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BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10−4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers., Author Summary BRCA1 mutation carriers have increased and variable risks of breast and ovarian cancer. To identify modifiers of breast and ovarian cancer risk in this population, a multi-stage GWAS of 14,351 BRCA1 mutation carriers was performed. Loci 1q32 and TCF7L2 at 10q25.3 were associated with breast cancer risk, and two loci at 4q32.2 and 17q21.31 were associated with ovarian cancer risk. The 4q32.3 ovarian cancer locus was not associated with ovarian cancer risk in the general population or in BRCA2 carriers and is the first indication of a BRCA1-specific risk locus for either breast or ovarian cancer. Furthermore, modeling the influence of these modifiers on cumulative risk of breast and ovarian cancer in BRCA1 mutation carriers for the first time showed that a wide range of individual absolute risks of each cancer can be estimated. These differences suggest that genetic risk modifiers may be incorporated into the clinical management of BRCA1 mutation carriers.

Objective To evaluate the safety and efficacy of tamoxifen co-administration during conventional controlled ovarian hyperstimulation (COH) protocols for a fertility-preservation IVF cycle in breast cancer patients. Design Two groups: retrospective descriptive cohort study and prospective study. Setting Breast cancer oncology and fertility-preservation centers in a tertiary hospital. Patient(s) Two groups of breast cancer patients: premenopausal patients treated with adjuvant tamoxifen; and patients undergoing in vitro fertilization (IVF) for fertility preservation. Intervention(s) Fertility-preservation cycles, tamoxifen co-administration during conventional IVF. Main Outcome Measure(s) Endocrine records, and IVF results. Result(s) Estradiol (E 2 ) levels were chronically high (mean 2663 pmol/L, maximum: 10,000 pmol/L) in 38 of 46 breast cancer patients treated with adjuvant tamoxifen. Co-administration of tamoxifen (48 cycles) during conventional IVF or without tamoxifen (26 cycles), using either the long gonadotropin-releasing hormone–agonist or–antagonist protocols, resulted, respectively, in a mean of 12.65 and 10.2 oocytes retrieved, and 8.5 and 6.4 embryos cryopreserved. Average peak E 2 levels were 6,924 pmol/L and 5,093 pmol/L, respectively, but long-term recurrence risk (up to 10 years) was not increased. Conclusion(s) In breast cancer patients, co-administration of tamoxifen during conventional COH for fertility preservation does not interfere with IVF results. The high serum E 2 levels during COH should be considered safe, as it simulates the high prevalence of persistently high serum E 2 levels in premenopausal breast cancer patients safely treated with adjuvant tamoxifen.

The genetic basis for gastric and pancreatic cancer is largely undetermined. These cancers are overrepresented in hereditary non polyposis colon cancer (HNPCC), inherited cancer syndrome attributed to germline mutations primarily in the MSH2, MLH1 and MSH6 genes. Among Ashkenazi Jewish HNPCC cases, recurring mutations in the MSH2 (1906G>C; A636P) and MSH6 (c.3984_3987dupGTCA; c.3959_3962delCAAG) genes can be detected. The MSH6*c.3984_3987dupGTCA mutation was recently detected in an Ashkenazi family with inherited gastric cancer. We hypothesized that it may be possible to detect the recurring MSH2 and MSH6 mutations in Jewish individuals with familial and sporadic gastric and pancreatic cancer. To test this notion, we genotyped 143 unrelated Jewish Israeli patients with gastric (n = 23) and pancreatic (n = 120) cancer. The majority of cases (100/143–70%) were Ashkenazi Jews, and 10% (n = 16)—of mixed Ashkenazi-non Ashkenazi Jewish ancestry, and most participants (n = 96–67.1%) had a positive family history of cancer. Genotyping the MSH2*A636P mutation was performed by PCR followed by restriction enzyme digest, and the MSH6*c.3984_3987dupGTCA and c.3959_3962delCAAG mutations were detected by fragment size analysis by capillary electrophoresis and sequencing. None of the participants harbored any of the genotyped MSH2 or MSH6 mutations. We conclude that the recurring Ashkenazi MSH2 and MSH6 mutations contribute little if any to sporadic and familial gastric and pancreatic cases in Israeli patients.

Purpose Olaparib (AZD2281), an orally active poly (ADP-ribose) polymerase inhibitor that induces synthetic lethality in BRCA1- or BRCA2-deficient cells, has shown promising clinical efficacy in nonrandomized phase II trials in patients with ovarian cancer with BRCA1 or BRCA2 deficiency. We assessed the comparative efficacy and safety of olaparib and pegylated liposomal doxorubicin (PLD) in this patient population. Patients and Methods In this multicenter, open-label, randomized, phase II study, patients with ovarian cancer that recurred within 12 months of prior platinum therapy and with confirmed germline BRCA1 or BRCA2 mutations were enrolled. Patients were assigned in a 1:1:1 ratio to olaparib 200 mg twice per day or 400 mg twice per day continuously or PLD 50 mg/m2 intravenously every 28 days. The primary efficacy end point was Response Evaluation Criteria in Solid Tumors (RECIST) –assessed progression-free survival (PFS). Secondary end points included objective response rate (ORR) and safety. Results Ninety-seven patients were randomly assigned. Median PFS was 6.5 months (95% CI, 5.5 to 10.1 months), 8.8 months (95% CI, 5.4 to 9.2 months), and 7.1 months (95% CI, 3.7 to 10.7 months) for the olaparib 200 mg, olaparib 400 mg, and PLD groups, respectively. There was no statistically significant difference in PFS (hazard ratio, 0.88; 95% CI, 0.51 to 1.56; P = .66) for combined olaparib doses versus PLD. RECIST-assessed ORRs were 25%, 31%, and 18% for olaparib 200 mg, olaparib 400 mg, and PLD, respectively; differences were not statistically significant. Tolerability of both treatments was as expected based on previous trials. Conclusion The efficacy of olaparib was consistent with previous studies. However, the efficacy of PLD was greater than expected. Olaparib 400 mg twice per day is a suitable dose to explore in further studies in this patient population.

Susan M. Domchek, University of Pennsylvania School of Medicine, Philadelphia, PA Gillian Mitchell, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia Geoffrey J. Lindeman, Walter and Eliza Hall Institute of Medical Research and Royal Melbourne Hospital, Melbourne, Victoria, Australia Nadine M. Tung, Beth Israel/Deaconess Medical Center, Boston, MA Judith Balmana, Vall d’Hebron University Hospital, Barcelona, Spain Steven J. Isakoff, Massachusetts General Hospital, Boston, MA Rita Schmutzler, University of Cologne, Cologne, Germany M. William Audeh, Cedars Sinai Medical Center, Los Angeles, CA Niklas Loman, Skane University Hospital, Malmo, Sweden Clare Scott, Walter and Eliza Hall Institute of Medical Research and Royal Melbourne Hospital, Melbourne, Victoria, Australia Michael Friedlander, Prince of Wales Cancer Centre, Sydney, New South Wales, Australia Bella Kaufman, The Chaim Sheba Medical Center, Tel Aviv, Israel Judy E. Garber, Dana-Farber Cancer Institute, Boston, MA Andrew Tutt, Guy’s Hospital, King’s Health Partners Academic Health Sciences Centre, London, United Kingdom Mark E. Robson, Memorial Sloan-Kettering Cancer Center, New York, NY

BRCA1 and BRCA2 germline mutations substantially increase breast and ovarian cancer risk, yet penetrance is incomplete. The effects of oral contraceptives (OC) on breast cancer risk in mutation carriers are unclear, and the putative effect of parental origin of mutation on cancer risk has not been reported. Data on OC use and parental origin of the mutation were obtained at counseling from 888 BRCA1 (n = 638) or BRCA2 (n = 250) Jewish Israeli mutation carriers who were counseled and genotyped in a single medical center. Overall, 403 (45.4%) of participants had breast cancer (age at diagnosis 49.65 ± 12.2 years), 112 (12.6%) ovarian cancer (age at diagnosis 56.8 ± 10.8 years) and the rest (n = 373−42%) were asymptomatic carriers (age at counseling 40.7 ± 10.6 years). Of study participants, 472 (53.15%) ever used OC, and 298 used OC for at least 5 years. In 129 the mutation originated on the paternal side as judged by direct testing or obligate carriership and in 460 the mutation was maternally inherited. Multivariate logistic regression analysis, and stratifying for birth year, age at menarche, breast feeding, and number of births, showed that ever use of OC (Hazards Ratio-HR = 1.84 95% CI 1.465–2.314, P = 0.001) and paternal compared with maternal origin of mutation (OR = 1.55 95% CI 1.14–2.12, P = 0.006) were significantly associated with breast cancer and an earlier age at breast cancer diagnosis. The authors conclude that OC use and paternal origin of mutation affect breast cancer penetrance in Jewish BRCA1 and BRCA2 mutation carriers.

