanced solid tumors (ECHO-203) (NCT02318277).

BackgroundBromonitrozidine (RRx-001) is a minimally toxic, NLRP3 inhibitor that has been observed, in experimental systems, to also downregulate CD47, repolarize tumor associated macrophages (TAMs) and normalize aberrant tumor perfusion. This phase 1 pilot study was undertaken to determine the safety and feasibility of RRx-001 and nivolumab in patients with advanced cancer and no standard options.MethodsThis single arm, single site, open-label pilot study (NCT02518958) called PRIMETIME was designed to evaluate the safety profile of RRx-001 and nivolumab in patients with advanced malignancies and no other standard therapeutic options. A 3 + 3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. RRx-001 is infused once weekly while nivolumab is given at 3mg/kg once every 2 weeks. The RRx-001 starting dose was 2 mg IV weekly with 4 dose level escalations up to 16 mg IV weekly. From January 2015 to November 2015, twelve patients received treatment for only 4 cycles (total 12 weeks) with the combination due to unavailability of nivolumab, which was not supplied to the Sponsor. Treatment-emergent (all cause, TEAEs) and treatment-related (TRAEs) adverse events that occurred within 16 weeks of the first dose of RRx-001 and nivolumab were characterized according to CTCAE v4.03.ResultsTwelve patients received ≥1 dose of RRx-001 and nivolumab. One discontinuation occurred due to pneumonitis and one to voluntary withdrawal after a post-procedural infection. There were no DLTs. The main adverse event related to RRx-001 was infusion reaction (33.3%). The main adverse event related to the combination was pseudoprogression manifested by larger tumors in patients that were symptomatically improved (25%). The most common immune-related treatment-emergent AEs were pneumonitis (8.3%), and hypothyroidism (8.3%). The objective response rate at 12 weeks was 25% and the disease control rate (DCR) consisting of ≥SD was 67% by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 25% of the patients progressed on the combination.ConclusionsThe combination of RRx-001 and nivolumab was safe and well-tolerated with preliminary evidence of anti-cancer activity. Further clinical trials with RRx-001 and nivolumab are warranted.Clinical trial registrationClinicalTrials.gov identifier, NCT02518958.

BACKGROUND: Recurrence after resection of metastatic sarcoma is common. The gangliosides GM2, GD2 and GD3 are strongly expressed across sarcoma subtypes. We hypothesised that generation of anti-ganglioside antibodies would control micrometastases and improve outcomes in sarcoma patients who were disease-free after metastasectomy. METHODS: We conducted a randomised phase II trial of the immunological adjuvant OPT-821 with a KLH-conjugated ganglioside vaccine targeting GM2, GD2 and GD3, versus OPT-821 alone in patients with metastatic sarcoma following complete metastasectomy. Patients received 10 subcutaneous injections at Weeks 1, 2, 3, 8, 16, 28, 40, 52, 68 and 84 and were followed for evidence of recurrent disease. The primary end-point was relapse-free survival. Secondary end-points included overall survival and serologic response. RESULTS: A total of 136 patients were randomised, 68 to each arm. The mean age was 51.2, 52.2% were male, 90.4% had relapsed disease, 86.8% had high-grade tumours and 14% had ≥4 metastases resected. Histologies included leiomyosarcoma (33%), spindle cell sarcoma (14%), undifferentiated pleomorphic sarcoma (13%), osteosarcoma (10%), synovial sarcoma (9%), liposarcoma (9%) and others (12%). Most adverse events were Grade ≤2 (83.8% and 70.6% in the vaccine and adjuvant arms, respectively). The most common (≥20% of patients) were injection site reaction (89.7%), fatigue (44.1%) and pyrexia (27.9%) on the vaccine arm, and injection site reaction (69.1%) on the adjuvant only arm. The 1-year relapse-free survival rate (34.5% and 34.8% in the vaccine and OPT-821 monotherapy arm, respectively) did not differ between arms (P = 0.725). One-year overall survival rates were 93.1% and 91.5% in the vaccine and OPT-821 monotherapy arm, respectively (P = 0.578). Serologic responses at week 9 were more frequent on the vaccine arm (96.5% of patients) than in the adjuvant arm (32.8%), and the difference between groups was durable. CONCLUSIONS: A sustained serologic response to vaccination was induced with the vaccine, but no difference in recurrence-free or overall survival was observed between treatment arms. CLINICALTRIALS: gov identifier: NCT01141491.

BACKGROUND: Initial primary head and neck cancer (IPHNC) is associated with second primary lung cancer (SPLC). We studied this association in a population with a high proportion of African American (AA) patients. METHODS: Patients with IPHNC and SPLC treated between 2000 and 2017 were reviewed for demographic, disease, and treatment-related characteristics and compared to age-and-stage-matched controls without SPLC. Logistic and Cox regression models were used to analyze the relationship of these characteristics with the development of SPLC and overall survival (OS). RESULTS: Eighty-seven patients and controls were compared respectively. AA race was associated with a significantly higher risk of developing SPLC (OR 2.92, 95% CI 1.35-6.66). After correcting for immortal time bias, patients with SPLC had a significantly lower OS when compared with controls (HR 0.248, 95% CI 0.170-0.362). CONCLUSIONS: We show that AA race is associated with an increased risk of SPLC after IPHNC; reasons of this increased risk warrant further investigation.

