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The impact of coronavirus disease 2019 vaccination on viral characteristics of breakthrough infections is unknown. In this prospective cohort study, incidence of severe acute respiratory syndrome coronavirus 2 infection decreased following vaccination. Although asymptomatic positive tests were observed following vaccination, the higher cycle thresholds, repeat negative tests, and inability to culture virus raise questions about their clinical significance.

Denosumab is a fully human monoclonal antibody that binds to, and inhibits, the receptor activator of RANKL (TNFSF11) and might affect breast cancer biology, as shown by preclinical evidence. We aimed to assess whether denosumab combined with standard-of-care adjuvant or neoadjuvant systemic therapy and locoregional treatments would increase bone metastasis-free survival in women with breast cancer.In this international, double-blind, randomised, placebo-controlled, phase 3 study (D-CARE), patients were recruited from 389 centres in 39 countries. We enrolled women (aged ≥ 18 years) with histologically confirmed stage II or III breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. On eligibility confirmation, investigators at each site telephoned an interactive voice response system to centrally randomly assign patients (1:1) based on a fixed stratified permuted block randomisation list (block size 4) to receive either denosumab (120 mg) or matching placebo subcutaneously every 3-4 weeks, starting with neoadjuvant or adjuvant chemotherapy, for about 6 months and then every 12 weeks for a total duration of 5 years. Stratification factors were breast cancer therapy, lymph node status, hormone receptor and HER2 status, age, and geographical region. The primary endpoint was the composite endpoint of bone metastasis-free survival. This trial is registered with ClinicalTrials.gov, NCT01077154.Between June 2, 2010, and Aug 24, 2012, 4509 women were randomly assigned to receive denosumab (n=2256) or placebo (n=2253) and included in the intention-to-treat analysis. The primary analysis of the study was done when all patients had the opportunity to complete 5 years of follow-up with an analysis data cutoff date of Aug 31, 2017. The primary endpoint of bone metastasis-free survival was not significantly different between the groups (median not reached in either group; hazard ratio 0·97, 95% CI 0·82-1·14; p=0·70). The most common grade 3 or worse treatment-emergent adverse events, reported in patients who had at least one dose of the investigational product (2241 patients with denosumab vs 2218 patients with placebo), were neutropenia (340 [15%] vs 328 [15%]), febrile neutropenia (112 [5%] vs 142 [6%]), and leucopenia (62 [3%] vs 61 [3%]). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2241 patients treated with denosumab versus four (1%) of 2218 patients treated with placebo; treatment-emergent hypocalcaemia occurred in 152 (7%) versus 82 (4%). Two treatment-related deaths occurred in the placebo group due to acute myeloid leukaemia and depressed level of consciousness.Despite preclinical evidence suggesting RANKL inhibition might delay bone metastasis or disease recurrence in patients with early-stage breast cancer, in this study, denosumab did not improve disease-related outcomes for women with high-risk early breast cancer.Amgen.

Background Although rare cancers account for 27% of cancer diagnoses in the US, there is insufficient research on survivorship issues in these patients. An important issue cancer survivors face is an elevated risk of being diagnosed with new primary cancers. The primary aim of this analysis was to assess whether a history of rare cancer increases the risk of subsequent cancer compared to survivors of common cancers. Methods This was a prospective cohort study of 16,630 adults with personal and/or family history of cancer who were recruited from cancer clinics at 14 geographically dispersed US academic centers of the NIH-sponsored Cancer Genetics Network (CGN). Participants’ self-reported cancer histories were collected at registration to the CGN and updated annually during follow-up. At enrollment, 14% of participants reported a prior rare cancer. Elevated risk was assessed via the cause-specific hazard ratio on the time to a subsequent cancer diagnosis. Results After a median follow-up of 7.9 years, relative to the participants who were unaffected at enrollment, those with a prior rare cancer had a 23% higher risk of subsequent cancer (95% CI: -1 to 52%), while those with a prior common cancer had no excess risk. Patients having two or more prior cancers were at a 53% elevated risk over those with fewer than two (95% CI: 21 to 94%) and if the multiple prior cancers were rare cancers, risk was further elevated by 47% (95% CI: 1 to 114%). Conclusion There is evidence suggesting that survivors of rare cancers, especially those with multiple cancer diagnoses, are at an increased risk of a subsequent cancer. There is a need to study this population more closely to better understand cancer pathogenesis. Electronic supplementary material The online version of this article (10.1186/s12885-019-5358-1) contains supplementary material, which is available to authorized users.

We sought to uncover genetic drivers of hormone receptor–positive (HR+) breast cancer, using a targeted next-generation sequencing approach for detecting expressed gene rearrangements without prior knowledge of the fusion partners. We identified intergenic fusions involving driver genes, including PIK3CA, AKT3, RAF1, and ESR1, in 14% (24/173) of unselected patients with advanced HR+ breast cancer. FISH confirmed the corresponding chromosomal rearrangements in both primary and metastatic tumors. Expression of novel kinase fusions in nontransformed cells deregulates phosphoprotein signaling, cell proliferation, and survival in three-dimensional culture, whereas expression in HR+ breast cancer models modulates estrogen-dependent growth and confers hormonal therapy resistance in vitro and in vivo. Strikingly, shorter overall survival was observed in patients with rearrangement-positive versus rearrangement-negative tumors. Correspondingly, fusions were uncommon ( Significance: By using a powerful clinical molecular diagnostic assay, we identified expressed intergenic fusions as frequent contributors to treatment resistance and poor survival in advanced HR+ breast cancer. The prevalence and biological and prognostic significance of these alterations suggests that their detection may alter clinical management and bring to light new therapeutic opportunities. Cancer Discov; 8(3); 336–53. ©2017 AACR. See related commentary by Natrajan et al., p. 272. See related article by Liu et al., p. 354. This article is highlighted in the In This Issue feature, p. 253

Purpose Precision oncology relies on frequent pathologic, molecular, and genomic assessments of tumor tissue to guide treatment selection, evaluate pharmacodynamic effects of novel agents, and determine drug resistance mechanisms. Newer forms of analyses such as drug screens in cell lines and patient-derived xenografts demand increasing amounts of tissue material. It remains unknown how the need for serial biopsies with large numbers of tumor cores relates to tissue yields and biopsy complication rates. Materials and Methods In this study, we performed a retrospective analysis of 199 focal liver biopsies performed in 143 patients in the setting of oncologic research protocols (research biopsy group) over a 4-year period at a single-intervention oncology service. Practice patterns and complication rates were compared with those related to 1,522 consecutive biopsies performed in 1,154 patients in whom two cores were obtained for standard clinical management of patients (standard biopsy). Results In the research biopsy group, 1,100 tissue cores (average, 5.5 cores per procedure) were harvested and distributed to trial sponsors, internal research laboratories, and pathology services. The complication rate in this cohort was 0.5% for major complications (one of 199) and 1.0% for minor complications managed conservatively (two of 199). In the standard biopsy control group, major complications were observed in 1.4% of procedures (22 of 1,522) and minor complications in 0.2% (three of 1,522). These complication rates were not statistically different. Conclusion Harvesting extra tissue cores through coaxial needles during focal liver biopsies does not increase complication rates and yields valuable tissue for additional experimental testing.

Background/AimsFor single arm trials, a treatment is evaluated by comparing an outcome estimate to historically reported outcome estimates. Such a historically controlled trial is often analyzed as if the estimates from previous trials were known without variation and there is no trial-to-trial variation in their estimands. We develop a test of treatment efficacy and sample size calculation for historically controlled trials that considers these sources of variation.MethodsWe fit a Bayesian hierarchical model, providing a sample from the posterior predictive distribution of the outcome estimand of a new trial, which, along with the standard error of the estimate, can be used to calculate the probability that the estimate exceeds a threshold. We then calculate criteria for statistical significance as a function of the standard error of the new trial and calculate sample size as a function of difference to be detected. We apply these methods to clinical trials for amyotrophic lateral sclerosis using data from the placebo groups of 16 trials.ResultsWe find that when attempting to detect the small to moderate effect sizes usually assumed in amyotrophic lateral sclerosis clinical trials, historically controlled trials would require a greater total number of patients than concurrently controlled trials, and only when an effect size is extraordinarily large is a historically controlled trial a reasonable alternative. We also show that utilizing patient level data for the prognostic covariates can reduce the sample size required for a historically controlled trial.ConclusionThis article quantifies when historically controlled trials would not provide any sample size advantage, despite dispensing with a control group.

Registries provide a unique tool for tracking quality of life in rare cancer survivors, whose survivorship experience is less known than for common cancers. This paper reports on these outcomes in 321 patients enrolled in the Rare Cancer Genetics Registry diagnosed with rare gastrointestinal, genitourinary, gynecologic, sarcoma, head/neck, or hematologic cancers. Four outcomes were assessed, reflecting registrants’ self-reported physical and mental health, psychological distress, and loneliness. Combining all patients into a single analysis, regression was used to evaluate the association between outcomes and socio-demographic and clinical factors. Median time since diagnosis was 3 years (range 0–9); 69 % were no longer in treatment. Poorer physical health was reported in registrants who were older at diagnosis, unmarried, and still in treatment. Poorer mental status was associated with younger diagnosis age and unmarried status. Psychological distress varied by cancer type and was higher among currently treated and unmarried registrants. Greater loneliness was reported in registrants with gynecological cancers, and those who were less educated or unmarried. The physical and mental health profile of rare cancer survivors is similar to what is reported for common cancers. Unmarried participants reported poorer outcomes on all measures of quality of life. Furthermore, physical and mental health were not significantly different by cancer type after adjustment for diagnosis age, whether currently in treatment and marital status. Thus, the combined analysis performed here is a useful way to analyze outcomes in less common diseases. Our findings could be valuable in guiding evaluation and intervention for issues impacting quality of life. Rare cancer survivors, particularly those without spousal support, should be monitored for challenges to the physical as well as psychological aspects of quality of life.