Approximately one-third of patients with advanced, HER2-positive breast cancer develop brain metastases. A significant proportion of women experience central nervous system (CNS) progression after standard radiation therapy. The optimal treatment in the refractory setting is undefined. This study evaluated the toxicity and efficacy of lapatinib in combination with chemotherapy among patients with HER2-positive, progressive brain metastases. Patients with HER2-positive breast cancer with progressive brain metastases after trastuzumab and cranial radiotherapy were included. The primary endpoint was CNS objective response, defined as a ≥ 50% volumetric reduction of CNS lesion(s) in the absence of new or progressive CNS or non-CNS lesions, or increasing steroid requirements. The study was closed early after 22 of a planned 110 patients were enrolled due to excess toxicity and lack of efficacy in the lapatinib plus topotecan arm. The objective response rate (ORR) in the lapatinib plus capecitabine arm was 38% (exact 95% confidence interval [CI] 13.9-68.4). No responses were observed in the lapatinib plus topotecan arm. Although the study was stopped prior to full enrollment, some promising indications of CNS activity were noted for lapatinib plus capecitabine. The combination of lapatinib plus topotecan was not active and was associated with excess toxicity.

The incretin hormone glucagon-like peptide (GLP)-1 is secreted from intestinal L cells in response to food intake, and promotes insulin secretion and pancreatic β-cell proliferation. Reduced GLP-1 levels are observed in obesity and type 2 diabetes mellitus (T2DM) and are associated with reduced insulin secretion and increased insulin resistance. GLP-1 mediates its activities through activation of a G-protein coupled receptor, which is expressed in the pancreas, as well as other tissues. Long-acting GLP-1 receptor (GLP-1R) agonists, such as exendin-4, are currently approved for the treatment of T2DM. As obesity and T2DM are associated with increased risk of breast cancer, we aimed to explore the effects of GLP-1 and exendin-4, on breast cancer cells. Treatment with GLP-1 or exendin-4 reduced viability and enhanced apoptosis of breast cancer cells but did not affect viability of nontumorigenic cells. Moreover, exendin-4 attenuated tumor formation by breast cancer cells in athymic mice. Treatment with either GLP-1 or exendin-4 elevated cAMP levels, activated the down-stream target CREB, and enhanced CRE promoter transcription, in breast cancer cells. Moreover, inhibition of exendin-4-induced adenylate cyclase activation restored cell viability, thus suggesting cAMP as a principle mediator of exendin-4 anti-tumorigenic activity. While the pancreatic form of the GLP-1R could not be detected in breast cancer cells, several lines of evidence indicated the existence of an alternative GLP-1R in mammary cells. Thus, internalization of GLP-1 into MCF-7 cells was evidenced, infection of MCF-7 cells with the pancreatic receptor enhanced proliferation, and treatment with exendin-(9–39), a GLP-1R antagonist, further increased cAMP levels. Our studies indicate the incretin hormone GLP-1 as a potent inducer of cAMP and an inhibitor of breast cancer cell proliferation. Reduced GLP-1 levels may, therefore, serve as a novel link between obesity, diabetes mellitus, and breast cancer.

Intracellular signaling mediated by the receptor activator of nuclear factor-κB [Rank, encoded by the tumor necrosis factor receptor superfamily, member 11a (Tnfrsf11a) gene] is fundamental for mammary gland development in mice, regulating the expansion of stem and progenitor cell compartments. Conversely, Rank overexpression in mice promotes abnormal proliferation and impairs differentiation, leading to an increased incidence of tumorigenesis. Here, we show that a common genetic variant near the 5′-end of TNFRSF11A, rs7226991, is associated with breast cancer risk in the general population and among carriers of mutations in the breast cancer 2, early onset (BRCA2) gene. Akin to the results of the Cancer and Genetics Markers of Susceptibility initiative, combined analysis of rs7226991 in two Spanish case–control studies (1,365 controls and 1,323 cases in total) revealed a significant association with risk: odds ratio (OR) = 0.88, 95% confidence interval (CI) 0.78–0.98, P trend = 0.025. Subsequent examination of BRCA1 (n = 1,017) and BRCA2 (n = 885) mutation carriers revealed a consistent association in the latter group: weighted hazard ratio (wHR) = 0.70; 95% CI 0.55–0.88; and P trend = 0.003; compared to BRCA1 mutation carriers, wHR = 0.91; 95% CI 0.76–1.10; and P trend = 0.33. The results of this study need to be replicated in other populations and with larger numbers of BRCA1/2 mutation carriers.

Exposure to estrogen has a major effect on breast cancer risk. A polymorphism (−34 T > C; rs743572) in the cytochrome P450c17alpha gene (CYP17A1) encoding an enzyme which controls estrogen levels was reportedly associated with breast cancer risk in average risk populations. The effect of this polymorphism on breast or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has not been thoroughly investigated. With this aim, 2,221 BRCA1 and BRCA2 mutation carriers (1,313 with breast cancer, 279 with ovarian cancer, and 695 asymptomatic carriers), with either BRCA1 (n = 1693) or BRCA2 (n = 528) germline mutations from seven centers were genotyped for the −34 T > C CYP17 polymorphism. Genotyping was accomplished using Taqman allelic discrimination, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) or PCR-based restriction-fragment length polymorphism analysis, and limited sequencing. Data were analyzed using Cox proportional hazards models. The hazard ratios (HRs) for breast cancer was 1.02 (95% CI 0.89–1.17, p = 0.74) and 1.10 (95% CI 0.72–1.67, p = 0.66) for BRCA1 and BRCA2 mutation carriers, respectively. The HRs for ovarian cancer were 1.17 (0.94–1.46, p = 0.17) and 0.91 (0.31–2.67, p = 0.86) for BRCA1 and BRCA2 mutation carriers, respectively. Results remained unaltered when the Israeli cohort (primarily Ashkenazim) was evaluated separately. In conclusion, there was no overall evidence for an association of the −34 T > C CYP17 polymorphism with either breast or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.

BACKGROUND Mass vaccination is the principal preventive measure against a smallpox outbreak after an act of bioterrorism. Vaccination of subjects who received immunosuppressive therapies is problematic because of smallpox vaccine reactogenicity. Moreover, long-term immunity to vaccinia might be affected. OBJECTIVE The objective of the study was to examine the effect of cytotoxic chemotherapy on long-term immunity to vaccinia. METHODS In a case-control study, 67 patients with breast cancer who received cytotoxic chemotherapy and who were disease free for at least 1 year were matched with healthy controls according to age, sex, and the number of smallpox vaccinations received. Markers of immunity to smallpox were examined. Forty-one patients with breast cancer who did not receive chemotherapy were used to assess the affect of cancer and radiotherapy on immunity to smallpox. RESULTS Patients with breast cancer who received chemotherapy had lower levels of vaccinia total immunoglobulin G and immunoglobulin G1 (expressed as enzyme-linked immunosorbent assay units per milliliter), neutralizing antibodies, vaccinia:memory B cell ratio (expressed as a percentage), and interferon-gamma level (expressed as picograms per milliliter), compared with healthy control individuals. CONCLUSIONS Immunity to smallpox is reduced after receipt of chemotherapy for breast cancer. This finding should be considered when planning smallpox vaccination campaigns. The effect of immunosuppressive treatments on persistence of immunity should be tested with respect to additional vaccines or natural infections.

