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Background: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.Methods: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers.Results: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10−5), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10−6). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10−13 for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0–12.6 and PR-positive OR = 1.7, 95% CI: 1.3–2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4–4.4; P = 4.4 × 10−14), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18–0.35; P = 2.3 × 10−15). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%).Conclusions/Impact: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis. Cancer Epidemiol Biomarkers Prev; 21(1); 134–47. ©2011 AACR.

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Summary Background Therapies targeting HER2 have improved clinical outcomes in HER2-positive breast and gastric cancers, and are emerging as potential treatments for HER2-positive metastatic colorectal cancer. MyPathway evaluates the activity of targeted therapies in non-indicated tumour types with potentially predictive molecular alterations. We aimed to assess the activity of pertuzumab and trastuzumab in patients with HER2-amplified metastatic colorectal cancer. Methods MyPathway is an ongoing, phase 2a, multiple basket study. Patients in this subset analysis were aged 18 years or older and had treatment-refractory, histologically confirmed HER2-amplified metastatic colorectal cancer with measurable or evaluable disease and an Eastern Cooperative Oncology Group performance status score of 2 or less, enrolled from 25 hospitals or clinics in 16 states of the USA. Patients received pertuzumab (840 mg loading dose, then 420 mg every 3 weeks, intravenously) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks, intravenously). The primary endpoint was the proportion of patients who achieved an objective response based on investigator-reported tumour responses. Analyses were done per protocol. This ongoing trial is registered with ClinicalTrials.gov , number NCT02091141 . Findings Between Oct 20, 2014, and June 22, 2017, 57 patients with HER2-amplified metastatic colorectal cancer were enrolled in the MyPathway study and deemed eligible for inclusionin this cohort analysis. Among these 57 evaluable patients, as of Aug 1, 2017, one (2%) patient had a complete response and 17 (30%) had partial responses; thus overall 18 of 57 patients achieved an objective response (32%, 95% CI 20–45). The most common treatment-emergent adverse events were diarrhoea (19 [33%] of 57 patients), fatigue (18 [32%] patients), and nausea (17 [30%] patients). Grade 3–4 treatment-emergent adverse events were recorded in 21 (37%) of 57 patients, most commonly hypokalaemia and abdominal pain (each three [5%] patients). Serious treatment-emergent adverse events were reported in ten (18%) patients and two (4%) of these adverse events (ie, chills and infusion-related reaction) were considered treatment related. There were no treatment-related deaths. Interpretation Dual HER2-targeted therapy with pertuzumab plus trastuzumab is well tolerated and could represent a therapeutic opportunity for patients with heavily pretreated, HER2-amplified metastatic colorectal cancer. Funding F Hoffmann-La Roche/Genentech.