In resource-constrained environments many patients with human epidermal growth factor receptor 2 (HER2)+ early breast cancer are currently not offered adjuvant anti-HER2 therapy. For patients who might be able to receive the tyrosine kinase inhibitor (TKI) lapatinib (e.g. after patent expiration), it is important to identify subgroups of patients for whom anti-HER2 TKI therapy could be beneficial. To do this, we used data from 2489 patients with centrally confirmed HER2+ disease enrolled in the adjuvant Tykerb Evaluation After Chemotherapy (TEACH) trial, investigating the effect of lapatinib in patients with HER2+ early breast cancer not treated with trastuzumab. We performed subgroup analyses and number-needed-to-treat (NNT) calculations using patient and tumour associated predictors. Hormone receptor negative (HR-) patients on lapatinib had a significantly prolonged disease-free survival (DFS) compared to HR- patients on placebo (hazard ratio 0.64, P=0.003). For patients with HR- disease, starting treatment with lapatinib ≤1 year from diagnosis improved DFS by 12.1% [2.1-22.1] at 2 years and 15.7% [4.1-27.2] at 5 years. Depending on lymph node status and time since diagnosis the NNT for recurrence (at 5 years) was between 5.9 (node positive patients1 year from diagnosis) and 15.9. These numbers are in range with numbers reported for up-front adjuvant trastuzumab for HR unselected patients (e.g. 15.6 for DFS at 4 years in HERA). In a subgroup analysis of the adjuvant TEACH trial, we show that anti-HER2 monotherapy with a TKI is beneficial as adjuvant therapy in a subgroup of patients. NNT in HER2+ HR- patients are in range with those reported from up-front adjuvant trastuzumab trials.

Background: For a potentially lethal chronic disease like cancer, it is often infeasible to compare treatments on the basis of overall survival, so a combined outcome such as progression-free survival (which is the time from randomization to progression or death) has become an acceptable primary endpoint. The rationale of using an efficacy measure that is dominated by the time to progression is that an effective treatment will delay progression and when treatment is stopped at progression, the effect of treatment after this time is small. However, often trials that show a significant benefit for delaying progression but not on overall survival are not universally viewed as providing convincing evidence that the drug should become the standard of care. Methods: We propose that when there is a significant treatment effect of delaying progression, a Bayesian analysis of overall survival should be undertaken. We suggest using a joint piecewise exponential model, where the treatment effect on the hazard for progression and for death after progression is captured through two distinct parameters. We develop a plot of the overall survival advantage of the new therapy versus the prior distribution of the relative hazard for death after progression. This plot can augment the discussion about whether the new treatment is beneficial on survival. Results: In the example of an early breast cancer trial for which a new treatment significantly delayed disease recurrence, our Bayesian analysis showed that with very reasonable assumptions on the effects of treatment after recurrence, there is a high probability that the new treatment improves overall survival. Conclusion: For a clinical trial for which treatment delays progression, the proposed method can improve the interpretability of the survival comparison using data from the study.

Individuals whose families meet the Amsterdam II clinical criteria for hereditary non-polyposis colorectal cancer are recommended to be referred for genetic counseling and to have colonoscopic screening every 1-2 years. To assess the uptake and knowledge of guideline-based genetic counseling and colonoscopic screening in unaffected members of families who meet Amsterdam II criteria and their treating endoscopists.Participants in the Family Health Promotion Project who met the Amsterdam II criteria were surveyed regarding their knowledge of risk-appropriate guidelines for genetic counseling and colonoscopy screening. Endoscopy/pathology reports were obtained from patients screened during the study to determine the follow-up recommendations made by their endoscopists. Survey responses were compared using Fisher's Exact and the χ(2) test. Concordance in participant/provider-reported surveillance interval was assessed using the kappa statistic.Of the 165 participants, the majority (98%) agreed that genetics and family history are important predictors of CRC, and 63% had heard of genetic testing for CRC, although only 31% reported being advised to undergo genetic counseling by their doctor, and only 7% had undergone genetic testing. Only 26% of participants reported that they thought they should have colonoscopy every 1-2 years and 30% of endoscopists for these participants recommended 1-2-year follow-up colonoscopy. There was a 65% concordance (weighted kappa 0.42, 95% CI 0.24-0.61) between endoscopist recommendations and participant reports regarding screening intervals.A minority of individuals meeting Amsterdam II criteria in this series have had genetic testing and reported accurate knowledge of risk-appropriate screening, and only a small percentage of their endoscopists provided them with the appropriate screening recommendations. There was moderate concordance between endoscopist recommendations and participant knowledge suggesting that future educational interventions need to target both health-care providers and their patients.

PURPOSE: Advances in cancer detection and treatment have resulted in a growing population of long-term survivors, but even years after treatment has concluded many survivors report physical symptoms that interfere with daily living. While there are studies of late effects following common cancers, less is known about these complications in rare cancers. This study focuses on the physical symptoms reported by long-term survivors enrolled in the NIH-sponsored Rare Cancer Genetics Registry. METHODS: The Rotterdam Symptom Checklist-Modified was administered to evaluate the severity of physical symptoms commonly reported by long-term cancer survivors. Logistic regression was used to assess association between symptoms and demographic and clinical factors. RESULTS: In 309 subjects with a median time of 7.6 years from a diagnosis of one or more rare cancers the median number of symptoms present per participant was 7. The most prevalent symptom reported was tiredness/lack of energy, which was present/very bothersome in 70%/25% of registrants. Women, non-whites, current smokers, and upper GI cancer survivors are particularly affected. Overall, symptom prevalence was similar across rare cancer types, time since diagnosis, and type of treatment. CONCLUSIONS: Rare cancer survivors continue to experience troublesome symptoms many years after diagnosis, regardless of cancer type or treatment modality. IMPACT FOR CANCER SURVIVORS: There is a need for continued emphasis on smoking cessation in cancer survivors as well as enhanced monitoring of long-term complications in female, non-white, and upper GI cancer survivors.

Background: Several (neo)adjuvant treatments for patients with HER2-positive breast cancer have been compared in different randomized clinical trials. Since it is not feasible to conduct adequate pairwise comparative trials of all these therapeutic options, network meta-analysis offers an opportunity for more detailed inference for evidence-based therapy. Methods: Phase II/III randomized clinical trials comparing two or more different (neo)adjuvant treatments for HER2-positive breast cancer patients were included. Relative treatment effects were pooled in two separate network meta-analyses for overall survival (OS) and disease-free survival (DFS). Results: 17 clinical trials met our eligibility criteria. Two different networks of trials were created based on the availability of the outcomes: OS network (15 trials: 37,837 patients); and DFS network (17 trials: 40,992 patients). Two studies-the ExteNET and the NeoSphere trials-were included only in this DFS network because OS data have not yet been reported. The concept of the dual anti-HER2 blockade proved to be the best option in terms of OS and DFS. Chemotherapy (CT) plus trastuzumab (T) and lapatinib (L) and CT + T + Pertuzumab (P) are probably the best treatment options in terms of OS, with 62.47% and 22.06%, respectively. In the DFS network, CT + T + Neratinib (N) was the best treatment option with 50.55%, followed by CT + T + P (26.59%) and CT + T + L (20.62%). Conclusion: This network meta-analysis suggests that dual anti-HER2 blockade with trastuzumab plus either lapatinib or pertuzumab are probably the best treatment options in the (neo)adjuvant setting for HER2-positive breast cancer patients in terms of OS gain. Mature OS results are still expected for the Aphinity trial and for the sequential use of trastuzumab followed by neratinib, the treatment that showed the best performance in terms of DFS in our analysis., SCOPUS: re.j, info:eu-repo/semantics/published

Purpose The identification of patients with metastatic triple-negative breast cancer (mTNBC) who are expected to benefit from platinum-based chemotherapy is of interest. We conducted a single-arm phase II clinical trial of single-agent platinum for mTNBC with biomarker correlates. Patients and Methods Patients with mTNBC received first- or second-line cisplatin (75 mg/m2) or carboplatin (area under the concentration-time curve 6) by physician's choice once every 3 weeks. Coprimary end points were objective response rate (RR) and response prediction by p63/p73 gene expression. Secondary and exploratory end points included toxicity assessment, RR in cisplatin versus carboplatin, and RR in molecularly defined subgroups, including BRCA1/2 mutation carriers. Results Patients (N = 86; 69 as first-line therapy) received cisplatin (n = 43) or carboplatin (n = 43). RR was 25.6% (95% CI, 16.8% to 36%) and was numerically higher with cisplatin (32.6%) than with carboplatin (18.7%). RR was 54.5% in patients with germline BRCA1/2 mutations (n = 11). In patients without BRCA1/2 mutations (n = 66), exploratory analyses showed that a BRCA-like genomic instability signature (n = 32) discriminated responding and nonresponding tumors (mean homologous recombination deficiency–loss of heterozygosity/homologous recombination deficiency–large-scale state transitions [HRD-LOH/HRD-LST] scores were 12.68 and 5.11, respectively), whereas predefined analysis by p63/p73 expression status (n = 61), p53 and PIK3CA mutation status (n = 53), or PAM50 gene expression subtype (n = 55) did not. Five of the six long-term responders alive at a median of 4.5 years lacked germline BRCA1/2 mutations, and two of them had increased tumor HRD-LOH/HRD-LST scores. Conclusion Platinum agents are active in mTNBC, especially in patients with germline BRCA1/2 mutations. A measure of tumor DNA repair function may identify patients without mutations who could benefit from platinum therapy agents. Prospective controlled confirmatory trials are warranted.