Background: The Lapatinib Expanded Access Program (LEAP) was designed to provide access to lapatinib plus capecitabine for HER2-positive metastatic breast cancer patients who previously received an anthracycline, a taxane, and a trastuzumab and had no other treatment options. Patients and methods: LEAP opened globally and enrollment continued until lapatinib received regulatory approval in each participating country. Patients were assessed for progression-free survival (PFS) and overall survival (OS) and monitored for serious adverse events (SAEs). Results: As of 30 September 2008, 4283 patients from 45 countries enrolled in LEAP. The median treatment duration was 24.7 weeks. The most common drug-related SAEs were diarrhea (9.7%), vomiting (4.3%), and nausea (2.4%) and were mainly grade 3 or higher. The incidences of special interest SAEs were decreased left ventricle ejection fraction (0.5%), interstitial lung disease/pneumonitis (0.2%), and serious hepatobiliary events (0.4%). This safety profile is consistent with the overall lapatinib program. The median PFS and OS were 21.1 [95% confidence interval (CI) = 20.1– 22.3] and 39.6 (95% CI = 37.7–40.7) weeks, respectively (n = 4006). Subgroup analysis showed longer PFS and OS in patients who had not received prior capecitabine. Conclusions: These results demonstrate the safety and efficacy of lapatinib in a broader patient population compared with a clinical trial.

Objectives: HER2/neu (HER2) overexpression occurs in approximately 20% of breast cancers and is associated with aggressive disease. Although a significant number of HER2-positive tumors also express hormone receptors (HR), the effects HR expression has on clinical characteristics, including response to trastuzumab among HER2-positive breast cancer, has not been elucidated yet. Methods: A retrospective analysis of consecutive metastatic HER2-positive breast cancer patients was conducted in 2 medical centers. Associations between hormone receptors expression and clinical variables, and metastatic spread pattern and survival were studied. Results: The study population included 137 metastatic HER2-positive breast cancer patients, 56 of them were HR-positive and 81 were HR-negative. No significant differences between the 2 groups were found for demographic and clinical characteristics, including age, stage at diagnosis, tumor histology, and grade. Similar response rate to trastuzumab was observed in both study groups. Significantly, longer, median, disease-free, and overall survival was noted among the HR-positive patients. Patients in the HR-negative group had significantly more liver metastases, a trend for more brain metastases, and less bone metastases. There was a strong trend for more visceral metastases in the HR-negative group. Conclusions: Our results suggest an important role for HR expression in modulating metastases predilection and disease progression in HER2-positive breast cancer.

The CHEK2*I157T missense mutation, reported in ethnically diverse, high-risk families, moderately increases breast and colon cancer risk. The present study assessed whether this mutation represents a founder mutation. Participants identified in high risk clinics or from consecutive cancer patients in Israel, Poland, Latvia, and Finland, were either carriers of the CHEK2*I157T mutation or non-carrier family members. Multi-locus genotyping employed two intragenic markers and five CHEK2 gene flanking markers, spanning about 645 kb. Haplotyping was done when families were available for phasing. Overall, 101 individuals (83 I157T*CHEK2 mutation carriers) were genotyped: 16 Finnish individuals from 11 families (14 mutation carriers, two non-carrier family members), 50 Polish individuals (20 families) (35 carriers, 15 non-carriers), 28 unrelated Latvian mutation carriers, and seven Israeli participants (two families) (six mutation carriers, one non-carrier). Overall 36/83 mutation carriers (43%) were diagnosed with breast cancer, 15/83 (18%)-colon cancer, three-ovarian cancer, one-thyroid cancer, and the rest (n = 28) were asymptomatic. A common core haplotype was detected in all I157T*CHEK2 mutation carriers of Israeli, Polish, and Finnish origin between markers D22S275-D22S689 (approximately 258 kb), with a different allele pattern in Latvians. In conclusion, CHEK2*I157T missense mutation is a founder mutation in ethnically diverse populations, but may also be a mutational hotspot.

Only about 40% of the familial aggregation of breast cancer can be attributed to germline mutations in currently identified genes, primarily BRCA1 and BRCA2. A recent genome-wide association study focusing on Jewish Ashkenazi high risk women identified a novel locus on chromosome 6 as putatively containing breast cancer susceptibility genes, a locus that contains two seemingly novel candidate genes: RNF146 and ECHDC1. To further explore the role of these two genes in inherited predisposition to breast cancer. High risk, cancer affected Jewish Ashkenazi women, were genotyped for harboring germline mutations in the coding exons of both the RNF146 and ECHDC1 genes, using direct sequencing. All participants were Ashkenazim, of high risk families, and affected with cancer: 104 with breast cancer [age at diagnosis (mean +/- SD) 51 +/- 11.1 years], and one with ovarian cancer (61 years). None was a carrier of the predominant Jewish BRCA1/BRCA2 mutations. An intronic sequence alteration was detected in 4/105 genotyped patients in intron 3 of the ECHDC1 gene. No other sequence alterations were detected in the genomic regions analyzed of the RNF146 and ECHDC1 genes in any of the study participants. Mutations in the coding regions of the RNF146 and ECHDC1 genes do not contribute to the burden of inherited predisposition of breast cancer in Ashkenazi high risk women.

Objective To address optimal timing of sentinel lymph node biopsy (SLNB) in breast cancer patients undergoing neoadjuvant treatment. Methods The study population included 117 patients with locally advanced cancer with clinically negative nodes treated with primary chemotherapy. Group 1 underwent SLNB and completion axillary lymph node dissection (ALND) in conjunction with lumpectomy/mastectomy, after neoadjuvant treatment (n = 31). Group 2 underwent SLNB followed by neoadjuvant therapy and subsequently surgery and completion of ALNDs (n = 58). Group 3 was treated using the same sequence as group 2, however, completion ALND was performed only for patients with positive sentinel lymph nodes (SLNs) (n = 28). Results SLN identification was lowest in group 1 compared to groups 2 and 3 (87% and 98.8% respectively; P =

Mutations in currently known genes account for only a subset of breast/ovarian cancer risk families. Three loci (2p, 4q, 22q) seemingly harbor breast cancer susceptibility genes. To explore their putative role in Jewish women, 46 affected women representing 22 high risk families were genotyped with D2S2211, D4S392, D22S278 and D22S283 and two flanking markers for each locus, and mutational analysis of ID2 (Chromosome 2) and SULT1E1 (Chromosome 4) genes was carried out in seemingly linked families. No ID2 gene mutations were detected in 8 women from the 4 families seemingly linked to D2S2211, whereas a missense mutation (His224Gln) in one affected woman from a single family was detected among 9 women from the 4 families linked to D4S392. This mutation was not found among 153 high risk, 98 sporadic breast/ovarian cancer patients, or 97 healthy controls. The SULT1E1 gene may need to be further explored as candidate breast cancer gene.

Purpose Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor (EGFR) and human EGFR 2 (HER-2), demonstrated clinical activity in four of five IBC patients in phase I trials. We conducted a phase II trial to confirm the sensitivity of IBC to lapatinib, to determine whether response is HER-2 or EGFR dependent, and to elucidate a molecular signature predictive of lapatinib sensitivity. Patients and Methods Our open-label multicenter phase II trial (EGF103009) assessed clinical activity and safety of lapatinib monotherapy in patients with recurrent or anthracycline-refractory IBC. Patients were assigned to cohorts A (HER-2–overexpressing [HER-2+]) or B(HER-2–/EGFR+) and fresh pretreatment tumor biopsies were collected. Results Forty-five patients (30 in cohort A; 15 in cohort B) received lapatinib 1,500 mg once daily continuously. Clinical presentation and biomarker analyses demonstrated a tumor molecular signature consistent with IBC. Lapatinib was generally well tolerated, with primarily grade 1/2 skin and GI toxicities. Fifteen patients (50%) in cohort A had clinical responses to lapatinib in skin and/or measurable disease (according to Response Evaluation Criteria in Solid Tumors) compared with one patient in cohort B. Within cohort A, phosphorylated (p) HER-3 and lack of p53 expression predicted for response to lapatinib (P < .05). Tumors coexpressing pHER-2 and pHER-3 were more likely to respond to lapatinib (nine of 10 v four of 14; P = .0045). Prior trastuzumab therapy and loss of phosphate and tensin homolog 10 (PTEN) did not preclude response to lapatinib. Conclusion Lapatinib is well tolerated with clinical activity in heavily pretreated HER-2+, but not EGFR+/HER-2–, IBC. In this study, coexpression of pHER-2 and pHER-3 in tumors seems to predict for a favorable response to lapatinib. These findings warrant further investigation of lapatinib monotherapy or combination therapy in HER-2+ IBC.