Background: Breast Cancer (BC) is a heterogeneous disease comprising distinct subtypes defined at present by tumor molecular markers. Over the past decades, more effective treatments targeted to specific markers have been developed and tested in clinical trials. While clinical trials have demonstrated the impact of these targeted treatments on recurrence and mortality rates, little is known about survival patterns associated with specific subtypes in the general population. We examined overall survival outcomes according to tumor subtype and stage in a diverse, population-based cohort of BC patients (pts) in California. Methods: Through the California (CA) Cancer Registry, we identified all female CA residents diagnosed with primary invasive BC between 1/1/2005 and 12/31/2011. We classified these cancers as early breast cancer (EBC, stages I-III) vs. de novo metastatic (MBC, stage IV). We further grouped these cancers into 4 subtypes based on HER2 and hormone receptor (HR) status. For a subset of women with available survival data, we calculated the proportion surviving at 3 years (yrs), and median overall survival using the Kaplan-Meier method. Results: 118,817 EBC pts (61.4% HR+/HER2-, 9.9% HR+/HER2+, 13.3% unclassified, 4.9% HR-/HER2+, and 10.6% triple-negative (TN)) and 6,268 MBC pts (43.7% HR+/HER2-, 13.0% HR+/HER2+, 23.3% unclassified, 8.9% HR-/HER2+, and 10.7% TN) were identified. Table 1 presents survival time in EBC vs. MBC, and for each of the receptor subtypes of BC. For EBC, 3-yr survival rate was highest (95.1%) for HR+/HER2- pts and shortest (84.3%) for TN. For the HER2- and HER2+ overall groups (regardless of HR status), 3-yr survival was similar (93.3% vs. 92.5%, respectively). The longest survival for de novo MBC was observed for the HR+/HER2+ subtype (median OS: 45.3 months (mos)), compared to 38.7 mos for the HR+/HER2- subtype, 23.1 mos for the HR-/HER2+ subtype and 12.7 mos for the TN subtype. For the overall HER2+ and HER2- subtypes, HER2+ MBC had slightly better survival (3-yr rate: 47.6% and median OS: 33.6 mos) than HER2- MBC pts (3-yr rate: 44.8% and median OS: 30.9 mos). Conclusions: This study demonstrates the relevance of subtype on the OS of BC pts in a large population of CA women. Although HER2+ status is a negative prognostic factor, survival was similar between HER2+ and HER2- pts, likely due to available treatments targeting HER2. TNBC pts had the shortest survival, especially when they presented with metastatic disease. There remains an urgent unmet need for more effective treatments for TNBC. Table 1. Survival by stage (EBC vs de novo MBC) and BC subtypeEBCde novo MBCSubtypeN3-yr Survival (95% CI)N3-yr Survival (95% CI)Median OS (95% CI) (months)HR+/HER2-3811895.1 (94.8-95.3)135152.5 (49.8-55.1)38.7 (35.9-41.3)HR+/HER2+692094.6 (94.1-95.2)45055.1 (50.4-59.6)45.3 (36.5-50.5)Unclassified1081391.2 (90.6-91.7)89426.0 (23.1-28.9)11.9 (9.7-13.8)HR-/HER2+358988.4 (87.3-89.4)33337.5 (32.3-42.7)23.1 (19.2-27.4)TN708384.3 (83.4-85.1)35717.7 (13.9-21.9)12.7 (11.2-14.1)HER2-neg*4555093.3 (93.1-93.6)174544.8 (42.4-47.1)30.9 (28.6-33.6)HER2-pos*1063592.5 (92.0-93.0)79747.6 (44.0-51.0)33.6 (30.7-37.1)* Pts with available HER2 data, but missing HR data were included Citation Format: Christina A Clark, Scarlett Lin Gomez, Li Tao, Lisa Moy, Juan Yang, Lisa Wang, Mary S Beattie, Jennifer Eng-Wong, Melissa Brammer, Laura Chu. Breast cancer subtype and survival in a population-based cohort of patients from California [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-07-21.