Pretransplant conditioning with Fludarabine (Flu)-Busulfan (Bu) is safe, but clofarabine (Clo) has improved antileukemic activity. Hypothesis: Flu+Clo-Bu (FCB) yields superior progression-free survival (PFS) after allogeneic transplantation. We randomized 250 AML/MDS patients aged 3-70, Karnofsky Score ≥80, with matched donors, to FCB (n = 120) or Flu-Bu (n = 130), stratifying complete remission (CR) vs. No CR, (NCR). HCT-CI scores varied, from 0 to 10. All evaluable patients engrafted. Median follow-up was 66 months (interquartile range: 58-80). Three-year relapse incidence (RI), 25% with FCB, vs. 39% with Flu-Bu (p = 0.018), offset by higher non-relapse mortality, 22.6% (95%CI: 16-30.2%) vs. 12.3% (95%CI: 6.5-19%). Three-year PFS was 52% (95%CI: 44-62%) (FCB), vs. 48% (95%CI: 41-58%) (Flu-Bu). FCB benefited CR patients less, NCR patients age ≤ 60 had 3-year 34% RI (95%CI: 19-49%) (FCB) vs. 56% (95%CI: 38-70%) after Flu-Bu (p = 0.037). NCR patients >60 years had 3-year RI 10.0% (FCB), vs. 56.0%, after Flu-Bu (p = 0.003). Bayesian regression analysis including treatment-covariate interactions showed FCB superiority in NCR patients with low HCT-CI (0-2). Serious adverse event profiles were similar for the regimens. Conditioning with FCB did not improve PFS overall, but improved disease control in NCR patients, mandating confirmatory trials. Remission status and HCT-CI should be considered when using FCB.

BackgroundProgression in tumor assessments is often detected at a follow-up appointment rather than when actual change in progression has occurred, which can bias PFS outcomes.AimWe sought to evaluate the frequency of tumor assessment scans in clinical trials of anti-cancer interventions and to compare this to recommended (National Comprehensive Cancer Network) and real-world frequencies of tumor assessments.MethodsIn a cross-sectional analysis, we searched for articles published in the three top oncology journals between July 2017 and June 2020. We included articles that were RCTs of patients that had unresectable or metastatic solid tumors and used an intervention that was designed to be anti-tumor. We abstracted median PFS survival for each group, the PFS hazard ratio, frequency of tumor assessment scans, tumor type, intervention type, and information regarding the study.ResultsWe found that, in the 182 comparisons (163 articles), less frequent tumor assessment (occurring more than 9 weeks between assessments) was associated with higher median PFS values for both the intervention group (p

Secondary central nervous system lymphoma (SCNSL) is associated with poor prognosis and new therapeutic approaches are needed. The pivotal trial that led to US Food and Drug Administration (FDA) approval of axicabtagene ciloleucel excluded patients with SCNSL and human immunodeficiency virus. In this multi-institutional retrospective study, 14 SCNSL patients treated with axicabtagene ciloleucel, 3 of whom had human immunodeficiency virus, experienced rates of severe neurotoxicity and complete response of 32% and 58%, respectively. This is similar to rates observed in the pivotal ZUMA-1 trial that led to the approval of axi-cel at median follow-up of 5.9 months. Chimeric antigen receptor T-cell therapy is potentially a life-saving therapy for SCNSL patients and should not be withheld.

PurposeCell-free DNA (cfDNA) offers a noninvasive approach to monitor cancer. Here we develop a method using whole-exome sequencing (WES) of cfDNA for simultaneously monitoring the full spectrum of cancer treatment outcomes, including minimal residual disease (MRD), recurrence, evolution, and second primary cancers.Experimental designThree simulation datasets were generated from 26 patients with cancer to benchmark the detection performance of MRD/recurrence and second primary cancers. For further validation, cfDNA samples (n = 76) from patients with cancer (n = 35) with six different cancer types were used for performance validation during various treatments.ResultsWe present a cfDNA-based cancer monitoring method, named cfTrack. Taking advantage of the broad genome coverage of WES data, cfTrack can sensitively detect MRD and cancer recurrence by integrating signals across known clonal tumor mutations of a patient. In addition, cfTrack detects tumor evolution and second primary cancers by de novo identifying emerging tumor mutations. A series of machine learning and statistical denoising techniques are applied to enhance the detection power. On the simulation data, cfTrack achieved an average AUC of 99% on the validation dataset and 100% on the independent dataset in detecting recurrence in samples with tumor fractions ≥0.05%. In addition, cfTrack yielded an average AUC of 88% in detecting second primary cancers in samples with tumor fractions ≥0.2%. On real data, cfTrack accurately monitors tumor evolution during treatment, which cannot be accomplished by previous methods.ConclusionsOur results demonstrated that cfTrack can sensitively and specifically monitor the full spectrum of cancer treatment outcomes using exome-wide mutation analysis of cfDNA.

Therapy-related myeloid neoplasms (t-MN) are a distinct subgroup of myeloid malignancies with a poor prognosis that include cases of therapy-related myelodysplastic syndrome (t-MDS), therapy-related myeloproliferative neoplasms (t-MPN) and therapy-related acute myeloid leukemia (t-AML). Here, we report a series of patients with clinical features consistent with juvenile myelomonocytic leukemia (JMML), an overlap syndrome of MDS and myeloproliferative neoplasms that developed after treatment for another malignancy.