To evaluate health related quality of life (HRQOL) in TEACH, a phase III randomized placebo controlled trial of 12 months of adjuvant lapatinib in HER2 positive (HER2+) early breast cancer which demonstrated marginal benefit in disease-free survival.Women on TEACH completed the Short Form 36-item health survey (version2; SF-36v2) at the baseline, six and 12 months after therapy initiation and six monthly thereafter. Mean changes were compared between treatment groups for two summary measures (Physical and Mental Component Summary scores; PCS and MCS) and eight domain measures (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health), and in patients discontinuing therapy. A five-point change was deemed a Minimally Clinically Important Difference (MCID). Response analysis compared the proportion of patients demonstrating a MCID in HRQOL, and a regression analysis identified predictors of worsening HRQOL.3074 (97%) subjects completed baseline SF-36v2. During the initial 12 months, summary SF-36v2 scores decreased in both arms but did not reach Minimally Clinically Important Difference (MCID) despite significant incidences of diarrhoea and rash in lapatinib treated patients. At six months, women receiving lapatinib had more significant reductions (p0.01 versus placebo) in social functioning. Early treatment discontinuations were more frequent on lapatinib (32% versus 18%), and were associated with more substantial decrements of HRQOL in both arms. For those discontinuing primarily due to adverse events, decrements in HRQOL reached MCID in Mental Summary scores (MCS) only. Lower baseline HRQOL was a significant predictor of worsening HRQOL (p0.05).Despite frequent but usually mild toxicities, adjuvant lapatinib is not associated with clinically significant decreases in overall HRQOL. These placebo-controlled results may also help to inform physicians and patients using lapatinib in metastatic HER2 positive breast cancer.GlaxoSmithKline. The AVON Foundation NY supported PEG, DF and BM and The Friends of the Mater Foundation supported FB.

PURPOSE: Breast cancer (BC) has been associated with pregnancy if diagnosed within 5–10 years after delivery (pregnancy-associated BC, PABC). PABC carries a poor prognosis compared to sporadic BC in Western populations. Data are limited regarding PABC in Asian populations, where longer periods of breastfeeding, higher birth rates and a lower median age of BC at diagnosis have been noted, all of which are known to influence prognosis. METHODS: We used data two datasets of women treated for early BC in Shanghai 1990–2012 (n=10,161 and n=7,411). For the analysis of BC risk after pregnancy we compared the distribution of pregnancy in our dataset to that in Shanghai using age-specific fertility rates. For disease-free survival (DFS) evaluation, we restricted our data to women ≤45 years. RESULTS: Women 30, the RR was decreased. Patients with PABC had a higher risk of recurrence or death (hazard ratio (HR) for DFS 1.72, P=0.019) compared to women with non-PABC by univariable analysis. Age was eliminated from the multivariable model by backward selection, resulting in tumor stage (3 versus 1, HR=3.08, P

Background: Acquiring resistance to endocrine therapy is common in metastatic hormone-receptor-positive breast cancer (MBC). These patients most often transition either to next-line endocrine therapy or to systemic chemotherapy. However, withdrawal of endocrine therapy and observation as is selectively practiced in prostate cancer is another potential strategy for breast cancer patients. Methods: A prospective, single-arm phase II trial of aromatase inhibitor (AI) withdrawal was performed in women with MBC, who had disease progression on AI therapy. The primary objective was to estimate the clinical benefit rate (defined as complete or partial response, or stable disease for at least 24 weeks, by RECIST criteria). Participants were monitored clinically and radiographically off all therapy at 8, 16 and 24 weeks after treatment and every 12 weeks thereafter until disease progression. Results: Twenty-four patients (of 40 intended) were enrolled when the study was closed due to slow accrual. Clinical benefit rate overall was 46% (95% CI 26% to 67%). Median progression-free survival from time of AI withdrawal was 4 months. Two patients have remained progression free, off all treatment, for over 60 months. Conclusions: Despite suboptimal patient accrual, our results suggest that selected patients with metastatic breast cancer progressing on AI therapy can experience disease stabilisation and a period of observation after AI withdrawal. A randomised phase II trial is planned.

Purpose Liver injury is a serious adverse event leading to permanent discontinuation of lapatinib in affected patients. This study aimed to validate previously associated major histocompatibility complex (MHC) variants as predictors of risk of liver injury by using a large, randomized, placebo-controlled trial of lapatinib in human epidermal growth factor receptor 2–positive, early-stage breast cancer (Tykerb Evaluation After Chemotherapy [TEACH]: Lapatinib Versus Placebo In Women With Early-Stage Breast Cancer). Patients and Methods The frequency of ALT elevation cases was compared among four MHC variants in 1,194 patients randomly assigned to lapatinib. Cumulative ALT elevation time courses during treatment were also compared between carriers and noncarriers of specified MHC variants. Results In lapatinib-treated patients, there was a significant difference in ALT case incidence between HLA carriers and noncarriers. The highly correlated alleles HLA-DRB1*07:01 and HLA-DQA1*02:01 (study frequency, 22.4%) were associated with ALT elevation (odds ratio, 14) between cases (n = 37) and controls (n = 1,071). These associations strengthened at higher ALT elevation thresholds and in Hy's Law cases. In lapatinib-treated patients, the overall risk for National Cancer Institute-Common Terminology Criteria for Adverse Events grade 3 ALT elevation (> 5× upper limit of normal) was 2.1%; HLA allele carriers had an increased risk of 7.7%; in noncarriers, risk was reduced to 0.5%, comparable to ALT elevation for all patients receiving placebo. The increase in ALT case incidence in the lapatinib arm showed no evidence of plateau during 1 year of lapatinib treatment. Conclusion These results validate HLA-DRB1*07:01 allele carriage as a predictor of increased risk of lapatinib-induced liver injury and implicate an immune pathology. The HLA association could support clinical management of patients experiencing hepatotoxicity during lapatinib treatment.

To examine patient characteristics, treatment modalities, and human papillomavirus (HPV) prevalence to identify potential mediators of disparities that may lead to differences in outcomes for American Indians with head and neck squamous cell carcinoma (HNSCC).Historical cohort study.Community cancer centers.We reviewed all patients older than 18 years with a new diagnosis of HNSCC in South Dakota from 1999 to 2009. We assessed tissue samples from cases of oropharyngeal cancer for the presence of HPV DNA.In total, 474 white patients were compared with 32 American Indians. American Indians experienced significantly worse survival compared with whites (hazard ratio [HR], 0.59; P = .05), even after controlling for other factors such as age, sex, distance, Charlson comorbidity index, alcohol abuse, smoking, insurance, and disease stage. American Indians had a greater risk of alcohol abuse (68% vs 42%; P = .008), current smoking (67% vs 49%; P = .03), living more than 1 hour from a cancer center (81% vs 30%; P.001), lacking private insurance (24% vs 68%; P.001), and late-stage disease presentation (stages III and IV) (74% vs 55%; P = .04). There were no detected differences in age, sex, medical comorbidities, tumor site, tumor grade, HPV status, time to treatment, or type of treatment received.American Indians in South Dakota with HNSCC have poorer survival compared with white patients. Once presented to a cancer center, American Indians received nearly identical treatment to white patients. Disparities in outcomes arise primarily due to sociodemographic factors and later stage at presentation.

Background: Individuals with a strong family history of colorectal cancer have significant risk for colorectal cancer, although adherence to colonoscopy screening in these groups remains low. This study assessed whether a tailored telephone counseling intervention can increase adherence to colonoscopy in members of high-risk families in a randomized, controlled trial. Methods: Eligible participants were recruited from two national cancer registries if they had a first-degree relative with colorectal cancer under age 60 or multiple affected family members, which included families that met the Amsterdam criteria for hereditary non-polyposis colon cancer (HNPCC), and if they were due for colonoscopy within 24 months. Participants were randomized to receive a tailored telephone intervention grounded in behavioral theory or a mailed packet with general information about screening. Colonoscopy status was assessed through follow-up surveys and endoscopy reports. Cox proportional hazards models were used to assess intervention effect. Results: Of the 632 participants (ages 25–80), 60% were female, the majority were White, non-Hispanic, educated, and had health insurance. Colonoscopy adherence increased 11 percentage points in the tailored telephone intervention group, compared with no significant change in the mailed group. The telephone intervention was associated with a 32% increase in screening adherence compared with the mailed intervention (HR, 1.32; P = 0.01). Conclusions: A tailored telephone intervention can effectively increase colonoscopy adherence in high-risk persons. This intervention has the potential for broad dissemination to healthcare organizations or other high-risk populations. Impact: Increasing adherence to colonoscopy among persons with increased colorectal cancer risk could effectively reduce incidence and mortality from this disease. Cancer Epidemiol Biomarkers Prev; 23(4); 601–10. ©2014 AACR.