Introduction The Systemic Therapies for HER2-Positive Metastatic Breast Cancer Registry (SystHERs) is a US-based prospective observational cohort study currently enrolling patients with HER2-positive metastatic breast cancer (MBC). It began in 2012 and aims to provide real-world insight into the disease course, treatment patterns and associated clinical outcomes, and patient-reported experiences of disease. Here we describe the baseline characteristics of this population to date, including the proportion of patients with de novo and recurrent HER2-positive MBC. Methods SystHERs aims to enroll ∼1000 patients with HER2-positive MBC within 6 months of first metastatic diagnosis. At enrollment, investigators report whether patients have recurrent or de novo MBC, the latter defined as distant metastases at the time of initial MBC diagnosis. Results As of February 17, 2014, data are available from 306 of 319 enrolled patients. Forty-six percent (142/306) had de novo HER2-positive MBC. For the 54% (164/306) with recurrent HER2-positive MBC, median disease-free interval (DFI, defined here as time from early-stage breast cancer diagnosis to diagnosis of MBC) was 43.6 (range 0.5–270.2) months. For these patients with recurrent disease, 54% (89/164) received (neo)adjuvant HER2-targeted therapy. Baseline patient and tumor characteristics are shown below. CharacteristicOverall (n=306)De novo (n=142)Recurrent (n=164)Age, median (range)57 (27-86)54 (27-83)59 (30-86)Race, n (%)White233 (76)105 (74)128 (78)Black54 (18)28 (20)26 (16)Other8 (3)3 (2)5 (3)Not available11 (4)6 (4)5 (3)Ethnicity, n(%)Not Hispanic257 (84)120 (85)137 (84)Hispanic31 (10)17 (12)14 (9)Not available18 (6)5 (4)13 (8)Pre-menopausal, n (%)61 (20)42 (30)19 (12)Hormone receptor status, n (%)ER and/or PR positive209 (68)90 (63)119 (73)ER and PR negative92 (30)50 (35)42 (26)Unknown5 (2)2 (1)3 (2)Median number of metastatic sites, (range)2.0 (1-7)2.0 (1-6)2.0 (1-7)Sites of metastasis, n (%)Bone141 (46)76 (54)65 (40)Liver120 (39)63 (44)57 (35)Nodes89 (29)49 (35)40 (24)Lung87 (28)38 (27)49 (30)Chest wall43 (14)12 (9)31 (19)CNS30 (10)9 (6)21 (13) Conclusions The proportion of patients with de novo MBC appears to have increased over time to 46% in SystHERs, compared with 33% in RegistHER, a registry study that enrolled 1023 patients with HER2-positive MBC from 2003–2006 (Yardley et al, 2014), and predated the broad use of HER2-targeted therapy in the (neo)adjuvant setting. The DFI for patients with recurrent HER2-positive MBC also appears to be longer (median DFI 43.6 months in SystHERs vs. 32.6 months in registHER). We hypothesize that the proportion of patients with de novo MBC within the metastatic population is higher due to the use of advanced screening techniques which allow better detection of metastases, and due to a reduction in recurrences related to the availability of HER2-targeted adjuvant therapy. Changes in the population characteristics of patients with HER2-positive MBC may impact treatment strategies and have trial design implications. Updated data from approximately 500 patients are expected by the time of presentation. Citation Format: Debu Tripathy, Adam Brufsky, Melody Cobleigh, Mohammad Jahanzeb, Peter Kaufman, Ginny Mason, Musa Mayer, Joyce O'Shaughnessy, Hope Rugo, Sandra M Swain, Denise A Yardley, Mary Beattie, Bongin Yoo, Sara Hurvitz. Increasing proportion of de novo compared with recurrent HER2-positive metastatic breast cancer: Early results from the systemic therapies for HER2-positive metastatic breast cancer registry study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-07-14.

Purpose Detection of specific molecular alterations in tumors guides the selection of effective targeted treatment of patients with several types of cancer. These molecular alterations may occur in other tumor types for which the efficacy of targeted therapy remains unclear. The MyPathway study evaluates the efficacy and safety of selected targeted therapies in tumor types that harbor relevant genetic alterations but are outside of current labeling for these treatments. Methods MyPathway ( ClinicalTrials.gov identifier: NCT02091141) is a multicenter, nonrandomized, phase IIa multiple basket study. Patients with advanced refractory solid tumors harboring molecular alterations in human epidermal growth factor receptor-2, epidermal growth factor receptor, v-raf murine sarcoma viral oncogene homolog B1, or the Hedgehog pathway are treated with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. The primary end point is investigator-assessed objective response rate within each tumor-pathway cohort. Results Between April 1, 2014 and November 1, 2016, 251 patients with 35 different tumor types received study treatment. The efficacy population contains 230 treated patients who were evaluated for response or discontinued treatment before evaluation. Fifty-two patients (23%) with 14 different tumor types had objective responses (complete, n = 4; partial, n = 48). Tumor-pathway cohorts with notable objective response rates included human epidermal growth factor receptor-2–amplified/overexpressing colorectal (38% [14 of 37]; 95% CI, 23% to 55%) and v-raf murine sarcoma viral oncogene homolog B1 V600-mutated non–small-cell lung cancer (43% [six of 14]; 95% CI, 18% to 71%). Conclusion The four currently approved targeted therapy regimens in the MyPathway study produced meaningful responses when administered without chemotherapy in several refractory solid tumor types not currently labeled for these agents.