Introduction/backgroundSecond primary lung cancers (SPLC) are common following non-small cell lung cancer (NSCLC) treatment. Development of SPLC following stereotactic ablative radiation therapy (SABR) may differ as compared to surgical cohorts. We report incidence of and outcomes for SPLC detected by surveillance imaging in a cohort of patients treated with SABR.Materials/methodsPatients treated with SABR for node-negative NSCLC between February, 2007 to May, 2019 were retrospectively identified. Patient characteristics, frequency of surveillance imaging, development of SPLC, recurrence patterns, and survival were reviewed. Surveillance CT was performed Q3-4 month year 1, Q3-6 month year 2, Q6-12 month year 3-5, and Q12 month thereafter. Actuarial estimates of development of SPLC and overall survival (OS) were generated with competing risk analysis.ResultsWe identified 134 patients treated with SABR with ≥6 months follow up. Eighteen (13.4%) developed a total of 21 SPLC at a median of 28.5 months (range 3.0-84.7 months) following SABR, 19 (90.5%) biopsy-proven. Twenty (95.2%) SPLC were detected by surveillance imaging. Three patients developed 2 metachronous SPLC. Three and 5 year SPLC estimates were 11.7% and 13.1%. Eighteen (85.7%) SPLC were treated with curative intent. Two and 3 year estimate of OS following detection of SPLC was 79.8% and 54.7%.ConclusionSPLC were more common in our cohort than other published studies. Outcomes following surveillance detected SPLC are similar to those of de novo early stage lung cancers. The high frequency of SPLC in our cohort suggests further studies to refine overall surveillance in very high-risk populations are needed.

PurposePreclinical data suggest the combination of an anti-programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600-mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti-programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with BRAF V600-mutant unresectable or metastatic melanoma.MethodsPatients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic BRAF V600-mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692).ResultsAt data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P = .042 [one-sided; nonsignificant]). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade ≥ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm.ConclusionThe study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.

We compared secondary primary malignancy risk (SPM) in HIV-uninfected and HIV-infected Hodgkin lymphoma (HL) survivors. We used data from the California Cancer Registry on patients diagnosed with HL from 1990 to 2015 (all ages included), and standardized incidence ratios (SIRs) and multivariable competing risk models for analyses. Of 19,667 survivors, 735 were HIV-infected. Compared with the general population, the risk of SPM was increased by 2.66-fold in HIV-infected and 1.92-fold in HIV-uninfected survivors. Among HIV-infected survivors, median time to development of SPM was shorter (5.4 years) than in HIV-uninfected patients (8.1 years). Additionally, the highest risk of SPM was observed

Clonal hematopoiesis (CH) mutations are common among individuals without known hematologic disease. CH mutations have been associated with numerous adverse clinical outcomes across many different studies. We systematically reviewed the available literature for clinical outcomes associated with CH mutations in patients without hematologic disease. We searched PubMed, EMBASE, and Scopus for eligible studies. Three investigators independently extracted the data, and each study was verified by a second author. Risk of bias was assessed using the Newcastle-Ottawa Scale. We identified 32 studies with 56 cohorts that examine the association between CH mutations and clinical outcomes. We conducted meta-analyses comparing outcomes among individuals with and without detectable CH mutations. We conducted meta-analyses for cardiovascular diseases (nine studies; HR = 1.61, 95% CI = 1.26-2.07, p = .0002), hematologic malignancies (seven studies; HR = 5.59, 95% CI = 3.31-9.45, p

BackgroundTherapeutic options are needed for metastatic melanoma refractory to therapies directed against programmed cell death-1. High-dose interleukin-2 has the potential to overcome programmed cell death-1 resistance.Case presentationWe report three consecutive Caucasian patients, two female (60 and 55 years old) and one male (56 years old), refractory to anti-programmed cell death-1 therapy who were treated with concurrent nivolumab and standard-dosing bolus high-dose interleukin-2. We did not see any unexpected toxicities with overlapping treatments as compared with either high-dose interleukin-2 or nivolumab alone.ConclusionsThe tolerance and disease control observed among the three patients in this limited series support formal exploration of this combination.

BackgroundSecondary cancers account for 16% of all new cancer diagnoses, with breast cancer (BC) the most common secondary cancer. We have shown that secondary BC has unique characteristics and decreased survival compared with primary BC in adolescent and young adults (AYA; 15-39 years old). However, older BC populations are less well studied.MethodsFemales (age ≥ 15 years) diagnosed with primary BC during 1991-2015 (n = 377,167) and enrolled in the California Cancer Registry were compared with those with secondary BC (n = 37,625) by age (15-39, 40-64, ≥ 65 years). We examined BC-specific survival (BCSS) accounting for other causes of death as a competing risk using multivariable Cox proportional hazards regression.ResultsMost secondary BC patients were of older age (15-39, n = 777; 40-64, n = 15,848; ≥ 65, n = 21,000). Compared with primary BC treatment, secondary BCs were more often treated with mastectomy and less often with chemotherapy and/or radiation. BCSS was shorter in secondary BC patients than primary BC patients, but the survival difference between secondary and primary BC diminished with age [15-39 hazard ratio (HR): 2.09, 95% confidence interval (CI) 1.83-2.39; 40-64 HR: 1.51; 95% CI 1.44-1.58; ≥ 65 HR: 1.14; 95% CI 1.10-1.19]. Survival differences were most pronounced in women with hormone receptor positive disease and Hispanic and Asian/Pacific Islanders 40-64 years of age.ConclusionsWhen BC is diagnosed following a prior cancer of any organ site, BCSS is worse than when compared with patients for whom BC is the primary diagnosis, suggesting that we may need to tailor our treatments for women with secondary BC.