Background: In women with early-stage breast cancer, the skeleton represents one of the most common sites for metastases and represents approximately 40% of all first recurrences. Preclinical studies demonstrated that inhibition of RANKL significantly delays skeletal tumor formation, reduces skeletal tumor burden, and prolongs survival of tumor-bearing mice. Denosumab, a human IgG2 monoclonal antibody, binds RANKL with high specificity and affinity thus inhibiting RANKL activity. Denosumab has been approved for the prevention of skeletal-related events (SREs) in patients with established bone metastases from solid tumors. Purpose: The D-CARE trial is designed to assess if denosumab treatment prolongs bone metastasis-free survival (BMFS; primary endpoint) in the adjuvant breast cancer setting. Secondary endpoints include disease-free survival (DFS) and overall survival. Additional endpoints include safety, patient reported outcomes (pain, health utilities), as well as exploratory including breast density, time to first on-study SRE following the development of bone metastasis and biomarkers. Methods: In this global, randomized, double-blind, and placebo-controlled phase 3 trial, approximately 4500 women with stage II or III breast cancer at high risk for recurrence were randomized. High risk is defined as biopsy evidence of breast cancer in regional lymph nodes, tumor size > 5 cm (T3), or locally advanced disease (T4). Patients must be receiving or planned to receive standard-of-care adjuvant/neoadjuvant therapy (chemo-, endocrine, or HER-2 targeted), alone or in combination. Patients with a prior history of breast cancer (except DCIS or LCIS) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization, or any intravenous BP use, were not eligible. Patients were randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. Supplemental vitamin D (≥ 400 IU) and calcium (≥ 500 mg) are required. The primary efficacy and two interim efficacy analyses are planned and will be event-driven. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154, began enrolling patients in June 2010 and completed enrollment in late 2012. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-02.

Patients with hormone receptor–positive early breast cancer have a continuous yearly rate of recurrence extending out to 15 years after having received adjuvant endocrine therapy with tamoxifen for 5 years (1). More than half of the recurrences and about two-thirds of breast cancer deaths in this group will occur beyond 5 years from diagnosis (ie, late recurrences and death) (1). The National Cancer Institute of Canada (NCIC) Clinical Trials Group MA.17 trial was a randomized, placebo-controlled trial demonstrating that extended endocrine therapy with letrozole improves disease-free survival (DFS) (2), distant DFS (DDFS), and overall survival (OS) in disease-free postmenopausal patients with hormonal receptor–positive breast cancer after 5 years of tamoxifen (3). Although extended antihormonal therapy has become standard practice and is endorsed by international clinical practice guidelines (4,5), understanding which patients will actually benefit from longer treatment is paramount to individualized therapy. The status of primary tumor estrogen receptor (ER) and progesterone receptor (PR) expression has been suggested, but not confirmed, as a way to identify patients who have increased benefit from extended letrozole (5). Patients with ER+ and PR+ tumors have been shown to have improved DFS (P = .02) when compared with patients with ER+ and PR− tumors (6). Currently, however, there are no guideline-accepted biomarkers to stratify hormonal receptor–positive patients for prediction of benefit beyond the 5 years of adjuvant endocrine therapy. In addition, standard clinico-pathological factors and clinically available genomic signatures, including the 21-gene (Recurrence Score) assay (7) and the 70-gene assay (8), have greatest prognostic performance for recurrence risk within the first 5 years of adjuvant therapy. Identification of additional biomarkers to further stratify hormone receptor–positive tumors to predict those at risk of late recurrence and those who may or may not benefit from extended endocrine therapy would be of substantial clinical utility (9). We have previously demonstrated that the two-gene expression ratio, HOXB13/IL17BR (H/I), is a prognostic biomarker in both untreated and tamoxifen-treated early-stage ER+ breast cancer patients (10–13). However, potential assessment of H/I as a predictive biomarker for endocrine therapy has been limited by the analysis of retrospective/observational cohorts or by the use of single treatment arm cohorts from randomized trials (11–13). Herein, we have conducted a prospective–retrospective (14), nested case-control study in a subset of patients from NCIC Clinical Trials Group MA.17 trial to evaluate the performance of H/I for 1) prognostication of late disease recurrence and 2) prediction of treatment benefit from extended adjuvant letrozole therapy in patients with hormone receptor–positive early breast cancer.

Non-communicable diseases, including cancer, are overtaking infectious disease as the leading health-care threat in middle-income and low-income countries. Latin American and Caribbean countries are struggling to respond to increasing morbidity and death from advanced disease. Health ministries and health-care systems in these countries face many challenges caring for patients with advanced cancer: inadequate funding; inequitable distribution of resources and services; inadequate numbers, training, and distribution of health-care personnel and equipment; lack of adequate care for many populations based on socioeconomic, geographic, ethnic, and other factors; and current systems geared toward the needs of wealthy, urban minorities at a cost to the entire population. This burgeoning cancer problem threatens to cause widespread suffering and economic peril to the countries of Latin America. Prompt and deliberate actions must be taken to avoid this scenario. Increasing efforts towards prevention of cancer and avoidance of advanced, stage IV disease will reduce suffering and mortality and will make overall cancer care more affordable. We hope the findings of our Commission and our recommendations will inspire Latin American stakeholders to redouble their efforts to address this increasing cancer burden and to prevent it from worsening and threatening their societies.

Worldwide, many patients with HER2-positive early stage breast cancer do not receive trastuzumab-the standard adjuvant treatment. We investigated the efficacy and safety of adjuvant lapatinib for patients with trastuzumab-naive HER2-positive early-stage breast cancer, started at any time after diagnosis.This study was a placebo-controlled, multicentre, randomised phase 3 trial. Women outpatients from 405 [corrected] centres in 33 countries [corrected] with HER2-positive early-breast cancer who had previously received adjuvant chemotherapy but not trastuzumab were randomly assigned (1:1) to receive daily lapatinib (1500 mg) or daily placebo for 12 months. Randomisation was done with a computer-generated sequence, stratified by time since diagnosis, lymph node involvement at diagnosis, and tumour hormone-receptor status. Investigators, site staff, and patients were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00374322.Between August, 2006, and May, 2008, 3161 women were enrolled and 3147 were assigned to lapatinib (n=1571) or placebo (n=1576). After a median follow-up of 47·4 months (range 0·4-60·0) in the lapatinib group and 48·3 (0·7-61·3) in the placebo group, 210 (13%) disease-free survival events had occurred in the lapatinib group versus 264 (17%) in the placebo group (hazard ratio [HR] 0·83, 95% CI 0·70-1·00; p=0·053). Central review of HER2 status showed that only 2490 (79%) of the randomised women were HER2-positive. 157 (13%) of 1230 confirmed HER2-positive patients in the lapatinib group and in 208 (17%) of 1260 in the placebo group had a disease-free survival event (HR 0·82, 95% 0·67-1·00; p=0·04). Serious adverse events occurred in 99 (6%) of 1573 patients taking lapatinib and 77 (5%) of 1574 patients taking placebo, with higher incidences of grade 3-4 diarrhoea (97 [6%] vs nine [1%]), rash (72 [5%] vs three [1%]), and hepatobiliary disorders (36 [2%] vs one [1%]).Our data show that there was no significant difference in disease-free survival between groups when analysed in the intention-to-treat population. However, exploratory analyses restricted to patients who had HER2-positive disease confirmed by central fluorescence in-situ hybridisation review suggested marginal benefit with lapatinib in terms of disease-free survival. Thus lapatinib might be an option for women with HER2-positive breast cancer who do not or cannot receive adjuvant trastuzumab.GlaxoSmithKline.