1094 Background: Lap has single agent activity against BM in patients (pts) with HER2+ (ErbB2+) BC. Lap + Cap increases response rate, time to progression, and progression-free survival when compared with Cap alone in pts with refractory HER2+ BC. An exploratory analysis of the latter study (EGF100151) showed fewer pts on Lap + Cap developed BM at first relapse compared with Cap alone. The LEAP and ATU were designed to provide access to Lap before commercial availability and were initiated after EGF100151 enrollment was halted. Eligibility requirements for these programs were similar to EGF100151, i.e., pts had disease progression following prior taxane, anthracycline, and trastuzumab therapy. Although data were not formally collected via case report forms, we surveyed LEAP and ATU sites to ascertain the percent of pts with progressive BM at entry and response to Lap + Cap. Methods: LEAP/ATU sites that enrolled 15 or more pts were queried to provide data via worksheets or narratives regarding progressive ...

Germline mutations in BRCA1 and BRCA2 genes account for only 20-40% of familial breast cancer cases. The CHEK2 gene encodes a checkpoint kinase, involved in response to DNA damage, and hence is a candidate gene for breast cancer susceptibility. Indeed, the CHEK2*1100delC truncating mutation was reported in a subset of mostly North European breast cancer families. The rate of the CHEK2*1100delC variant in the Ashkenazi Jewish population was reported to be 0.3%.To evaluate whether CHEK2 germline mutations contribute to a breast cancer predisposition in Ashkenazi** Jewish high risk families.High risk Ashkenazi Jewish women, none of whom was a carrier of the predominant Jewish mutations in BRCA1/BRCA2, were genotyped for germline mutations in the CHEK2 gene by exon-specific polymerase chain reaction followed by denaturing gradient gel electrophoresis and sequencing of abnormally migrating fragments.Overall, 172 high risk women were genotyped: 75 (43.6%) with breast cancer (average age at diagnosis 49.6 +/- 9.6 years, mean +/- SD) and 97 asymptomatic individuals (age at counseling 48.3 +/- 8.2 years). No truncating mutations were noted and four previously described missense mutations were detected (R3W 1.2%, 1157T 1.2%, R180C 0.6% and S428F 5%), one silent polymorphism (E84E 20.5%) and one novel missense mutation (Y424H 1.2%). Segregation analysis of the 1157T and S428F mutations (shown to affect protein function) with the cancer phenotype showed concordance for the CHK2*1157T mutation, as did two of three families with the CHK2*S428F mutation.CHEK2 missense mutations may contribute to breast cancer susceptibility in Ashkenazi Jews.

155 Background: BRCA-mutated tumors are more susceptible to platinum therapy and PARP inhibitors due to underlying defects in homologous recombination repair of DNA damage. In preclinical models the potent oral PARP1/2 inhibitor veliparib was shown to enhance sensitivity to C and to have single-agent activity in BRCA+ cell lines. Phase 1 trials suggest promising antitumor activity and acceptable toxicity of veliparib plus C/P in triple-negative BC (Puhalla et al. Cancer Res 2012;72:PD09-06) and single-agent activity of veliparib in BRCA+ BC (Somlo et al. J Clin Oncol 2014;32:abstr. 1021). This phase III trial assesses efficacy and toxicity of veliparib plus C/P vs C/P alone in patients with HER2− BRCA-associated locally advanced or metastatic BC (NCT02163694). Methods: Phase III randomized, double-blind, placebo-controlled, multicenter trial. Eligible patients (female or male; ≥ 18 years) have HER2−metastatic/locally advanced unresectable BC with (suspected) deleterious BRCA1/2 germline mutations and received 2 or fewer prior lines of DNA-damaging chemotherapy for metastatic BC. In addition, patients must have received ≤ 1 prior line of platinum therapy (any setting) without progression within 12 months of completing treatment. Patients are randomized 2:1 to C/P with veliparib or C/P with placebo, stratified by estrogen and/or progesterone receptor expression, prior platinum therapy, and central nervous system metastases. Veliparib (120 mg p.o. BID) or placebo will be given on Days −2 to 5, C (AUC 6 mg/mL/min i.v.) on Day 1, and P (80 mg/m2i.v.) on Days 1, 8, and 15 (21-day cycles). Treatment continues until unacceptable toxicity or progressive disease (PD). Patients in the placebo arm who discontinue due to PD are eligible for crossover to veliparib monotherapy. The primary objective is to assess if the addition of veliparib to C/P increases progression-free survival; additional objectives include evaluation of overall survival, clinical benefit rate, objective response rate, quality of life, and safety. Enrollment began in July 2014 with a planned sample size of 270 patients. Clinical trial information: NCT02163694.

Tumor heterogeneity frequently develops through the course of disease, therapy and metastasis. This molecular evolution is a major challenge in the clinical setting and is the main reason for resistance to therapy. Although metastatic disease is the cause of death in breast cancer, most studies involve primary tumors compared to normal breast. An alternative approach of serial assessments can add an informative value and highlight important molecular players that may be otherwise underestimated. We sought to explore alterations through the course of disease by profiling serial samples from individual breast cancer cases followed from diagnosis to recurrence. We have assembled a unique cohort of patients having matched samples from pre-treatment, post-treatment and recurrent events. We collected paraffin-embedded samples and profiled miRNA expression across all samples for each patient using NanoString analysis. We hypothesized that expression modulations in individual patients through their course of disease can target miRNAs sets that differentially function at the various stages of the disease. We therefore used an innovative approach for analysis, identifying modulation patterns as opposed to differential absolute expression. We defined all the 8 possible patterns of expression modulations in 3 time points across the course of disease. For each pattern, we identified a set of miRNAs that are shared between patients by limiting the search algorithm to find modulations of at least 1.5 fold in at least 3 patients. Each miRNA set was examined for enrichments in known miRNAs datasets (METABRIC), for target predictions and for literature evidences. We found an agreement between the predicted pattern of each assigned miRNAs and the observed trend. For example, miRNAs assigned to a pattern of an increased expression post-treatment and a decrease at recurrence were found to be down-regulated in breast cancer and negatively correlated with the cell cycle pathway. Interestingly, we found that this miRNAs set can differentiate between individual patients, based on their response to therapy. All patients sharing the same pattern for its assigned set of miRNAs had a partial response to therapy. In contrast, patients that showed the opposite pattern demonstrated a minimal response to therapy. Finally, although this miRNA set were identified by the pattern dynamics, we found a significant difference in its average absolute expression level between patients having recurrence and patients that are recurrence free, suggesting that the identified miRNA set may have a prognostic value. In summary, examining serial assessments enabled us to identify significant molecular signatures characterizing breast cancer progression based on expression patterns through the course of disease. This longitudinal approach of profiling individual patients may have important consequences for personalized medicine. Citation Format: Maya Dadiani, Noa Bossel, Shani Paluch-Shimon, Gili Peri, Anya Pavlovski, Smadar Kahana-Edwin, Nora Balint, Adi Yosepovich, Adi Zundelevich, Einav Gal-Yam, Raanan Berger, Iris Barshack, Eytan Domany, Bella Kaufman. Tumor evolution inferred by patterns of miRNA expression through the course of disease, therapy and recurrence in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4011. doi:10.1158/1538-7445.AM2015-4011