As survival times of multiple myeloma (MM) patients continue to improve, second primary malignancies (SPM) have become an increasingly relevant long-term risk among MM survivors. Population studies since the 1950s have consistently observed an increased incidence of hematologic SPMs, specifically acute leukemia, among MM survivors. Prolonged treatment with alkylators, especially melphalan, was associated with an increased hematologic SPM risk; likewise, autologous stem cell transplantation appeared to minimally increase SPM risk. Immunomodulatory drugs, specifically lenalidomide, was associated with an increased SPM incidence, although most studies concluded that the benefits of therapy outweighed any risks of SPM. Newer anti-myeloma therapy such as proteasome inhibitors and monoclonal antibodies did not appear to increase SPM risk although robust long-term follow-up is lacking. This review discusses current understanding regarding SPMs among survivors of MM, how different host-, disease- and treatment-related factors contribute to SPM incidence and highlights emerging screening guidelines and prognosis for SPMs.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

Mutational heterogeneity can contribute to therapeutic resistance in solid cancers. In melanoma, the frequencies of intertumoral and intratumoral heterogeneity are controversial. We examined mutational heterogeneity within individual patients with melanoma using multiplatform analysis of commonly mutated driver and nonpassenger genes. We analyzed paired primary and metastatic tumors from 60 patients and multiple metastatic tumors from 39 patients whose primary tumors were unavailable (n = 271 tumors). We used a combination of multiplex SNaPshot assays, Sanger sequencing, mutation-specific PCR, or droplet digital PCR to determine the presence of BRAFV600, NRASQ61, TERT-124C>T, and TERT-146C>T mutations. Mutations were detected in BRAF (39%), NRAS (21%), and/or TERT (78%). Thirteen patients had TERTmutant discordant tumors; seven of these had a single tumor with both TERT-124C>T and TERT-146C>T mutations present at different allele frequencies. Two patients had both BRAF and NRAS mutations; one had different tumors and the other had a single tumor with both mutations. One patient with a BRAFmutant primary lacked mutant BRAF in at least one of their metastases. Overall, we identified mutational heterogeneity in 18 of 99 patients (18%). These results suggest that some primary melanomas may be composed of subclones with differing mutational profiles. Such heterogeneity may be relevant to treatment responses and survival outcomes.

Little is known about the incidence of late effects following non-Hodgkin lymphoma (NHL) among adolescent and young adult (AYA, 15-39 years) survivors. Using data from the California Cancer Registry linked to hospital discharge, we estimated the cumulative incidence of late effects at 10 years among AYAs diagnosed with NHL during 1996-2012, who survived ≥2 years. Cox proportional-hazards models were used to investigate the influence of sociodemographic and clinical factors on the occurrence of late effects. Of 4392 HIV-uninfected patients, the highest incident diseases were: endocrine (18·5%), cardiovascular (11·7%), and respiratory (5·0%), followed by secondary primary malignancy (SPM, 2·6%), renal and neurologic (2·2%), liver/pancreatic (2·0%), and avascular necrosis (1·2%). Among the 425 HIV-infected survivors, incidence was higher for all late effects, especially over threefold increased risk of SPM, compared to HIV-uninfected patients (8·1% vs. 2·6%). In multivariable models for HIV-uninfected patients, public or no health insurance (vs. private), residence in lower socioeconomic neighbourhoods (vs. higher), and receipt of a haematopoietic stem cell transplant were associated with a greater risk of most late effects. Our findings of substantial incidence of late effects among NHL AYA survivors emphasise the need for longterm follow-up and appropriate survivorship care to reduce morbidity and mortality in this vulnerable population.

ObjectivesTreatment-induced lesions represent a great challenge in neuro-oncology. The aims of this study were (i) to characterize treatment induced lesions in glioblastoma patients treated with chemoradiotherapy and heat-shock protein (HSP) vaccine and (ii) to evaluate the diagnostic accuracy of diffusion weighted imaging for differentiation between treatment-induced lesions and tumor progression.MethodsTwenty-seven patients with newly diagnosed glioblastoma treated with HSP vaccine and chemoradiotherapy were included. Serial magnetic resonance imaging evaluation was performed to detect treatment-induced lesions and assess their growth. Quantitative analysis of the apparent diffusion coefficient (ADC) was performed to discriminate treatment-induced lesions from tumor progression. Mann-Whitney U-test and receiver operating characteristic (ROC) curves were used for analysis.ResultsThirty-three percent of patients developed treatment-induced lesions. Five treatment-related lesions appeared between end of radiotherapy and the first vaccine administration; 4 lesions within the first 4 months from vaccine initiation and 1 at 3.5 years. Three patients with pathology proven treatment-induced lesions showed a biphasic growth pattern progressed shortly after. ADC ratio between the peripheral enhancing rim and central necrosis showed an accuracy of 0.84 (95% CI 0.63-1) for differentiation between progression and treatment-induced lesions.ConclusionOur findings do not support the iRANO recommendation of a 6-month time window in which progressive disease should not be declared after immunotherapy initiation. A biphasic growth pattern of pathologically proven treatment-induced lesions was associated with a dismal prognosis. The presence of lower ADC values in the central necrotic portion of the lesions compared to the enhancing rim shows high specificity for detection of treatment-induced lesions.

BackgroundThere are few reports of the association of other cancers with Ewing sarcoma in patients and their relatives. We use a resource combining statewide genealogy and cancer reporting to provide unbiased risks.MethodsUsing a combined genealogy of 2.3 million Utah individuals and the Utah Cancer Registry (UCR), relative risks (RRs) for cancers of other sites were estimated in 143 Ewing sarcoma patients using a Cox proportional hazards model with matched controls; however, risks in relatives were estimated using internal cohort-specific cancer rates in first-, second-, and third-degree relatives.ResultsCancers of three sites (breast, brain, complex genotype/karyotype sarcoma) were observed in excess in Ewing sarcoma patients. No Ewing sarcoma patients were identified among first-, second-, or third-degree relatives of Ewing sarcoma patients. Significantly increased risk for brain, lung/bronchus, female genital, and prostate cancer was observed in first-degree relatives. Significantly increased risks were observed in second-degree relatives for breast cancer, nonmelanoma eye cancer, malignant peripheral nerve sheath cancer, non-Hodgkin lymphoma, and translocation sarcomas. Significantly increased risks for stomach cancer, prostate cancer, and acute lymphocytic leukemia were observed in third-degree relatives.ConclusionsThis analysis of risk for cancer among Ewing sarcoma patients and their relatives indicates evidence for some increased cancer predisposition in this population which can be used to individualize consideration of potential treatment of patients and screening of patients and relatives.