Purpose Patient registries are used to monitor safety, examine real-world effectiveness, and may potentially contribute to comparative effectiveness research. To our knowledge, life sciences industry (LSI)-sponsored registries have not been systematically categorized. This study represents a first step toward understanding such registries over time. Methods Studies described as registries were identified in the ClinicalTrials.gov database. Characteristics from these registry records were abstracted and analyzed. Results Of 1202 registries identified, approximately 47% reported LSI sponsorship. These 562 LSI registries varied in focus: medical devices (n = 193, 34%), specific drugs (n = 173, 31%), procedures (n = 29, 5%), or particular diseases (n = 139, 25%). Thirty-three registries (

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Background Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) is an aggressive form of breast cancer and is historically associated with poor outcomes compared with HER2-negative MBC. Since 1998, four drugs have been globally approved for the targeted treatment of HER2-positive MBC. Additional advances in patient care—such as improved breast cancer screening, HER2 testing, and supportive care—have also occurred. The objective of this systematic review and meta-analysis is to determine whether there has been a cumulative change in survival over time in patients with HER2-positive advanced breast cancer based on results from interventional clinical trials (ICTs) and observational studies and to compare outcomes across these types of studies. Methods/Design A systematic search of Medline, EMBASE, and the Cochrane Central Register of Controlled Trials will be performed. Two investigators will independently assess each abstract for inclusion. English language reports of ICTs and observational studies that include patients with HER2-positive advanced breast cancer from 1987 onwards will be considered. The primary outcome of interest is overall survival; secondary outcomes include progression-free survival and safety. Data on clinical outcomes, as well as on study design, study population, treatment/intervention, methodological quality, and outcomes, will be extracted using a structured codebook developed by the authors for this study. Standard and cumulative random effects meta-analysis will be performed to derive pooled risk estimates, both overall and by study design, controlling for covariates such as aggregate demographic and clinical characteristics of patients, treatment/intervention, and study characteristics. Heterogeneity of studies will be evaluated using the I2 statistic. Differences in risk estimates by quality characteristics will be performed using meta-regression. Discussion This study will evaluate current and evolving trends in survival associated with HER2-positive advanced breast cancer over nearly 30 years and will build upon prior, less comprehensive, systematic analyses. This information is important to patients, healthcare providers, and researchers, particularly in the advanced disease setting, in which new therapies have been recently approved. Including observational studies allows us to evaluate real-world effectiveness; useful information will be gained by comparing findings from observational studies with those from ICTs. Systematic review registration PROSPERO CRD42014014345 Electronic supplementary material The online version of this article (doi:10.1186/s13643-015-0118-z) contains supplementary material, which is available to authorized users.

Background Amplification of the human epidermal growth factor receptor 2 (HER2) gene occurs in approximately 20% of invasive breast cancer cases and is associated with a more aggressive disease course than HER2-negative breast cancer. HER2-targeted therapies have altered the natural history of HER2-positive breast cancer, a trend that will likely further improve with the recent approval of new agents. A prospective, observational cohort study was designed and initiated to provide real-world insights into current treatment patterns, long-term survival, and patients’ experiences with initial and subsequent treatments for HER2-positive metastatic breast cancer (MBC). Methods/Design The Systematic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs) is a US-based prospective observational cohort study enrolling patients ≥18 years of age with recently diagnosed HER2-positive MBC not previously treated with systemic therapy in the metastatic setting. The primary objective of the study is to identify treatment patterns and clinical outcomes in recently diagnosed patients in a variety of practice settings. Secondary objectives include comparative efficacy, safety, and patient-reported outcomes (PROs). Healthcare resource utilization is an exploratory end point. Tumor tissue and blood sample collection is optional. The SystHERs registry will enroll approximately 1000 patients over a 3-year period, after which the study will continue for ≥5 years, allowing for a maximum follow-up of 8 years. The treating physician will determine all care and the frequency of visits. PRO measures will be completed at study enrollment and every 90 days. Clinical data will be abstracted quarterly from patient records. The first patient was enrolled in June 2012, and preliminary descriptive data based on 25% to 30% of the final study population are expected at the end of 2013, and as of April 25, 2014, 386 patients are enrolled. Discussion SystHERs is expected to provide in-depth data on demographic, clinicopathological, and treatment patterns and their associations with clinical outcomes, PROs, and healthcare resource utilization. Tumor tissue and DNA repositories will also be established for use in future translational research. Trial registration number NCT01615068 (ClinicalTrials.gov identifier).