Background: The PARPi olaparib (Ola) was recently granted FDA accelerated approval in advanced BMOC. Despite impressive clinical activity in BMOC, the impact of baseline pt factors remains unclear. We hypothesized that the platinum chemotherapy (Plt chemo) to PARPi interval (PTPI) can be used to refine the conventional prediction of response to PARPi based on the clinical categorization of pts into Plt sensitive (Plt-S) and Plt resistant (Plt-R). Methods: Retrospective study of pt with advanced BMOC treated in relapsed setting with ≥ 200 mg bid Ola between 4/2006 – 8/2013 in multiple centers. Pearson Chi2, odds ratios (OR) and Fisher’s exact probability tests were used for statistical analyses. Results: 108 advanced BMOC pts were assessed; median age 55y (range 38-79); 83 (77%) pts had high grade serous carcinoma. BRCA1:BRCA2 mutations ratio 71:29. Median prior lines of chemo: 3 (range 1-10). 41 (38%) pts had prior breast cancer (BC). 64% had Plt-S disease and 36% had Plt-R disease prior to Ola. Median PTPI was 53 weeks (w) (range 4-244). Median PTPI was 68.7w for Plt-S pts versus (vs) 25.9w for Plt-R pts (p < 0.0001). RECIST complete or partial responses (CR/PR) were observed in 23/65 (35%) Plt-S pts vs 5/38 (13%) Plt-R pts (p < 0.02). Pts with > 52w PTPI had higher CR/PR rates than those with < 52w PTPI independent of their Plt status (37% vs 18%, respectively, p = 0.053). Pts who had only 1 prior line of chemo had higher CR/PR rates vs pts who had > 1 prior line (p < 0.005). No differences in CR/PR rates were noted between pts with BRCA1 vs pts with BRCA2 mutations, pts with prior BC vs pts without, or use of chemo for BC vs none. Median progression-free survival was 70w for pts with PR/CR vs 28w for pts without (log-rank, p = 0.0004). Median survival was 161w for pts with CR/PR and 64w for pts without (log-rank, p = 0.0005). Conclusions: These data suggest that prediction of response to PARPi in advanced BMOC based on conventional Plt-S/Plt-R categorization may be refined by PTPI. Treatment of Plt-R BMOC pts with a non-Plt agent prior to Ola in order to prolong PTPI may be an appropriate clinical strategy. These findings should be validated prospectively in a larger data set.

TPS1109 Background: In a Phase II proof-of-concept study (NCT00494234), treatment with the PARP inhibitor olaparib (Lynparza; 400 mg twice daily [bid]; capsules) resulted in antitumor activity in p...

Background A Phase II study showed that the PARP inhibitor olaparib (400 mg bid; capsules) exerts antitumor activity in BC pts with a gBRCAm (Tutt et al Lancet 2010). Three Phase III trials of olaparib monotherapy have been initiated in BC pts with a gBRCAm: OlympiA (NCT02032823), Neo-Olympia (D081EC00005), OlympiAD (NCT02000622). Trial design OlympiANeo-OlympiaOlympiADSettingAdjuvant therapy for high-risk, primary TNBCNeo-adjuvant therapy for primary TNBCMetastatic BC (mBC)DesignRandomized (1:1), double-blind, parallel-groupRandomized (1:1:1), three-arm, parallel-groupRandomized (2:1), open-labelOlaparib monotherapy arm300 mg bid (tablet)300 mg bid (tablet) (Arm A)*300 mg bid (tablet)Comparator arm(s)PlaceboPlacebo + weekly paclitaxel 80 mg/m2 for 12 wks (Arm B)* Olaparib 100 mg bid (tablet) + weekly paclitaxel 80 mg/m2 for 12 wks (Arm C)*Physician's choice of capecitabine 2500 mg/m2 (d1-14 q21d), vinorelbine 30 mg/m2 (d1, d8 q21d) or eribulin 1.4 mg/m2 (d1, d8 q21d)Primary endpointIDFSpCR ratePFS (BICR)Secondary endpointsOS, DDFS, incidence of new cancersOS, EFS, DDFS, ORR at 12 wksOS, PFS2, ORR HRQoLHRQoLHRQoLOther objectivesSafety, tolerabilitySafety, tolerabilitySafety, tolerabilityTarget recruitment (pts)1320300310*Curative-intent surgery to be performed after 12 wks; pts will then receive olaparib 300 mg bid (Arm A), placebo (Arm B), or either weekly paclitaxel 80 mg/m2 for 12 wks (then olaparib 300 mg bid) or olaparib 300 mg bid (Arm C). BICR, blinded independent central review; d, days; DDFS, distant disease-free survival; EFS, event-free survival; IDFS, invasive disease-free survival; ORR, objective response rate; pCR, pathological complete response; q, every; PFS2, time to second disease progression or death; TNBC, triple-negative BC For each trial, eligible pts will have a BRCAm and will undergo gBRCAm testing (Myriad Integrated BRACAnalysis®) as part of the trial. For OlympiA, pts must be at high risk of recurrence and have completed local treatment and either neoadjuvant (without pCR) or adjuvant chemotherapy. Neo-Olympia pts can have operable, locally advanced or inflammatory BC, must have a tumor >2cm by clinical exam (or >1cm by radiological exam) and have completed four cycles of anthracycline plus carboplatin without progression. OlympiAD pts can have TNBC or HER2– BC, and must have received prior anthracycline and taxane in the adjuvant or metastatic setting, and ≤2 chemotherapy lines for mBC. OlympiA pts will be treated for up to 12 months (m); efficacy will be assessed q3m up to 24m, then q6m up to 60m, then q12m. Neo-Olympia pts will be treated for 12 wks (w) pre-surgery, then for 40w post-surgery. In OlympiAD, PFS will be assessed by RECIST v1.1; radiologic exams will be performed at baseline, q6w up to 6m, then q12w until progression. In OlympiA and OlympiAD, IDFS and PFS will be analyzed using stratified log-rank tests; for Neo-Olympia, pCR rate will be analyzed with an adjusted logistic regression model. Primary analyses will be undertaken after 330 IDFS events (OlympiA), surgery (Neo-Olympia) and 230 PFS events (OlympiAD). Enrollment began in Mar 2014 for OlympiAD, Apr 2014 for OlympiA and is expected to begin in Q3 2014 for Neo-Olympia. Citation Format: Mark Robson, Andrew Tutt, Judith Balmaña, Bella Kaufman, Judy Garber, Charles Geyer, James Ford, Priyanka Sharma, Mary Stuart, Helen Mann, Peter A Fasching. OlympiA, Neo-Olympia and OlympiAD: Randomized phase III trials of olaparib in patients (pts) with breast cancer (BC) and a germline BRCA1/2 mutation (gBRCAm) [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 OT1-1-04.

Numerous studies have examined the association between body weight, nutritional factors, physical activity and the risk for primary breast cancer. Relatively few studies, however, have examined the associations between these issues and the recurrence of the disease and cure of the primary tumor. Today, three areas of focus are actively being researched for breast cancer survivors: body weight, diet composition and physical activity with specific emphasis on the risk for recurrence, survival and quality of life. Increased body weight or BMI (Body Mass Index) at diagnosis was found to be a significant risk factor for recurrent disease, decreased survival, or both. Overall obesity has been shown to adversely affect prognosis. Appropriate weight control may be particularly beneficial for breast cancer survivors. Breast cancer survivors should be encouraged to achieve and maintain a healthy weight. Limiting fat intake can reduce the risk of breast cancer recurrence. Increasing consumption of vegetables and fruits seems to have possible beneficial effects during and after treatments. To date physical activity after breast cancer diagnosis has been found to reduce the risk of death. The greatest benefit occurred in women who performed the equivalent of walking 3-5 hours per week at an average pace. Safe weight loss via increased physical activity and healthful food choices should be encouraged for normal, overweight or obese breast cancer survivors in order to improve survival and life quality.

Founder mutations in the BRCA1 and BRCA2 genes have been discovered in the Ashkenazic Jewish population, but a founder mutation(s) has not been discovered among non-Ashkenazi Jews (NAJ). Two BRCA1 mutations (P1812A, P25T), and a BRCA2 mutation (5164del4) have been detected in NAJ high-risk families. We studied the prevalence of these three mutations in 270 high-risk NAJ families, including 85 from Iraq/Iran, 67 from North Africa, 27 from Yemen, 50 from the Balkan region, and 41 with mixed ancestry. The three mutations were detected only in individuals related to the original families. We conclude that the P1812A and P25T BRCA1 and 5164del4 BRCA2 mutations are not likely to be founder mutations in NAJ high-risk families. We also assessed the pathogenicity of the BRCA1 P1812A mutation in vitro using reporter gene assays in yeast and mammalian cells. We found that the BRCA1 P1812A variant activity assays yielded a slightly reduced reporter gene activity. Thus, there is some uncertainty as to the pathogenicity of BRCA1 P1812A.