Background: Near-infrared optical measurements have been recently shown to offer a promising non-invasive way for monitoring breast neoadjuvant chemotherapy (NAC) and predicting outcome. In particular, snapshots of tissue oxy and deoxy-hemoglobin concentration as well as water and lipid content have been demonstrated to be sensitive to therapy-induced changes. In this study, we extend optical measurements to capture additional hemodynamic and metabolic biomarkers revealed by dynamically imaging breast tissue during fractional mammographic compression. Using our dynamic tomographic optical breast imaging (TOBI) system we evaluate the early prediction performance of this advanced technology. Methods: We are conducting a pilot feasibility study in female patients with unilateral locally advanced breast cancer undergoing standard-of-care NAC. Pre-treatment and day 7 post-treatment TOBI scans are obtained, with additional (optional) scans on day 1 of each subsequent chemotherapy cycle. Both breasts are compressed in turn to 4–8 lbs of force, and optical images are acquired once every 2 seconds over two minutes. Time-resolved oxy-(HbO), deoxy-(HbR), and total-(HbT) hemoglobin concentration and hemoglobin oxygen saturation (SO2) are calculated. The compression-induced rate of change of HbT correlates with changes in tissue blood volume indicative of biomechanical properties. The evolution of tissue SO2 is modeled to obtain an index of the ratio of oxygen metabolism to blood flow. Therapy induced changes are quantified, and comparisons between changes in responders vs. non-responders are performed (response is defined here as >50% reduction in the largest tumor diameter). Results: We have enrolled 20 patients so far, of which 90% (N = 18) completed both the day 0 and day 7 scans. 17 patients have undergone surgery at this point. We focused our initial analysis on 5 HER2+ patients, of which two were non-responders, and three were responders according to our criteria. Four patients received taxol+herceptin+lapatinib, while the other received taxol+lapatinib only. In this small subgroup, the non-responders had an average increase of 1% in total hemoglobin concentration (HbT) from day 0 to day 7, while the responders had an average 12% decrease in HbT, respectively. We also noted different trends in the evolution of the tissue oxygen consumption to blood flow ratio, which increased 32% in non-responders from day 0 to day 7, while decreasing 11% in responders. Conclusions: The large percentage of enrolled patients that completed both initial scans demonstrates the feasibility of using dynamic optical breast tomography for breast neoadjuvant chemotherapy monitoring. Results in a small cohort of 5 HER2+ patients suggested a decreasing trend in HbT for responders as observed by previous studies. We also report for the first time an increase in the metabolic ratio of oxygen consumption to blood flow in non-responders vs. a decrease in responders. These initial results of our on-going study suggest that dynamic TOBI can detect changes due to treatment and may have predictive value for the treatment outcome and supports further studies of this non-invasive and portable tool for chemotherapy monitoring. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-06-27.

HER2-overexpressing breast cancer (BC) is common among young patients and poses a public health burden. Adjuvant anti-HER2/neu therapy with trastuzumab reduces the risk of recurrence and improves survival.A web-based survey was sent to 386 physicians of the "TEACH" trial in 2011 to determine access to HER2/neu testing and treatment patterns for HER2-overexpressing BC.There were 151 responders (39%) from 28 countries. Ninety-seven percent reported HER2/neu expression is routinely measured in their institutions by immunohistochemistry (85%), FISH (80%) and other methods (16%). Twenty percent of responders from Asia reported that the test was not routinely available. Forty-eight percent of participants reported instances when adjuvant HER2-directed therapy was recommended to a patient who eventually did not receive it. Reasons for not receiving trastuzumab was cost (73%, p 0.0001) in low- and middle-income countries and co-morbidities in high-income countries (43%, p = 0.003).This survey reflects the availability of HER2/neu testing and anti-HER2/neu therapy among physicians who participated in TEACH. A high proportion of women with HER2-overexpressing BC may not receive standard adjuvant therapy due to unavailability of the test and cost of therapy. Despite having some limitations, such as a possible selection bias of participating physicians, variable definitions of access to healthcare among respondents, and changes in trastuzumab availability since 2011, our results demonstrate that access to care and region of practice impact the implementation of cancer treatments.

Background/Objectives The purpose of this study is to compare surgically resected intraductal papillary mucinous neoplasms (IPMNs) in patients with and without a family history of pancreatic cancer to gain insight into differences that may suggest the need for differential management. Methods A retrospective review of patients who underwent resection of an IPMN at the Massachusetts General Hospital (1990–2011) was conducted. Three hundred and twenty-four patients of whom 45 (13.9%) had a family history of pancreatic cancer were identified. Patients with (PFH) and without (NFH) a family history of pancreatic cancer were compared. Results There were no differences in demographic characteristics between groups. Extra-pancreatic malignancies diagnosed prior to the IPMN were more common in those with a PFH (35.6% vs 20.1%, p = 0.03). There were no differences in IPMN characteristics between groups including no difference in the presence of invasive disease ( p = 0.55). Concurrent pancreatic ductal adenocarcinomas were more common in those with a PFH (11.1% vs 2.9%, p = 0.02). The survival in the PFH group was marginally lower than the NFH group, a difference found to be attributable to the higher prevalence of extra-pancreatic malignancies. Conclusion Characteristics of surgically resected IPMNs are not different between patients with and without a family history of pancreatic cancer. Most importantly, the incidence of invasive disease is not different, suggesting that these lesions may not be more aggressive when they occur in the presence of a family history of pancreatic cancer.

Colorectal cancer (CRC) is a significant cause of mortality and morbidity in the United States, much of which could be prevented through adequate screening. Consensus guidelines recommend that high-risk groups initiate screening earlier with colonoscopy and more frequently than average risk persons. However, a large proportion of high risk individuals do not receive regular colonoscopic screening. The Family Health Promotion Project (FHPP) is a randomized-controlled trial to test the effectiveness of a telephone-based counseling intervention to increase adherence to risk-appropriate colonoscopy screening in high risk individuals. Unaffected members of CRC families from two national cancer family registries were enrolled (n = 632) and randomized to receive either a single session telephone counseling intervention using Motivational Interviewing techniques or a minimal mail-out intervention. The primary endpoint, rate of colonoscopy screening, was assessed at 6, 12 and 24 months post-enrollment. In this paper, we describe the research design and telephone counseling intervention of the FHPP trial, and report baseline data obtained from the two high risk cohorts recruited into this trial. Results obtained at baseline confirm the need for interventions to promote colonoscopy screening among these high risk individuals, as well as highlighting several key opportunities for intervention, including increasing knowledge about risk-appropriate screening guidelines, and providing both tailored risk information and barriers counseling.

Purpose: Women at familial/genetic ovarian cancer risk often undergo screening despite unproven efficacy. Research suggests each woman has her own CA125 baseline; significant increases above this level may identify cancers earlier than standard 6- to 12-monthly CA125 > 35 U/mL. Experimental Design: Data from prospective Cancer Genetics Network and Gynecologic Oncology Group trials, which screened 3,692 women (13,080 woman-screening years) with a strong breast/ovarian cancer family history or BRCA1/2 mutations, were combined to assess a novel screening strategy. Specifically, serum CA125 q3 months, evaluated using a risk of ovarian cancer algorithm (ROCA), detected significant increases above each subject's baseline, which triggered transvaginal ultrasound. Specificity and positive predictive value (PPV) were compared with levels derived from general population screening (specificity 90%, PPV 10%), and stage-at-detection was compared with historical high-risk controls. Results: Specificity for ultrasound referral was 92% versus 90% (P = 0.0001), and PPV was 4.6% versus 10% (P > 0.10). Eighteen of 19 malignant ovarian neoplasms [prevalent = 4, incident = 6, risk-reducing salpingo-oophorectomy (RRSO) = 9] were detected via screening or RRSO. Among incident cases (which best reflect long-term screening performance), three of six invasive cancers were early-stage (I/II; 50% vs. 10% historical BRCA1 controls; P = 0.016). Six of nine RRSO-related cases were stage I. ROCA flagged three of six (50%) incident cases before CA125 exceeded 35 U/mL. Eight of nine patients with stages 0/I/II ovarian cancer were alive at last follow-up (median 6 years). Conclusions: For screened women at familial/genetic ovarian cancer risk, ROCA q3 months had better early-stage sensitivity at high specificity, and low yet possibly acceptable PPV compared with CA125 > 35 U/mL q6/q12 months, warranting further larger cohort evaluation. Clin Cancer Res; 23(14); 3628–37. ©2017 AACR.

Background: Her2/neu overexpression is an independent adverse prognostic factor present in approximately 25% of invasive breast cancers. HER2−overexpressing breast cancer is particularly common in younger patients and therefore poses a significant public health burden. Anti-Her2/neu adjuvant trastuzumab significantly reduces the risk of recurrence as well as improves survival. In view of the serious potential ramifications of not receiving anti-Her2/neu therapy when appropriate, we undertook this international project to determine clinical access to Her2/neu testing and treatment patterns for women with HER2/neu-positive early breast cancer. Methods: A web-based survey was sent to 386 physicians from 33 countries who participated in the “TEACH” trial, a double blind placebo-controlled phase III study of a novel anti-Her2/neu therapy, lapatinib, in women with primary Her2/neu-positive breast cancer. The survey contained 27 questions addressing physician and patient demographics, access to Her-2/Neu testing in everyday clinical practice, and anti-Her2/neu treatment options in a variety of clinical scenarios. Results: One hundred and fifty one participants (39%) from 28 countries answered the survey. Ninety eight percent of the participants reported having Her2/neu tumor expression routinely measured for clinical practice in their institutions by immunohistochemistry (83%), FISH (78%) and other methods (17%). Among Asian physicians, 18% did not have routine testing available and sent primary tumors for central testing for TEACH eligibility. Forty eight percent of physicians surveyed reported instances when they had recommended adjuvant Her2-directed therapy to a patient who eventually did not receive it. The proportion of physicians from developing countries that reported patients not receiving therapy was higher than those from developed countries (68% vs. 38%, respectively). The main reason for not receiving trastuzumab was cost in developing countries, while in more developed countries patient refusal and co-morbidities were the main reasons. Discussion: This survey reflects availability of HER2 breast tumor testing and anti-Her2/neu therapy among physicians from 28 countries worldwide who participated in an anti-Her2/neu therapy clinical trial of a free anti-Her2/neu therapy. These results indicate that a high proportion of women with Her2/neu-overexpressing breast cancer may not receive standard anti-Her2/neu adjuvant therapy especially in developing countries, the barrier to treatment being cost of therapy. We are extending our access to care survey project to a more unselected diverse group of physicians in developing countries. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-26.