Background There is lack of consensus regarding the use of breast MRI for routine surveillance for second breast cancer events in women with a personal history of breast cancer. Purpose To compare performance of surveillance mammography with breast MRI. Materials and Methods This observational cohort study used prospectively collected data and included 13 266 women age 18 years and older (mean age, 60 years ± 13) with stage 0-III breast cancer who underwent 33 938 mammographic examinations and 2506 breast MRI examinations from 2005 to 2012 in the Breast Cancer Surveillance Consortium. Women were categorized into two groups: mammography alone (n = 11 745) or breast MRI (n = 1521). Performance measures were calculated by using end-of-day assessment and occurrence of second breast cancer events within 1 year of imaging. Logistic regression was used to compare performance for breast MRI versus mammography alone, adjusting for women, examination, and primary breast cancer characteristics. Analysis was conducted on a per-examination basis. Results Breast MRI was associated with younger age at diagnosis, chemotherapy, and higher education and income. Raw performance measures for breast MRI versus mammography were as follows, respectively: cancer detection rates, 10.8 (95% confidence interval [CI]: 6.7, 14.8) versus 8.2 (95% CI: 7.3, 9.2) per 1000 examinations; sensitivity, 61.4% (27 of 44; 95% CI: 46.5%, 76.2%) versus 70.3% (279 of 397; 95% CI: 65.8%, 74.8%); and biopsy rate, 10.1% (253 of 2506; 95% CI: 8.9%, 11.3%) versus 4.0% (1343 of 33 938; 95% CI: 3.7%, 4.2%). In multivariable models, breast MRI was associated with higher biopsy rate (odds ratio [OR], 2.2; 95% CI: 1.9, 2.7; P < .001) and cancer detection rate (OR, 1.7; 95% CI: 1.1, 2.7; P = .03) than mammography alone. However, there were no differences in sensitivity (OR, 1.1; 95% CI: 0.4, 2.9; P = .84) or interval cancer rate (OR, 1.1; 95% CI: 0.6, 2.2; P = .70). Conclusion Comparison of the performance of surveillance breast MRI with mammography must account for patient characteristics. Whereas breast MRI leads to higher biopsy and cancer detection rates, there were no significant differences in sensitivity or interval cancers compared with mammography. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Newell in this issue.

BackgroundIn this retrospective study, data from patients listed in the Korea Central Cancer Registry during 1993-2014 were analysed, to investigate the incidence and survival of second primary cancers (SPCs) after a diagnosis of primary peritoneal, epithelial ovarian, and fallopian tubal (POFT) cancer.MethodsThe standardised incidence ratio (SIR) and survival outcomes of patients with SPCs among POFT cancer survivors were analysed.ResultsAmong 20,738 POFT cancer survivors, 798 (3.84%) developed SPCs, at an average interval of 5.50 years. SPC risk in POFT survivors (SIR, 1.29) was higher compared to the general population. The most high-risk type of SPC was leukaemia (3.07) followed by the lung and bronchus (1.80), colon (1.58), rectum and rectosigmoid junction (1.42), thyroid (1.34), and breast (1.26). In women aged

Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen. The primary end point was overall survival. Results CPX-351 significantly improved median overall survival versus 7+3 (9.56 v 5.95 months; hazard ratio, 0.69; 95% CI, 0.52 to 0.90; one-sided P = .003). Overall remission rate was also significantly higher with CPX-351 versus 7+3 (47.7% v 33.3%; two-sided P = .016). Improved outcomes were observed across age-groups and AML subtypes. The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351. Early mortality rates with CPX-351 and 7+3 were 5.9% and 10.6% (two-sided P = .149) through day 30 and 13.7% and 21.2% (two-sided P = .097) through day 60. Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML. The safety profile of CPX-351 was similar to that of conventional 7+3 therapy.

Purpose The aim of the current study was to characterize the risk of interval invasive second breast cancers within 5 years of primary breast cancer treatment. Methods We examined 65,084 surveillance mammograms from 18,366 women with a primary breast cancer diagnosis of unilateral ductal carcinoma in situ or stage I to III invasive breast carcinoma performed from 1996 to 2012 in the Breast Cancer Surveillance Consortium. Interval invasive breast cancer was defined as ipsilateral or contralateral cancer diagnosed within 1 year after a negative surveillance mammogram. Discrete-time survival models-adjusted for all covariates-were used to estimate the probability of interval invasive cancer, given the risk factors for each surveillance round, and aggregated across rounds to estimate the 5-year cumulative probability of interval invasive cancer. Results We observed 474 surveillance-detected cancers-334 invasive and 140 ductal carcinoma in situ-and 186 interval invasive cancers which yielded a cancer detection rate of 7.3 per 1,000 examinations (95% CI, 6.6 to 8.0) and an interval invasive cancer rate of 2.9 per 1,000 examinations (95% CI, 2.5 to 3.3). Median cumulative 5-year interval cancer risk was 1.4% (interquartile range, 0.8% to 2.3%; 10th to 90th percentile range, 0.5% to 3.7%), and 15% of women had ≥ 3% 5-year interval invasive cancer risk. Cumulative 5-year interval cancer risk was highest for women with estrogen receptor- and progesterone receptor-negative primary breast cancer (2.6%; 95% CI, 1.7% to 3.5%), interval cancer presentation at primary diagnosis (2.2%; 95% CI, 1.5% to 2.9%), and breast conservation without radiation (1.8%; 95% CI, 1.1% to 2.4%). Conclusion Risk of interval invasive second breast cancer varies across women and is influenced by characteristics that can be measured at initial diagnosis, treatment, and imaging. Risk prediction models that evaluate the risk of cancers not detected by surveillance mammography should be developed to inform discussions of tailored surveillance.