To evaluate whether nasal intermittent mandatory ventilation (NIMV) compared with nasal continuous positive airway pressure (NCPAP) would decrease the requirement for endotracheal ventilation in the treatment of respiratory distress syndrome (RDS) in preterm infants35 weeks.Randomized, controlled, prospective, single-center study. Forty-one infants were randomized to NCPAP and 43 comparable infants to NIMV (birth weight 1533 +/- 603 vs 1616 +/- 494 g, gestational age 30.6 +/- 3.0 vs 31.1 +/- 2.3 weeks, P = .5, respectively).Infants treated with NIMV and with NCPAP had comparable cardio-respiratory status at study entry. In the total cohort, infants treated initially with NIMV needed less endotracheal ventilation than infants treated with NCPAP (25% vs 49%, P.05) with a similar trend in infants1500 g; 31% vs 62%, P =. 06). When controlling for weight and gestational age, NIMV was more successful in preventing endotracheal ventilation (P.05). Infants treated with NIMV had a decreased incidence of bronchopulmonary dysplasia (BPD) compared with those treated with NCPAP (2% vs 17%, P. 05, in the total cohort and 5% vs 33%, P. 05, for infants1500 g).NIMV compared with NCPAP decreased the requirement for endotracheal ventilation in premature infants with RDS. This was associated with a decreased incidence of BPD.

BACKGROUND The hormone ghrelin and the adipocytokines leptin and adiponectin participate in body weight regulation. In response to weight loss, ghrelin and adiponectin levels increase and leptin decreases. Cancer cachexia is a complex metabolic state, characterized by loss of muscle mass and adipose tissue together with anorexia. The authors hypothesized that responses of these hormones may be attenuated in cancer cachexia. METHODS Fasting plasma ghrelin, adiponectin, and leptin levels, as well as weight loss, were determined in 40 cancer patients: 18 of them suffered from cancer-induced cachexia, and 22 served as a comparison group. Hormone levels were measured before administration of cancer therapy. RESULTS A similar distribution of age, gender, and diagnosis was observed in both study groups, but the cachectic patients had higher rates of metastatic disease and lower albumin levels. No significant correlation was observed between plasma adiponectin levels and weight loss. Mean plasma ghrelin levels were higher among cachectic compared with noncachectic patients. Notably, the association between ghrelin levels and weight loss was only modest, and in a third of the cachectic patients, ghrelin levels were equal to or lower than those in the noncachectic group. Plasma leptin levels showed gender-dependent associations, and significantly lower levels were found among cachectic women but not among cachectic men. CONCLUSIONS Results suggested a gender-dependent attenuation of expected physiologic responses to weight loss among cancer cachexia patients. Thus, impaired response of adiponectin, ghrelin, and leptin may play a role in the pathogenesis of cancer cachexia syndrome. Cancer 2006. © 2006 American Cancer Society.

Type 2 diabetes mellitus is associated with increased incidence and inferior outcome of various malignancies. The aim of this study was to explore the impact of type 2 diabetes on breast cancer characteristics at presentation. The study population included 79 diabetic and 158 age-matched non-diabetic patients. Parity, country of birth, co-morbidity other than diabetes, and mode of diagnosis were similar in both groups. Mean body mass index (BMI) was higher among diabetic patients. Tumour stage and size were higher among diabetic patients and the differences remained significant after adjustment for BMI. Moreover, after adjustment for BMI, breast cancer among diabetic patients was more often hormone receptor negative. Our results show that diabetes mellitus is associated with negative prognostic factors at breast cancer presentation.

The Israeli Society for Clinical Oncology and Radiotherapy appointed experts in breast cancer therapy to assess the Society's policy regarding hormone replacement therapy (HRT) in breast cancer survivors with menopausal symptoms. The first policy letter was published in November 2002, and referred to available literature at that time which included retrospective data alone. The professional literature suggested no increased risk in breast cancer recurrence or cancer specific mortality, and no effect on overall survival with the use of HRT for a limited period (up to 3 years). This data served as the rationale for international prospective studies. Former committee recommendations and precautions are detailed in the original publication. In February 2004, the interim analysis of a prospective trial, the HABIT (Hormonal replacement therapy after breast cancer--is it safe?) was published. In that trial, breast cancer survivors with menopausal symptoms were randomized to HRT (estrogens with or without progestins) or no therapy for 2 years. A total of 434 women were recruited from centers in Scandinavia who participated with the International Breast Cancer and the European Organization for Research and Treatment groups. Analysis was restricted to 345 women with at least one follow up report; median follow-up period was 2.1 years. The relative risk for breast cancer event was 3.5 (95% C.I. 1.5-8.1) in HRT users as compared with the non-HRT group and the HABIT trial was terminated. Study limitations are discussed. Thereby, at this time HRT can no longer be considered safe in breast cancer survivors. Physicians treating breast cancer survivors for severe menopausal symptoms should present study results and alternative non-hormonal treatment options to allow patients optimized consented treatment decisions.

Tumor downstaging by preoperative neoadjuvant chemotherapy in patients with locally advanced breast tumors allows breast conservation in women who were previously candidates for mastectomy. Nevertheless, lumpectomy success in such cases cannot be fully achieved. The aim of this study was to create a quantitative tool for preoperative evaluation of the success of breast conservation in such patients.The study population included 100 consecutive patients with stage II and III breast cancer who were designated for lumpectomy and 19 patients who were designated for mastectomy. All patients received neoadjuvant therapy. Breast-conserving surgery was offered in accordance with clinical and esthetic criteria. Demographic details and clinical, imaging, and pathologic information were collected from medical files. A decision protocol for classifying patients to lumpectomy or mastectomy was built by using the Classification and Regression Trees procedure based on preoperative characteristics.Three factors were found to be the main predictors for successful breast conservation: absence of diffuse microcalcifications as seen in the pretreatment mammogram, a postchemotherapy tumor size of25 mm, and the existence of a circumscribed lesion on mammography.The use of these criteria as a basis for decision on the type of surgery may decrease the performance of unnecessary procedures.

A complication of breast conservation, which has been increasingly reported in the literature, is 'delayed cellulitis' in the treated breast. This is to be distinguished from wound infection in the breast following lumpectomy. This study reports 16 cases diagnosed with delayed cellulitis following breast conserving surgery, unresponsive to antibiotic therapy. Diagnostic criteria included: pain, erythema and edema in the operated breast. Symptoms appeared up to 10 months after surgery and time to resolution was seven and a half months. No patients had positive cytology and bacteriology tests were negative. Thirteen patients were observed, and three patients were treated with antibiotics with no apparent immediate effect. The appearance of breast cellulitis after surgery poses a problematic diagnostic and management dilemma. It is important to distinguish between this entity and infection, or inflammatory carcinoma. The picture may be attributed to impairment or occlusion of the lymphatic circulation in the breast. This seems to be a newly defined complication with an incidence of 3-5%.