Introduction: Pregnancy traditionally is considered a protective factor for breast cancer. Recent data suggests that pregnancy-associated breast cancer (PABC), a distinct biologic variant possibly related to breast involution, can occur up to 10 years post-partum and may carry a worse prognosis than that of age matched sporadic or nulliparous breast cancer. The Amazona project is a retrospective cohort of 4,912 Brazilian women with breast cancer that has previously reported on worse outcomes of patients according to type of institution where treatment was received (San Antonio 2009 abstr. 3082). We have assessed the outcomes of PABC in the Amazona cohort. Objectives: 1- To identify whether women who were diagnosed with breast cancer up to 10 years after their first pregnancy had worse disease free survival (DFS) and overall survival (OS) than nulliparous women (NW); 2- to assess if age at first pregnancy is related to age of breast cancer diagnosis and worse DFS or OS; 3- to assess whether number of pregnancies is associated with worse DFS or OS; 4- to assess whether time from first pregnancy to diagnosis or age of first pregnancy are associated with histological grade, clinical stage or tumor expression of ER, PR, and HER2. Methods: We analyzed 4836 women for whom parous history was available, in respect to DFS, OS, tumor clinical stage, histological grade, expression of ER, PR and HER2, according to age of first pregnancy, diagnosis up to 5 and 10 years after first pregnancy, and number of pregnancies, using NW as controls. Analysis of DFS and OS was done by Cox regression modeling adjusted for institution type, stage, ER, PR, HER2 and grade. Results: Our cohort had 1996 nulliparous women and 2840 parous women. The median follow up was 28 months and there were 318 deaths and 735 recurrences. We did not find any correlation between PABC with DFS (5 year interval HR 1.15, 95%CI 0.43−3.07; 10 year interval HR 1.01, 95%CI 0.57−1.81) or OS (5 year interval HR 1.88, 95%CI 0.6−5.94; 10 year interval HR 0.5, 95%CI 0.73−3.09), nor was there a correlation between age at first pregnancy with age of breast cancer diagnosis. We also did not see any difference between age of first pregnancy and DFS or OS. Women with 3 or more pregnancies had worse OS (HR 0.71, 95%CI 0.54−0.93) but not worse DFS (HR 0.93, 95%CI 0.76−1.13).Tumors diagnosed within 5 or 10 years from first pregnancy did not differ by grade, ER, PR, HER2, and clinical stage from those of NW. Women who had their first pregnancy after age 20 tended to have more ER positive (OR 1.99, 95%CI 1.49−2.65), PR positive (OR 1.40, 95%CI 1.06−1.87), and HER2 positive (OR 1.85, 95%CI 1.22−2.79) tumors than NW. Conclusions: In this large cohort of breast cancer patients from the diverse geographic and socioeconomic spectrum of Brazil we did not find any association between PABC or age of first pregnancy to DFS or OS. The association with worse OS but not DFS for women with 3 or more pregnancies might be due to confounding factors. PABC was not associated with worse clinical prognostic factors. Women who had their first pregnancy after age 20 were more likely to have ER+, PR+ and HER2 + tumors than nulliparous patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-08-17.

Late-breaking — abstract will be available at the meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S4-7.

Background: Breast cancer is the most common form of cancer and the leading cause of cancer death in women worldwide. More than 55% of breast cancer deaths occur in low and middle income countries. Although incidence rates for breast cancer are lower in developing countries, mortality rates are higher. This phenomenon has been attributed to limited access to care for breast cancer patients, including screening and early diagnosis as well as primary surgical, radiation and systemic therapies. Similar to trends in other poor and middle income countries, breast cancer mortality in Mexico is rising. The goal of this survey of physicians caring for patients with breast cancer in Mexico is to obtain information about current treatment patterns of newly diagnosed patients and to describe their clinical characteristics. Methods: A web-based closed survey has been sent to 854 physicians providing care to newly diagnosed breast cancer patients across Mexico, including medical oncologists and breast cancer surgeons. The survey instrument contains 35 questions assessing demographic data, access to diagnosis and treatment in a variety of clinical patient scenarios. The responses will be anonymous and entered automatically into a secure database for analysis. Fisher exact test will be used for the frequency analysis. Chi-squared statistics and Kendall correlation will be used for nominal and ordinal variables respectively. Results: The results will be presented at the 2011 San Antonio Breast Cancer Symposium. Conclusions: The results of this survey will highlight potential disparities in care received by breast cancer patients across the full geographic and socioeconomic spectrum of Mexico in order to highlight the need for uniform, quality based approaches for the diagnosis and treatment of breast cancer patients in Mexico, and will serve as an example of how one middle income country faces challenges and unmet medical needs regarding access to care of women with breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-11-12.

Previous screening trials for early detection of ovarian cancer in postmenopausal women have used the standard CA125 cut-point of 35 U/mL, the 98th percentile in this population yielding a 2% false positive rate, whereas the same cut-point in trials of premenopausal women results in substantially higher false positive rates. We investigated demographic and clinical factors predicting CA125 distributions, including 98th percentiles, in a large population of high-risk women participating in two ovarian cancer screening studies with common eligibility criteria and screening protocols. Baseline CA125 values and clinical and demographic data from 3,692 women participating in screening studies conducted by the National Cancer Institute–sponsored Cancer Genetics Network and Gynecologic Oncology Group were combined for this preplanned analysis. Because of the large effect of menopausal status on CA125 levels, statistical analyses were conducted separately in pre- and postmenopausal subjects to determine the impact of other baseline factors on predicted CA125 cut-points on the basis of 98th percentile. The primary clinical factor affecting CA125 cut-points was menopausal status, with premenopausal women having a significantly higher cut-point of 50 U/mL, while in postmenopausal subjects the standard cut-point of 35 U/mL was recapitulated. In premenopausal women, current oral contraceptive (OC) users had a cut-point of 40 U/mL. To achieve a 2% false positive rate in ovarian cancer screening trials and in high-risk women choosing to be screened, the cut-point for initial CA125 testing should be personalized primarily for menopausal status (50 for premenopausal women, 40 for premenopausal on OC, and 35 for postmenopausal women). Cancer Prev Res; 4(9); 1401–8. ©2011 AACR.

For clinical studies of chronic diseases, patients are followed to determine whether treatment results in either improvement or decline in their clinical status. During periodic exams, laboratory specimens are collected that are believed to reflect both the progression and improvement in the disease status. Often patients miss visits and return with a changed disease status, resulting in interval-censored laboratory markers and indicators of disease status. The goal of this paper is to propose a single test that would evaluate the relationship between a longitudinal marker and clinical progression or recovery when missing visits result in interval-censored covariate and outcome data. We apply our test to evaluate the relationship between treatment compliance and progression and remission of renal disease in diabetic patients.

Background: The MA.17 study showed that extended adjuvant endocrine therapy with letrozole (LET) after completing 5 years of tamoxifen (TAM) markedly reduced the risk of recurrence in women with ER+ early stage breast cancer and improved overall survival in women presenting with node +ve disease. The HOXB 13:IL17BR gene expression ratio (signature) has been shown to predict outcome in breast cancer patients treated with adjuvant tamoxifen monotherapy and provides additional information beyond that from known positive (ER and PR) and negative (Her-1 and Her-2) predictors of responsiveness to tamoxifen in node-ve women. We report a case control evaluation of the Breast Cancer Index (BCI; bioTheranostics, Inc.), which combines the HOXB13 and IL17BR twogene and the molecular grade index (MGI) gene expression signatures, with respect to distinguishing which patients are at risk of late recurrences and who would respond to extended endocrine therapy with LET. The prognostic and predictive utility of quantitative immunofluorescence of ER, PR, Her-2, tumor aromatase, COX-2, GATA3 and Nat1 in the TAM-PLACEBO and the TAM-LET cohorts will also be evaluated and compared to results derived by standard immunohistochemistry. Methods: FFPE tumor blocks were collected from patients who experienced a breast cancer recurrence up to unblinding of MA.17. Controls were matched 2:1 for age, tumor size, lymph node status, and prior chemotherapy, and were all disease free for longer than cases. All cases were reviewed for standard histopathology by two independent pathologists. RNA was extracted, amplified, converted to cDNA and subjected to RT-PCR with primers and probes to HOXB13, IL17BR, BUB1A, CENPA, NEK2, RACGAP1 and RRM2. ER, PR HER1, HER2, COX2, Aromatase, GATA3 and NAT1 will be analyzed by routine IHC techniques and by immunoflourescent Automated Quantitative Analysis (AQuA). Results: 105 cases and 210 matched controls are available for evaluation. All sections are under review and tissue microarrays have been performed on all cases and controls. Detailed results on the BCI and ER, PR, Her-2 will be available at the SABCS. Discussion: MA.17 has shown that extended adjuvant endocrine therapy after tamoxifen is effective at preventing disease recurrence given for an additional 5 years. Numerous clinical trials are exploring whether extending AIs will show this benefit, and there is an increasing need to improve the therapeutic index by distinguishing those at risk from those who are not. It is also important to determine which patients will benefit from the therapy and which will recur without benefit. The latter patients could be triaged to clinical trials of novel therapies to overcome endocrine resistance. This study will help to define these issues and pave the way for more effective selection of specific patients for adjuvant endocrine strategies. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-26.