PURPOSE: Hodgkin lymphoma (HL) survivors experience high risks of second cancers and cardiovascular disease, but no studies have considered whether the occurrence of these and other medical conditions differ by sociodemographic factors in adolescent and young adult (AYA) survivors. METHODS: Data for 5,085 patients aged 15-39 when diagnosed with HL during 1996-2012 and surviving ≥ 2 years were obtained from the California Cancer Registry and linked to hospitalization data. We examined the impact of race/ethnicity, neighborhood socioeconomic status (SES), and health insurance on the occurrence of medical conditions (≥ 2 years after diagnosis) and the impact of medical conditions on survival using multivariable Cox proportional hazards regression. RESULTS: Twenty-six percent of AYAs experienced at least one medical condition and 15% had ≥ 2 medical conditions after treatment for HL. In multivariable analyses, Black HL survivors had a higher likelihood (vs. non-Hispanic Whites) of endocrine [hazard ratio (HR) = 1.37, 95% confidence interval (CI) 1.05-1.78] and circulatory system diseases (HR = 1.58, CI 1.17-2.14); Hispanics had a higher likelihood of endocrine diseases [HR = 1.24 (1.04-1.48)]. AYAs with public or no insurance (vs. private/military) had higher likelihood of circulatory system diseases, respiratory system diseases, chronic kidney disease/renal failure, liver disease, and endocrine diseases. AYAs residing in low SES neighborhoods (vs. high) had higher likelihood of respiratory system and endocrine diseases. AYAs with these medical conditions or second cancers had an over twofold increased risk of death. CONCLUSION: Strategies to improve health care utilization for surveillance and secondary prevention among AYA HL survivors at increased risk of medical conditions may improve outcomes.

PurposeHodgkin lymphoma (HL) survivors experience high risks of second cancers and cardiovascular disease, but no studies have considered whether the occurrence of these and other medical conditions differ by sociodemographic factors in adolescent and young adult (AYA) survivors.MethodsData for 5,085 patients aged 15-39 when diagnosed with HL during 1996-2012 and surviving ≥ 2 years were obtained from the California Cancer Registry and linked to hospitalization data. We examined the impact of race/ethnicity, neighborhood socioeconomic status (SES), and health insurance on the occurrence of medical conditions (≥ 2 years after diagnosis) and the impact of medical conditions on survival using multivariable Cox proportional hazards regression.ResultsTwenty-six percent of AYAs experienced at least one medical condition and 15% had ≥ 2 medical conditions after treatment for HL. In multivariable analyses, Black HL survivors had a higher likelihood (vs. non-Hispanic Whites) of endocrine [hazard ratio (HR) = 1.37, 95% confidence interval (CI) 1.05-1.78] and circulatory system diseases (HR = 1.58, CI 1.17-2.14); Hispanics had a higher likelihood of endocrine diseases [HR = 1.24 (1.04-1.48)]. AYAs with public or no insurance (vs. private/military) had higher likelihood of circulatory system diseases, respiratory system diseases, chronic kidney disease/renal failure, liver disease, and endocrine diseases. AYAs residing in low SES neighborhoods (vs. high) had higher likelihood of respiratory system and endocrine diseases. AYAs with these medical conditions or second cancers had an over twofold increased risk of death.ConclusionStrategies to improve health care utilization for surveillance and secondary prevention among AYA HL survivors at increased risk of medical conditions may improve outcomes.

PurposeTo evaluate the incidence of colon cancer as a second primary cancer (CCSPC) and the survival outcomes of women with and without CCSPC after the diagnosis of endometrial cancer (EC).MethodsThe standardized incidence ratio (SIR) of CCSPC and survival outcomes of EC survivors with and without CCSPC were analyzed using data from January 1 1993 to December 31 2011, obtained from the Korea Central Cancer Registry.ResultsOf 14,797 EC survivors, 147 (0.99%) developed CCSPC after an average interval of 5.5 years. The SIR of CCSPC among EC survivors was 2.56, higher than that of colon cancer in the general population. The SIR of CCSPC was highest for the ascending (3.77), followed by the transverse (3.45), descending colon (2.06), and rectum (1.99). The risk of a proximal site of CCSPC was high, especially within 5 years after the diagnosis of EC in the ascending (SIR, 4.37) and transverse (4.91) colon, and in young survivors (

BackgroundAlthough it is known that the risk of a second breast cancer event among young women diagnosed with ductal carcinoma in situ (DCIS) is higher than in older women, the effect of current treatment options on long-term outcomes in this subgroup of women remains poorly defined. We aimed to evaluate national treatment trends and determine their effect on second breast cancer risk and overall survival among young women diagnosed with DCIS.Materials and methodsSurveillance, Epidemiology, and End Results data from 1998 to 2011 were used to analyze 3648 DCIS patients younger than age 40 years.ResultsAmong all treatment options, breast-conserving surgery (BCS) with radiation therapy (BCS + RT) was the most prevalent (36.1%) followed by mastectomy (MTX) without contralateral prophylactic MTX (CPM; 25.8%), BCS alone (22.2%), and MTX with CPM (15.8%). Risk of a second ipsilateral event was > 5-fold and > 2-fold lower within 2 years and 5 years of initial DCIS diagnosis, respectively, in women who received BCS + RT compared with BCS alone; and overall survival was 3-fold higher in women who received BCS + RT. However, MTX with or without CPM did not show an increase in overall survival compared with BCS + RT. In addition, although the percentage of young women who receive MTX with CPM has increased in recent years, MTX with CPM did not show an increased benefit in survival compared with MTX without CPM.ConclusionThe results of our study suggest that more aggressive treatments do not offer survival benefits over BCS + RT; thus, clinical treatment options in young women with DCIS should be carefully considered.