Background: Veliparib is a potent, oral PARP inhibitor that inhibits DNA repair, primarily through single strand break repair. BRCA1/2 mutated tumors are defective in homologous recombination, leading to more error prone mechanisms of DNA repair and increased sensitivity to PARP inhibition. Veliparib and TMZ recently demonstrated promising activity in BRCA1/2 mutation carriers, and veliparib and C/P is being evaluated in a CTEP Phase 1 study. This Phase 2 multinational study will evaluate veliparib in combination with TMZ and in combination with C/P compared to an active, placebo-controlled arm of C/P in subjects with BRCA1 or BRCA2 mutation and metastatic breast cancer. Methods: Approximately 240 subjects will be randomized in a 1:1:1 ratio to: 1) Veliparib 40 mg BID D1-7 + TMZ (150–200 mg/m2 QD D1-5) of every 28 day cycle; or 2) Veliparib 120 mg BID D1-7 + C (AUC 6, D3) and P (175 mg/m2, D3) of every 21 day cycle or 3) placebo BID D1-7 + C/P. Key eligibility includes known deleterious BRCA1/2 mutation, ≤1 prior chemotherapy for metastatic disease, and no prior platinum agent. Randomization will be stratified by hormone receptor positive versus negative, prior vs. no prior cytotoxic therapy, and ECOG 0–1 vs 2. The primary objective is progression-free survival (PFS) using RECIST 1.1. Secondary objectives include overall survival, objective response rate, duration of response and safety/tolerability. Optional paired tissue biopsies will be obtained at baseline and at progression to evaluate markers of response and resistance. Additional correlatives for response include assessment of peripheral blood, CTCs, and archived tissue for markers of disease status, gene methylation and mutational status, and tumor-specific alteration of cellular proteins/peptides and/or nucleic acids. Using the log-rank test for PFS, with 150 PFS events the study will have ≥ 80% power at 2-sided α level of 0.05 to detect a statistically significant treatment effect assuming a true hazard ratio of 0.58 favoring the 2 treatment groups containing veliparib. As of June 11, 2012, 5 subjects have been enrolled. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-07.

Background: A Phase II study (NCT00494234) showed that the oral PARP inhibitor olaparib (400 mg bid; capsules) exerts antitumour activity in BC pts with a gBRCAm (Tutt et al Lancet 2010). Three Phase III trials of olaparib monotherapy have been initiated in BC pts with a gBRCAm: OlympiA (NCT02032823), Neo-Olympia (D081EC00005), OlympiAD (NCT02000622). Trial design: Trial designs are summarized in the Table. For each trial, eligible pts will have a BRCAm and will undergo gBRCAm testing (Myriad Integrated BRACAnalysis®) as part of the trial. For OlympiA, pts must be at high risk of recurrence and have completed local treatment and either neoadjuvant (without pCR) or adjuvant chemotherapy. For Neo-Olympia, pts can have operable, locally advanced or inflammatory BC, must have a tumour >2 cm by clinical exam (or >1 cm by radiological exam) and must have completed four cycles of anthracycline plus carboplatin without disease progression. For OlympiAD, pts can have TNBC or HER2-negative BC, and must have received prior anthracycline and taxane in the adjuvant or metastatic setting, and ≤2 chemotherapy lines for mBC. In OlympiA, pts will receive treatment for up to 12 months; efficacy will be assessed q 3 months up to 24 months, then q 6 months up to 60 months, then q 12 months. In Neo-Olympia, pts will receive treatment for 12 wks pre-surgery and then for 40 wks post-surgery. In OlympiAD, PFS will be assessed by RECIST v1.1; radiologic exams will be performed at baseline, q 6 wks up to 6 months, and then q 12 wks until disease progression. In OlympiA and OlympiAD, IDFS and PFS, respectively, will be analyzed using stratified log-rank tests; for Neo-Olympia, pCR rate will be analyzed with an adjusted logistic regression model. Primary analyses will be undertaken after 330 IDFS events (OlympiA), surgery (Neo-Olympia) and 230 PFS events (OlympiAD). Enrolment began in March 2014 for OlympiAD, April 2014 for OlympiA and is expected to begin in Q3 2014 for Neo-Olympia. OlympiA Neo-Olympia OlympiAD Setting Adjuvant treatment for high-risk, primary TNBC Neo-adjuvant treatment for primary TNBC Metastatic BC (mBC) Design Randomized (1:1), double-blind, parallel-group Randomized (1:1:1), three-arm, parallel-group Randomized (2:1), open-label Olaparib monotherapy arm 300 mg bid (tablet) 300 mg bid (tablet) (Arm A)* 300 mg bid (tablet) Comparator arm(s) Placebo Placebo + weekly paclitaxel 80 mg/m2 for 12 wks (Arm B)* Physician's choice of capecitabine 2500 mg/m2 (d1-14 q 21d), vinorelbine 30 mg/m2 (d1, d8 q 21d) or eribulin 1.4 mg/m2 (d1, d8 q 21d) Olaparib 100 mg bid (tablet) + weekly paclitaxel 80 mg/m2 for 12 wks (Arm C)* Primary endpoint IDFS pCR rate PFS (BICR) Secondary endpoints OS, DDFS, incidence of new cancers OS, EFS, DDFS, ORR at 12 wks OS, PFS2, ORR HRQoL HRQoL HRQoL Other objectives Safety, tolerability Safety, tolerability Safety, tolerability Target recruitment (pts) 1320 300 310 *Curative-intent surgery to be performed after 12 wks, after which pts will receive olaparib 300 mg bid (Arm A), placebo (Arm B), or either weekly paclitaxel 80 mg/m2 for 12 wks (followed by olaparib 300 mg bid) or olaparib 300 mg bid (Arm C) BICR, blinded independent central review; d, days; DDFS, distant disease-free survival; EFS, event-free survival; IDFS, invasive disease-free survival; ORR, objective response rate; OS, overall survival; pCR, pathological complete response; PFS, progression-free survival; q, every; PFS2, time to second disease progression or death; TNBC, triple-negative breast cancer; wks, weeks Disclosure: J. Garber: Research funding – Myriad; M. Stuart: AZ employee and owns stock in AZ; H. Mann: AZ employee and owns stock in AZ. All other authors have declared no conflicts of interest.

601 Background: Lapatinib (L) was associated with shorter progression-free survival (PFS) than trastuzumab (T) when combined with a taxane (Tax) as first line therapy for HER2+ MBC. We report the e...

1023 Background: Pathological complete response (pCR) has been demonstrated to serve as a surrogate for outcome in patients receiving neo-adjuvant systemic therapy (NAT) for triple negative (TN) br...

BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and/or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5′ untranslated region of RAD51 (135C/G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 ( 185delAG , 5382insC ) or BRCA2 ( 6174delT ) mutations. Of this group, 164 were affected with breast and/or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51 - 135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) = 1.18 for disease in RAD51 - 135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51 - 135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women ( P = 0.07). Survival analysis in BRCA2 carriers showed RAD51 - 135C increased risk of breast and/or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6–9.8, P = 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3–9.2, P = 0.01) for breast cancer in BRCA2 carriers who were RAD51 - 135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51 - 135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages.

Seventy cancer patients suffering from visceral or somatic pain received continuous epidural methadone (EM) analgesia. Initially, 4 mg of 0.1% methadone was given three times daily. If this dose proved ineffective, it was gradually increased to 8 mg four times daily. With this regimen good pain control was obtained in 56 patients (80%). Patients continued the EM therapy for periods up to 140 days, with an average duration of 27 days. Morphine was substituted for methadone in 14 patients (20%). Four of these patients responded well and continued treatment for an average of 18 days. No serious side effects have been observed with EM. With a proper selection of patients and following strict therapy guidelines, epidural methadone is efficacious in treating cancer pain.

610 Background: The gold standard endpoint in randomized clinical trials (RCTs) in MBC is OS, which has the disadvantage of requiring extended follow-up and being confounded by subsequent anti-cancer therapies. Although therapeutics have been approved based on PFS, its use as a primary endpoint is controversial. This study, the first IPD meta-analysis of targeted agents in MBC, aimed to collect data from RCTs of HER2-targeted agents in HER2+ MBC, assessing to what extent PFS correlates with, and may be used as, a surrogate for OS. Methods: A search was conducted in April 2011. Eligible RCTs accrued HER2+ MBC patients (pts) in 1992-2008. Collaboration was obtained from industrial partners (Roche, GSK) for industry-led studies. Investigator-assessed PFS was defined as the time from randomization to clinical or radiological progression, or death. A correlation approach was used: at the individual level, to estimate the association between PFS and OS using a bivariate survival model and at the trial level, to estimate the association between treatment effects on PFS and OS. Squared correlation values close to 1.0 would indicate strong surrogacy. Results: The search strategy resulted in 2137 eligible pts in 13 RCTs testing trastuzumab or lapatinib. We collected IPD data from 1963 pts in 9 RCTs. One phase II RCT did not have sufficient follow-up data so that 1839 pts in 8 RCTs were retained (5 evaluating trastuzumab, 3 lapatinib); 6 out of 8 RCTs were first-line. At the individual level, the Spearman rank correlation using Hougaard copula was equal to r=0.66 (95% CI 0.65 to 0.66) corresponding to an r2 of 0.42. At the trial level, the squared correlation between treatment effects on PFS and OS was provided by R2=0.33 (95% CI -0.22 to 0.86) using Hougaard copula and R2=0.53 (95% CI 0.22 to 0.83) using log hazard ratios from Cox models. Conclusions: In RCTs of HER2-targeted agents in HER2+ MBC, PFS is moderately correlated with OS and treatment effects on PFS are modestly correlated with treatment effects on OS, similarly to first-line chemotherapy in MBC (Burzykowski et al JCO 2008). PFS does not completely substitute for OS.