Metastatic ovarian cancer (OvCa) frequently recurs due to chemoresistance, highlighting the need for nonoverlapping combination therapies that mechanistically synergize to eradicate residual disease. Photodynamic therapy (PDT), a photochemistry-based cytotoxic modality, sensitizes ovarian tumors to platinum agents and biologics and has shown clinical promise against ovarian carcinomatosis. We introduce a three-dimensional (3D) model representing adherent ovarian micrometastases and high-throughput quantitative imaging methods to rapidly screen the order-dependent effects of combining benzoporphyrin-derivative (BPD) monoacid A–based PDT with low-dose carboplatin. 3D ovarian micronodules grown on Matrigel were subjected to BPD-PDT either before or after carboplatin treatment. We developed custom fluorescence image analysis routines to quantify residual tumor volume and viability. Carboplatin alone did not eradicate ovarian micrometastases at a dose of 400 mg/m2, leaving surviving cores that were nonsensitive or impermeable to chemotherapy. BPD-PDT (1.25 μmol/L·J/cm2) created punctate cytotoxic regions within tumors and disrupted micronodular structure. Treatment with BPD-PDT prior to low-dose carboplatin (40 mg/m2) produced a significant synergistic reduction [P < 0.0001, analysis of covariance (ANCOVA)] in residual tumor volume [0.26; 95% confidence interval (95% CI), 0.19–0.36] compared with PDT alone (0.76; 95% CI, 0.63–0.92) or carboplatin alone (0.95; 95% CI, 0.83–1.09), relative to controls. This synergism was not observed with the reverse treatment order. Here, we demonstrate for the first time the use of a 3D model for micrometastatic OvCa as a rapid and quantitative reporter to optimize sequence and dosing regimens of clinically relevant combination strategies. This approach combining biological modeling with high-content imaging provides a platform to rapidly screen therapeutic strategies for a broad array of metastatic tumors. Cancer Res; 70(22); 9319–28. ©2010 AACR.

501Background: Denosumab (Dmab) is a potent RANK ligand inhibitor approved for the management of treatment induced bone loss in early breast (EBC) and prevention of skeletal morbidity associated with metastatic bone disease. Preclinical data suggested that Dmab could prevent development of bone metastases. This trial evaluated the addition of Dmab to standard (neo)adjuvant therapy for high-risk EBC patients (pts). Methods: 4509 pts with EBC (93.5% node+) from 407 centers were randomized to standard loco-regional and (neo)adjuvant therapy plus either Dmab 120mg sc or matching placebo (P) monthly x 6 then 3 monthly for up to 5 years. In addition to routine clinical follow-up, pts underwent annual CT and bone scan imaging to screen for recurrence. Primary endpoint was bone metastasis free survival (BMFS) defined as first bone metastatic event confirmed by central imaging review or death from any cause. Secondary endpoints included disease free survival (DFS), DFS in the postmenopausal (PM) subgroup, overall ...

Purpose: Oropharyngeal squamous cell carcinoma (OPSCC) associated with human papilloma virus (HPV) is rapidly growing in incidence. Despite better prognosis than OPSCC associated with traditional risk factors, treatment failure still occurs in a significant proportion of patients. We had identified the antiapoptotic protein Bcl2 as a marker for poor outcome in advanced OPSCC treated with concurrent chemoradiation. To determine whether Bcl2 and HPV together might further characterize treatment response, we examined whether the prognostic value of Bcl2 was independent of HPV status. Experimental Design: Pretreatment tumor biopsies from 68 OPSCC patients were tested for HPV by in situ hybridization and were immunostained for Bcl2 to evaluate relations with disease-free (DFS) and overall survival following platin-based concurrent chemoradiation. Median follow-up among surviving patients was 47 months (range, 10-131 months). Results: Bcl2 and HPV independently predicted DFS and overall survival. Hazard ratios (with 95% confidence interval) for positive versus negative status in bivariate Cox proportional hazard analysis of DFS were 6.1 (1.8-21) for Bcl2 and 0.11 (0.035-0.37) for HPV. Only 1 of 32 HPV-positive/Bcl2-negative tumors recurred. Pretreatment Bcl2 expression was specifically associated with distant metastasis; five of six distant metastases occurred in the Conclusions: Independent of HPV status, pretreatment Bcl2 expression identifies a subset of OPSCC patients having increased risk of treatment failure, particularly through distant metastasis, after concurrent chemoradiation. Considering HPV and Bcl2 together should help in devising better personalized treatments for OPSCC. Clin Cancer Res; 16(7); 2138–46. ©2010 AACR.

Background It can be difficult to conduct pediatric clinical trials because there is often a low incidence of the disease in children, making accrual slow or infeasible. In addition, low mortality and morbidity in this population make it impractical to achieve adequate power. In this case, the only evidence for treatment efficacy comes from adult trials. Since pediatric care providers are accustomed to relying on evidence from adult studies, it is natural to consider borrowing information from adult trials.Purpose The goal of this article is to propose a Bayesian approach to the design and analysis of pediatric trials to allow borrowing strength from previous or simultaneous adult trials.Methods We apply a hierarchical model for which the efficacy parameter from the adult trial and that of the pediatric trail are considered to be draws from a normal distribution. The choice of (the variance of) this distribution is guided by discussion with medical experts. We show that with this information, one can calculate the sample size required for the pediatric trial. We discuss how inference of these studies in pediatric populations depends on the parameter that captures the similarity of the treatment efficacy in adults compared to children.Results The Bayesian approach can substantially increase the power of a pediatric clinical trial (or equivalently decrease the number of subjects required) by formally leveraging the data from the adult trial.Limitations Our method relies on obtaining a value for the inter-study variability, ν, which may be difficult to describe to a clinical investigator.Conclusions The Bayesian approach has the potential of making pediatric clinical trials feasible because it has the effect of borrowing strength from adult trials, thus requiring a smaller pediatric trial to show efficacy of a drug in children. Clinical Trials 2009; 6: 297—304. http://ctj.sagepub.com

The NIH project 'Inflammatory and Host Response to Injury' (Glue) is being conducted to study the changes in the body over time in response to trauma and burn. Patients are monitored for changes in their clinical status, such as the onset of and recovery from organ failure. Blood samples are drawn over the first days and weeks after the injury to obtain gene expression levels over time. Our goal was to develop a method of selecting genes that differentially expressed in patients who either improved or experienced organ failure. For this, we needed a test for the association between longitudinal gene expressions and the time to the occurrence of ordered categorical outcomes indicating recovery, stable disease, and organ failure. We propose a test for which the relationship between the gene expression and the events is modeled using the cumulative proportional odds model that is a generalization of the pooling repeated observation method. Given the high-dimensionality of the microarray data, it was necessary to control for the multiplicity of the testing. To control for the false discovery rate (FDR), we applied both a permutational approach as well as Efron's empirical estimation method. We explore our method through simulations and provide the analysis of the multi-center, longitudinal study of immune response to inflammation and trauma (http://www.gluegrant.org).

To evaluate the risk of breast cancer (BC) and the contributing risk factors in women after supradiaphragmatic irradiation (SDI) for Hodgkin's lymphoma (HL).Medical records of 248 women 60 years of age or less who received SDI for stage I/II HL between 1964 and 2001 at Massachusetts General Hospital were retrospectively reviewed.The median age at SDI was 26 years (range, 5.7-59.3). The median follow-up was 15.2 years (range, 0.1-41.3). In 36 patients, BC developed (bilaterally in 11 patients) at a median interval of 18.4 years (range, 4.3-33.8) after SDI. Based on data from the National Cancer Institute Surveillance, Epidemiology, and End Results program, the standardized morbidity ratio (SMR) for the first BC after SDI was 9.78 (95% confidence interval [CI], 4.64-18.11, p0.0001). The SMR of patients who received radiation before age of 30 years was 19.05 (95% CI, 12.33-28.13) compared with 4.64 (95% CI, 2.31-8.30) for patients aged 30 years or more at the time of treatment (p0.00003). Risk for BC was significantly higher 15 years or more after SDI compared with the risk during the first 15 years (p = 0.0026). None of HL characteristics or treatment details was associated with higher risk of BC after adjusting for age and calendar time.Age at irradiation and time since therapy appear to be the only significant risk factors for development of BC after treatment of HL. The risk is significantly higher 15 years or more after radiation and for women treated before age 30 years. Long-term surveillance strategies are indicated for women at risk.

Familial aggregation studies are a common first step in the identification of genetic determinants of disease. If aggregation is found, more refined genetic studies may be undertaken. Complex ascertainment schemes are frequently employed to ensure that the sample contains a sufficient number of families with multiple affected members, as required to detect aggregation. For example, an eligibility criterion for a family might be that both the mother and daughter have disease. Adjustments must be made for ascertainment to avoid bias. We propose adjusting for complex ascertainment schemes through a joint model for the outcomes of disease and ascertainment. This approach improves upon previous simplifying assumptions regarding the ascertainment process.