BACKGROUND:The adverse impact of second primary malignancies (SPMs) on survival is substantial for adolescents and young adults (AYAs; ie, those 15-39 years old). No studies have evaluated whether the latency time between the first malignancy (the primary malignancy [PM]) and the SPM affects cancer-specific survival (CSS). METHODS:A multivariate Cox proportional hazards regression with Surveillance, Epidemiology, and End Results data for 13 regions from 1992 to 2008 was used to ascertain whether the latency time (1-5 vs ≥ 6 years) to the development of an SPM affected the CSS and overall survival with respect to either the PM or SPM for AYAs with common SPMs. RESULTS:The majority of 1515 AYAs with an SPM had their PM diagnosed between the ages of 26 and 39 years (74.2%) and an SPM diagnosed within 1 to 5 years (72.9%) of the PM's diagnosis. Overall, AYAs that developed an SPM 1 to 5 years after the diagnosis (vs ≥ 6 years) had an increased risk of death from cancer (hazard ratio [HR], 2.52; 95% confidence interval [CI], 1.92-3.29) as well as any cause (HR, 2.60; 95% CI, 2.04-3.32). Specifically, for AYAs with an SPM that was leukemia or a colorectal, breast, or central nervous system malignancy, a shorter latency time (1-5 years) from their PM diagnosis was associated with an overall significantly increased risk of death (2.6-fold) from either their PM or that particular SPM. However, latency did not appear to affect the CSS with respect to either the PM or SPM for AYA patients with a lymphoma or sarcoma SPM. CONCLUSIONS:Most AYAs who develop an SPM do so within 1 to 5 years of their primary cancer diagnosis, and they have an increased risk of death from cancer in comparison with AYAs with an SPM developing after longer survivorship intervals. Cancer 2018;124:1260-8. © 2017 American Cancer Society.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of human cancer and has an increasing annual incidence. Although most cSCC is cured with office-based therapy, advanced cSCC poses a significant risk for morbidity, impact on quality of life, and death. This document provides evidence-based recommendations for the management of patients with cSCC. Topics addressed include biopsy techniques and histopathologic assessment, tumor staging, surgical and nonsurgical management, follow-up and prevention of recurrence, and management of advanced disease. The primary focus of these recommendations is on evaluation and management of primary cSCC and localized disease, but where relevant, applicability to recurrent cSCC is noted, as is general information on the management of patients with metastatic disease.

Basal cell carcinoma (BCC) is the most common form of human cancer, with a continually increasing annual incidence in the United States. When diagnosed early, the majority of BCCs are readily treated with office-based therapy, which is highly curative. In these evidence-based guidelines of care, we provide recommendations for the management of patients with BCC, as well as an in-depth review of the best available literature in support of these recommendations. We discuss biopsy techniques for a clinically suspicious lesion and offer recommendations for the histopathologic interpretation of BCC. In the absence of a formal staging system, the best available stratification based on risk for recurrence is reviewed. With regard to treatment, we provide recommendations on treatment modalities along a broad therapeutic spectrum, ranging from topical agents and superficially destructive modalities to surgical techniques and systemic therapy. Finally, we review the available literature and provide recommendations on prevention and the most appropriate follow-up for patients in whom BCC has been diagnosed.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of human cancer and has an increasing annual incidence. Although most cSCC is cured with office-based therapy, advanced cSCC poses a significant risk for morbidity, impact on quality of life, and death. This document provides evidence-based recommendations for the management of patients with cSCC. Topics addressed include biopsy techniques and histopathologic assessment, tumor staging, surgical and nonsurgical management, follow-up and prevention of recurrence, and management of advanced disease. The primary focus of these recommendations is on evaluation and management of primary cSCC and localized disease, but where relevant, applicability to recurrent cSCC is noted, as is general information on the management of patients with metastatic disease.

Basal cell carcinoma (BCC) is the most common form of human cancer, with a continually increasing annual incidence in the United States. When diagnosed early, the majority of BCCs are readily treated with office-based therapy, which is highly curative. In these evidence-based guidelines of care, we provide recommendations for the management of patients with BCC, as well as an in-depth review of the best available literature in support of these recommendations. We discuss biopsy techniques for a clinically suspicious lesion and offer recommendations for the histopathologic interpretation of BCC. In the absence of a formal staging system, the best available stratification based on risk for recurrence is reviewed. With regard to treatment, we provide recommendations on treatment modalities along a broad therapeutic spectrum, ranging from topical agents and superficially destructive modalities to surgical techniques and systemic therapy. Finally, we review the available literature and provide recommendations on prevention and the most appropriate follow-up for patients in whom BCC has been diagnosed.

BackgroundChildren with Down syndrome (DS) are at increased risk of developing acute leukemia and are more prone to acute toxicities. We studied the incidence and severity of chronic health conditions among survivors of childhood leukemia with DS compared with those without DS.MethodsChronic health conditions reported by questionnaire were compared between 154 pediatric leukemia survivors with DS and 581 without DS, matched by leukemia, age at diagnosis, race/ethnicity, sex, radiation location and chemotherapy exposure using Cox models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Subjects were selected from 7139 5-year survivors of leukemia in the Childhood Cancer Survivor Study.ResultsRisk of at least 1 late onset chronic health condition (grade 1-5) was similar in the DS population compared with the non-DS group (HR, 1.1; 95% CI, 0.7-1.5). Serious chronic health conditions (grade 3-5) were more common in DS survivors (HR, 1.7; 95% CI, 1.1-2.6), as were ≥ 3 chronic health conditions (grades 1-5) (HR, 1.7; 95% CI, 1.2-2.4). The 25-year cumulative incidence of any condition (grades 1-5) was 83% for DS survivors and 69% for non-DS survivors.ConclusionLeukemia survivors with DS have therapy-related chronic health conditions comparable to those of similarly treated survivors without DS, with a few notable exceptions: 1) an increased risk of cataracts, hearing loss, and thyroid dysfunction compared with survivors without DS (though these are known risks in the DS population), 2) decreased risk of second cancers, and 3) increased risk of severe or multiple conditions. Practitioners should be aware of these risks during and after therapy. Cancer 2018;124:617-25. © 2017 American Cancer Society.