1040 Background: The randomized phase III TURANDOT trial compared first-line BEV plus paclitaxel (PAC) vs BEV plus capecitabine (CAP) in HER2-negative metastatic BC (mBC). BEV-based regimens are often favored in TNBC [Dawood 2012] because of efficacy in subgroup analyses and a lack of effective treatments. We performed an exploratory subgroup analysis of TURANDOT to provide more data on BEV-based therapy in TNBC. Methods: Patients (pts) with HER2-negative mBC who had received no prior chemotherapy for mBC were randomized to either BEV–PAC (BEV 10 mg/kg d1 and 15 + PAC 90 mg/m2 d1, 8, and 15 q4w) or BEV–CAP (BEV 15 mg/kg d1 + CAP 1000 mg/m2bid d1–14 q3w). The primary endpoint was overall survival (OS); secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and safety. Results: Of 561 pts treated, 130 had TNBC. Baseline characteristics were typical of a poor-prognosis population and generally balanced between treatment arms, although fewer pts receiving BEV–PAC than BEV–CAP had ECOG PS 1/2 (25% vs 40%, respectively), positive lymph nodes (56% vs 72%), metastatic disease at first diagnosis (19% vs 30%), and liver metastases (27% vs 43%). Median age was 54 vs 56 years, respectively. At data cut-off, median follow-up was 21.4 vs 19.2 mo for BEV–PAC and BEV–CAP, respectively. The safety profiles in the TNBC subgroup were similar to the overall population. The predominant grade ≥3 AEs were hematologic AEs and neuropathy with BEV–PAC and hand-foot syndrome and diarrhea with BEV–CAP. Conclusions: One-year OS rates up to 78% in TURANDOT are among the highest seen in TNBC. BEV-based therapy is a valid option in a setting with limited active treatments. BEV–PAC may be favored based on 1-year OS, PFS, and ORR. Clinical trial information: NCT00600340. [Table: see text]

11024 Background: The oral PARP inhibitor olaparib has shown antitumor activity as monotherapy in patients (pts) with breast and ovarian cancer with gBRCA1/2 mutations. This multicenter non-comparative study evaluated whether tumors in gBRCA1/2 mutation carriers are responsive to olaparib regardless of tumor type (NCT01078662). Methods: Heavily pretreated pts with advanced cancer refractory to standard therapy (98% of breast cancer pts had ≥3 lines of prior chemotherapy for metastatic disease) and with a gBRCA1/2 mutation, received olaparib 400 mg bid (capsule) until disease progression. Primary objective: tumor response by RECIST 1.1. Secondary objectives: PFS, OS and safety. Results: 298 pts received treatment and were evaluable. Enrollment is complete, 33 pts remain on study. Median duration of treatment in this heavily pretreated population was 5.5 months (range

The adjustment and psychological distress of 166 cancer patients, who are new immigrants from the former Soviet Union, was assessed and compared to that of 288 healthy new immigrants from the the former Soviet Union. The healthy new immigrants had many adjustment problems and their psychological distress was fairly high. The cancer patients reported extremely severe psychological distress. In the healthy immigrants, age contributed to distress while family support had significant protective effects especially in the male immigrants. In the patients, these differences were even more extreme with family support being protective in the male group but not in the female group. Intrusiveness (IES) seems to be maladaptive adding to distress. The results clearly indicate that additional stresses, such as immigration, make cancer patients more vulnerable. The results also suggest possible interventions, especially those that will help to decrease intrusiveness.

278 Background: Somatic inactivation of genes involved in homologous recombination (HR) may confer increased sensitivity to poly (ADP-ribose)- polymerase (PARP) inhibition and DNA cross-linking agents (eg. mitomycin C, platinum-based chemotherapy). Studies in BRCA associated ovarian cancer have demonstrated favorable outcomes with platinum based treatments. The role of BRCA mutations in pancreatic cancer outcome is understudied. In this study, the clinical features and therapeutic responses of BRCA 1/2 mutation carriers with pancreatic malignancies are reported. Methods: Patients with BRCA1/2 -associated pancreatic ductal adenocarcinoma (PDAC) diagnosed between January 1994-June 2012 were identified from clinical databases at three participating institutions. Demographic, clinical, and therapeutic response data were collected and analyzed using non-parametric models. Progression-free (PFS) and overall survival (OS) were analyzed. Results: Overall, 63 patients with PDAC and a BRCA1 (n=17), BRCA2 (n=43) or both (n=1) mutations were included. Mean age at diagnosis was 60.2 (range 33-83), 37 (58.7%) were male, 48 (76.2%) were Jewish, 26 (41.3%) were smokers, 55 (87.3%) had a family history of malignancy of which 18 (32.7%) had a history of PDAC. Twenty-five (39.7%) patients underwent a primary resection, and 30 (47.6%) had stage IV disease at presentation. PFS on platinum-based first-line chemotherapy in 12 metastatic BRCA positive cases (median: 90 days) was not statistically different than that of non-platinum chemotherapy treated carriers (n=18, median: 92 days) (p= 0.6412). Two patients with advanced disease were down-staged from unresectable to resectable using combination gemcitabine/cisplatin therapy. One of these is disease free at 50 months after surgery. Median OS for all 51 patients (excluding patients receiving experimental treatments) was 14.02 months (9.48-18.2). Conclusions: The natural history of BRCA associated PDAC appears similar to non-carriers. The role of platinum agents in these individuals remains unclear as data are not mature, however, to date, no difference in median PFS was observed. Surgical downstaging may be possible in a subset of these patients.

PURPOSE The aim of this study was to evaluate the ability of the immunomodulator AS101 to prevent chemotherapy-induced neutropenia and thrombocytopenia and thus allow patients to receive full-dose antineoplastic agents according to protocol design. We also aimed to determine the production level of various hematopoietic growth factors in treated patients. PATIENTS AND METHODS This study of 44 unresectable or metastatic non-small-cell lung cancer (NSCLC) patients was an open-label prospective randomized study of standard chemotherapy alone versus chemotherapy plus AS101. Each patient received carboplatin (300 mg/m2 intravenously [IV] on day 1 of a 28-day cycle, and etoposide (VP-16) (200 mg/m2 orally) on days 3, 5, and 7 of each cycle. AS101 was administered at 3 mg/m2 three times per week starting 2 weeks before chemotherapy. RESULTS AS101, which manifested no major toxicity, significantly reduced neutropenia and thrombocytopenia and thus allowed all treated patients to receive full-dose antineoplastic agents, in contrast to only 28.5% of the control group. Continuous treatment with AS101 significantly reduced the number of days per patient of thrombocytopenia and neutropenia and did not provide protection to tumor cells as reflected by the higher overall response rate compared with the chemotherapy-alone arm. Interestingly, AS101 treatment also significantly prevented chemotherapy-induced alopecia. These effects correlate with the ability of AS101-treated patients to increase significantly the production of colony-stimulating factors (CSFs) interleukin-1 alpha (IL-1 alpha) and IL-6. CONCLUSION AS101 has significant bone marrow (BM)-sparing effects and prevents hair loss in chemotherapy-treated patients, with minimal overall toxicity. These effects are probably due to increased production of IL-1 alpha, IL-6, and granulocyte-macrophage (GM)-CSF.