Traditionally, meta-analysis methods have been developed and used to combine data from several independent clinical trials as well as observational studies, but have not been as widely used in survey research. This paper describes the steps in conducting such a meta-analysis of surveys, to obtain a single summary estimate from a combination of individual-level and summary data. The methods are applied in the context of a project aimed at obtaining an estimate of the prevalence of use of electronic health records.

The aims of this study were to assess the frequency and determinants of ( 1 ) treatment with angiotensin-converting enzyme inhibitors (ACE-I) and ( 2 ) progression to proteinuria in the presence of ACE-I treatment in patients with type 1 diabetes and microalbuminuria. A clinic-based cohort study of patients with type 1 diabetes was begun in 1991. The patients who were included in this study ( n = 373) are the cohort members who received a diagnosis of microalbuminuria during a 2-yr baseline observation and were followed for 10 yr with frequent assessments of urinary albumin excretion and biennial examinations. Progression to proteinuria occurred when the median urinary albumin excretion during a 2-yr interval exceeded 299 μg/min. During the decade-long study, the proportion of patients who had a history of microalbuminuria and were treated with ACE-I rose from 17 to 67%. Patients who started this treatment had (on average) higher BP, higher urinary albumin excretion, and longer diabetes duration than those who did not. Microalbuminuria often progressed to proteinuria (6.3/100 person-years) in those who were treated. Poor glycemic control and elevated serum cholesterol were the major determinants/predictors of this progression. Although treatment with ACE-I increased during the past decade, it was not completely effective, because microalbuminuria progressed to proteinuria in many treated patients. Poor glycemic control and elevated serum cholesterol were the major determinants/predictors for progression while on ACE-I treatment. The mechanisms that are responsible for the frequent failure of ACE-I to prevent progression of microalbuminuria to proteinuria in a clinical setting are not clear.

Familial aggregation studies seek to identify diseases that cluster in families. These studies are often carried out as a first step in the search for hereditary factors affecting the risk of disease. It is necessary to account for age at disease onset to avoid potential misclassification of family members who are disease-free at the time of study participation or who die before developing disease. This is especially true for late-onset diseases, such as prostate cancer or Alzheimer's disease. We propose a discrete time model that accounts for the age at disease onset and allows the familial association to vary with age and to be modified by covariates, such as pedigree relationship. The parameters of the model have interpretations as conditional log-odds and log-odds ratios, which can be viewed as discrete time conditional cross hazard ratios. These interpretations are appealing for cancer risk assessment. Properties of this model are explored in simulation studies, and the method is applied to a large family study of cancer conducted by the National Cancer Institute-sponsored Cancer Genetics Network (CGN).

Introduction: Worldwide, many patients with HER2+ (human epidermal growth factor receptor 2-positive) early breast cancer (BC) do not receive adjuvant trastuzumab. Hazards of recurrence of these patients with respect to hormone receptor status of the primary tumor have not been described. Methods: Using data from 1,260 patients randomized to placebo in the adjuvant TEACH trial, we report 10-year annual hazards of recurrence in HER2+ patients not treated with anti-HER2 therapy. Results: Disease-free survival (DFS) was 75% after 5 and 61% after 10years, respectively. Patients with HER2+hormone receptor-positive (HR+ (hormone receptor-positive); ER+ (estrogen receptor-positive) or PR+ (progesterone receptor-positive)) disease had a significantly better DFS than patients with HER2+HR- (ER-/PR-) disease (hazard ratio 0.72, P=0.02). This difference was explainable by a significantly higher hazard of recurrence in years 1 to 5 in HER2+HR- compared to HER2+HR+ patients, with a mean risk of recurrence of 9%/year for HR- versus 5%/year in HR+ patients (hazard ratio 0.59, P=0.002 for years 1 to 5). The high early risk of recurrence of HER2+HR- patients declined sharply over time, so that it was similar to that seen in HER2+HR+ patients in years 6 to 10 (hazard ratio 0.97, P=0.92 for years 6 to 10). Conclusions: Our results show that outcomes in HER2+ patients with early BC not receiving anti-HER2 therapy strongly depend on HR expression. The very high early risk of relapse seen in HER2+HR- patients is particularly relevant in health care settings with limited access to adjuvant anti-HER2 treatment. The event rates shown for subpopulations of HER2+ BC patients suggest that in resource-constrained environments patients with HER2+HR- early BC should be prioritized for consideration of adjuvant anti-HER2 therapy., SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose Different prognostic factors stratify patients with pancreatic adenocarcinoma. The purpose of this study was to determine whether preoperative CA19-9 levels can predict stage of disease or survival and whether a change in preoperative to postoperative CA19-9 or the postoperative CA19-9 predicts overall survival. Patients and Methods Four hundred twenty-four consecutive patients with pancreatic adenocarcinoma underwent resection between January 1, 1985 and January 1, 2004. Of the patients with a bilirubin less than 2 mg/dL, 176 had preoperative CA19-9 values, and 111 had pre- and postoperative CA19-9 values. Survival was measured from the first postoperative CA19-9 level measured (median, 39 days) until death or last follow-up. A multivariate failure time model was fit using clinical, operative, pathologic, and adjuvant treatment characteristics, and a categorization was defined by the values and changes in CA19-9 before and after surgery. Results Of the 176 patients, 128 (73%) had T3 lesions, and 99 (56%) had N1 disease; 138 patients (78%) underwent pancreaticoduodenectomy. Median preoperative CA19-9 levels were lower in N0 patients compared with patients with positive nodes (nine v 164 U/mL, respectively; nonparametric P = .06) and in T1/T2 patients versus T3 patients (41 v 162 U/mL, respectively; P = .03). Median follow-up time (n = 111) was 1.8 years (range, 1 to 12.9 years), with overall actuarial 1-, 3-, and 5-year survival rates of 70%, 36%, and 30%, respectively. Significant predictors of survival on multivariate analysis included a decrease in CA19-9 (P = .0005), negative lymph nodes (P = .001), lower T stage (P = .0008), and postoperative CA19-9 less than 200 U/mL (P = .0007). Conclusion In patients with pancreatic adenocarcinoma, preoperative CA19-9 correlates with stage of disease. Both a postoperative decrease in CA19-9 and a postoperative CA19-9 value of less than 200 U/mL are strong independent predictors of survival, even after adjusting for stage. CA19-9 levels should be included in a patient's perioperative care and should be considered for prognostic nomograms.

PurposeAn accurate evaluation of the penetrance of BRCA1 and BRCA2 mutations is essential to the identification and clinical management of families at high risk of breast and ovarian cancer. Existing studies have focused on Ashkenazi Jews (AJ) or on families from outside the United States. In this article, we consider the US population using the largest US-based cohort to date of both AJ and non-AJ families.MethodsWe collected 676 AJ families and 1,272 families of other ethnicities through the Cancer Genetics Network. Two hundred eighty-two AJ families were population based, whereas the remainder was collected through counseling clinics. We used a retrospective likelihood approach to correct for bias induced by oversampling of participants with a positive family history. Our approach takes full advantage of detailed family history information and the Mendelian transmission of mutated alleles in the family.ResultsIn the US population, the estimated cumulative breast cancer risk at age 70 years was 0.46 (95% CI, 0.39 to 0.54) in BRCA1 carriers and 0.43 (95% CI, 0.36 to 0.51) in BRCA2 carriers, whereas ovarian cancer risk was 0.39 (95% CI, 0.30 to 0.50) in BRCA1 carriers and 0.22 (95% CI, 0.14 to 0.32) in BRCA2 carriers. We also reported the prospective risks of developing cancer for cancer-free carriers in 10-year age intervals. We noted a rapid decrease in the relative risk of breast cancer with age and derived its implication for genetic counseling.ConclusionThe penetrance of BRCA mutations in the United States is largely consistent with previous studies on Western populations given the large CIs on existing estimates. However, the absolute cumulative risks are on the lower end of the spectrum.

Purpose This study evaluates the efficacy and toxicity of whole-brain radiation therapy (WBRT) as salvage therapy for immunocompetent patients who failed initial high-dose methotrexate for primary CNS lymphoma (PCNSL). Patients and Methods The study cohort included 27 consecutive patients who failed initial high-dose methotrexate and then received salvage WBRT (median dose, 36 Gy). Actuarial survival was measured from the initiation of radiotherapy. Results Ten patients (37%) achieved a complete radiographic response (CR), and 10 patients (37%) a partial response to WBRT, for a 74% overall radiographic response rate. At the time of maximal response, Karnofsky performance status improved in 12 (44%) of 27 patients and at least stabilized in 67%. Median estimated survival from initiation of WBRT was 10.9 months (range, 0.3 to 63.7 months). The univariate predictor of longer survival was age less than 60 years at the time of WBRT (P = .028). Among patients who survived 4 months, achievement of a CR to WBRT by 4 months (P = .002) predicted longer survival. Late treatment-associated neurotoxicity was diagnosed in four patients (15%) and was significantly associated with total radiation doses greater than 36 Gy (P = .04). No patient treated with daily fractions less than 1.8 Gy developed late neurotoxicity. Conclusion For patients with PCNSL who experience treatment failure with methotrexate, WBRT provides high response rates (74%) and a median survival of 10.9 months. Age less than 60 years and response to WBRT predict post-WBRT survival. Modest rates of late neurotoxicity (15%) were seen and were associated with a total dose greater than 36 Gy.