This is a narrative study of the construction and reconstruction of professional knowledge, where narrative is understood as both phenomenon and method. It is the story of one teacher's professiona...

Germline mutations in BRCA1 and BRCA2 (BRCA1/2) are related to an increased lifetime risk of developing breast and ovarian cancer. Although risk-reducing salpingo-oophorectomy reduces the risk of both cancers, loss of fertility is a major concern. A recent study suggested an association between BRCA1 mutation and occult primary ovarian insufficiency. The objective of the current study was to determine whether BRCA1/2 mutation carriers have an earlier onset of natural menopause compared with unaffected women.White carriers of the BRCA1/2 gene (n = 382) were identified within the Breast Cancer Risk Program Registry at the University of California at San Francisco and compared with non-clinic-based white women in northern California (n = 765). The 2 groups were compared with regard to median age at the time of natural menopause before and after adjustment for known risk factors, and the role of smoking within each group was examined using the Kaplan-Meier approach for unadjusted analyses and Cox proportional hazards regression analyses for adjusted analyses.The median age at the time of natural menopause in the BRCA1/2 carriers was significantly younger than among the unaffected sample (50 years vs 53 years; P.001). The unadjusted hazard ratio for natural menopause when comparing BRCA1/2 carriers with unaffected women was 4.06 (95% confidence interval, 3.03-5.45) and was 3.98 (95% confidence interval, 2.87-5.53) after adjusting for smoking, parity, and oral contraceptive use. For BRCA1/2 carriers who were current heavy smokers (smoking ≥ 20 cigarettes/day), the median age at natural menopause was 46 years versus 49 years for nonsmokers (P = .027).The BRCA1/2 mutation was associated with a significantly earlier age at natural menopause, and heavy smoking compounded this risk. Because the relationship between menopause and the end of natural fertility is considered to be fixed, these findings suggest the risk of earlier infertility among BRCA1/2 carriers.

The purpose of this work was to determine the prognostic value of normal exercise myocardial perfusion imaging (MPI) tests and exercise echocardiography tests, and to determine the prognostic value of these imaging modalities in women and men.Exercise MPI and exercise echocardiography provide prognostic information that is useful in the risk stratification of patients with suspected coronary artery disease (CAD).We searched the PubMed, Cochrane, and DARE databases between January 1990 and May 2005, and reviewed bibliographies of articles obtained. We included prospective cohort studies of subjects who underwent exercise MPI or exercise echocardiography for known or suspected CAD, and provided data on primary outcomes of myocardial infarction (MI) and cardiac death with at least 3 months of follow-up. Secondary outcomes (unstable angina, revascularization procedures) were abstracted if provided. Studies performed exclusively in patients with CAD were excluded.The negative predictive value (NPV) for MI and cardiac death was 98.8% (95% confidence interval [CI] 98.5 to 99.0) over 36 months of follow-up for MPI, and 98.4% (95% CI 97.9 to 98.9) over 33 months for echocardiography. The corresponding annualized event rates were 0.45% per year for MPI and 0.54% per year for echocardiography. In subgroup analyses, annualized event rates were1% for each MPI isotope, and were similar for women and men. For secondary events, MPI and echocardiography had annualized event rates of 1.25% and 0.95%, respectively.Both exercise MPI and exercise echocardiography have high NPVs for primary and secondary cardiac events. The prognostic utility of both modalities is similar for both men and women.

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