ObjectivesWe investigated whether androgen deprivation therapy (ADT) in prostate cancer patients was associated with a decreased risk for second primary lung cancer in US veterans.MethodsProstate 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.ResultsAmong 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.ConclusionsADT in prostate cancer patients may be associated with decreased second primary lung cancer risk among US veterans.

ImportanceAlthough the increased incidence of second primary malignant neoplasms (SPMs) is a well-known late effect after cancer, few studies have compared survival after an SPM to survival of the same cancer occurring as first primary malignant neoplasm (PM) by age.ObjectiveTo assess the survival impact of SPMs in adolescents and young adults (AYAs) (15-39 years) compared with that of pediatric (

The effect of prior malignancy on the risk of developing, and prognosis of, acute lymphoblastic leukemia (ALL) is unknown. This observational study utilized the California Cancer Registry to estimate the risk of developing ALL after a prior malignancy using standardized incidence ratios (SIRs, 95% confidence intervals). ALL occurring after a malignancy with an SIR>1 (increased-risk (IR) malignancies) was considered secondary ALL (s-ALL). Adjusted hazard ratios (aHRs, 95% confidence intervals) compared the effect of s-ALL with de novo ALL on overall survival. A total of 14 481 patients with ALL were identified (1988-2012) and 382 (3%) had a known prior malignancy. Any prior malignancy predisposed patients to developing ALL: SIR 1.62 (1.45-1.79). Hematologic malignancies (SIR 5.57, 4.38-6.98) and IR-solid tumors (SIR 2.11, 1.73-2.54) increased the risk of developing ALL. s-ALL increased the risk of death compared with de novo ALL (aHR 1.38 (1.16-1.63)) and this effect was more pronounced among younger patients (age

BackgroundEwing sarcoma survivors (ESSs) are at increased risk for treatment-related complications. The incidence of treatment-related morbidity and late mortality with aging is unknown.MethodsThis study reports survival probabilities, estimated with the Kaplan-Meier method, and the cumulative incidence of cause-specific mortality and chronic conditions among ESSs in the Childhood Cancer Survivor Study who were treated between 1970 and 1986. Piecewise exponential models were used to estimate relative rates (RRs) and 95% confidence intervals (CIs) for these outcomes. Chronic conditions were graded with the Common Terminology Criteria for Adverse Events (version 4.03).ResultsAmong 404 5-year ESSs (median age at last follow-up, 34.8 years; range, 9.1-54.8 years), the 35-year survival rate was 70% (95% CI, 66%-74%). Late recurrence (cumulative incidence at 35 years, 15.1%) was the most common cause of death, and it was followed by treatment-related causes (11.2%). There were 53 patients with subsequent neoplasms (SNs; cumulative incidence at 35 years, 24.0%), and 38 were malignant (14.3% at 35 years). The standardized incidence ratios were 377.1 (95% CI, 172.1-715.9) for osteosarcoma, 28.9 (95% CI, 3.2-104.2) for acute myeloid leukemia, 14.9 (95% CI, 7.9-25.5) for breast cancer, and 13.1 (95% CI, 4.8-28.5) for thyroid cancer. Rates of chronic conditions were highest for musculoskeletal (RR, 18.1; 95% CI, 12.8-25.7) and cardiac complications (RR, 1.8; 95% CI, 1.4-2.3). Thirty-five years after the diagnosis, the cumulative incidences of any chronic conditions and 2 or more chronic conditions were 84.6% (95% CI, 80.4%-88.8%) and 73.8% (95% CI, 67.8%-79.9%), respectively.ConclusionsWith extended follow-up, ESSs' risk for late mortality and SNs does not plateau. Treatment-related chronic conditions develop years after therapy, and this supports the need for lifelong follow-up. Cancer 2017;123:2551-60. © 2017 American Cancer Society.

With the addition of rituximab and other treatment advances, survival after diffuse large B-cell lymphoma (DLBCL) has improved, but subsequent primary malignancies (SPMs) have emerged as an important challenge for DLBCL survivorship. We calculated standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for SPMs among 23 879 patients who survived at least 1 year after a first primary DLBCL diagnosed during 1989-2012, compared to the general population in California. Cumulative incidence (CMI) of SPMs, accounting for the competing risk of death, also was calculated. We found that the incidence of acute myeloid leukaemia (AML) nearly doubled in the post-rituximab era [SIR (95% CI) 4·39 (2·51-7·13) pre- (1989-2000) and 8·70 (6·62-11·22) post-rituximab (2001-2012)]. Subsequent thyroid cancer was rare pre-rituximab, but increased substantially after 2001 [0·66 (0·08-2·37) vs. 2·27(1·44-3·41)]. The 5-year CMI for all SPMs (4·77% pre- vs. 5·41% post-rituximab, P = 0·047), AML (0·15% vs. 0·41%, P = 0·003), thyroid cancer (0·03% vs. 0·15%, P = 0·003) and melanoma (0·25% vs. 0·42%, P = 0·020) were greater in DLBCL patients diagnosed in the post- versus pre-rituximab period. This study provides insight into the changing pattern of SPM occurrence after the introduction of rituximab, which may elucidate the aetiology of SPMs and should guide future cancer surveillance efforts among DLBCL patients.