Citations

Abstract Increased de novo lipogenesis due to enhanced expression of several lipogenic enzymes has been found in many types of human cancers. Fatty acid synthase (FASN), the key enzyme in the de novo lipogenesis pathway, is one of the most commonly over-expressed lipogenic enzymes. Studies in the past decade have recognized FASN overexpression as a molecular marker for poor prognosis and malignant phenotype of many cancers. Tumor-associated FASN, by conferring growth and survival advantages rather than functioning as an anabolic energy-storage pathway, has also been suggested to play an active part in the development, maintenance, and metastatic progression of human cancers. More recently, FASN has been implicated in contributing to cellular resistance to several anticancer treatments. A variety of agents have been developed to target lipogenic enzymes and the key regulators involved in lipid metabolism in cancer cell for therapeutic purposes. The development of several FASN inhibitors has been reported from both academic labs and industries. When used in in vitro, xenograft and genetically induced mouse model studies, these inhibitors have supported FASN as an excellent target. A new generation of FASN inhibitors was developed at 3-V Biosciences that are highly specific, reversible inhibitors of FASN. One compound in this series, TVB-2640, is orally bioavailable and has progressed into Phase 1 clinical studies. The effect of two anti-FASN drugs in this series, TVB-3150 and TVB-3199 were tested for their effect on breast cancer cells. We demonstrated that the EC50 is between 9-50 nM, depending on the drug and the tested cell line. We then demonstrated that the drugs inhibited the anchorage-dependent and -independent growth of FASN expressing cells in a dose dependent manner. The apparent mechanism by which the FASN inhibitors promote inhibition of growth is by inducing apoptotic cell death in a time- and dose-dependent manner that involves regulation of apoptotic and pro-apoptotic proteins. Furthermore, the combination of the anti-FASN drugs with small molecule inhibitors of the antiapoptotic proteins Bcl-2 and Bcl-xL significantly increased the apoptotic effect in a synergistic manner compared to either of the synthetic inhibitors alone. In vivo studies demonstrate tumor growth inhibition without toxicity. Clinical development of a first-in-class, orally active, potent, and reversible FASN inhibitor as a novel cancer therapeutic is ongoing. Citation Format: Ruth Lupu, Anatilde Gonzalez Guerrico, Ashwani Khurana, Timothy Heuer, George Kemble, Chandra Mohan KVP. Small-molecule FASN inhibitors promote growth inhibition growth and apoptosis of breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2713. doi:10.1158/1538-7445.AM2014-2713

Abstract Background Cancer genomic investigations have identified recurrent genomic aberrations critical for cancer initiation, progression, and metastases. However, these investigations are typically performed in isolation, and the effects of treatment on the clonal selection of tumor cells are mostly unknown. We hypothesized that molecular profiling of residual tumors after neoadjuvant chemotherapy (NAC) would identify new drug targets/pathways in patients at high risk for disease recurrence. To better identify clonal populations of resistant breast cancer cells, we utilized DNA content-based flow sorting of nuclei to identify and isolate clonal populations for aCGH and next generation sequencing (NGS) both before and after NAC. Methods The Breast Cancer Genome Guided Therapy Study (BEAUTY) (NCT 02022202) is a prospective study of patients with high-risk breast cancer treated with neoadjuvant 12 weekly paclitaxel (T) +/- trastuzumab followed by 4 cycles of anthracycline based chemotherapy. Tumor tissue from baseline, residual disease from surgery, distant metastases, and patient derived xenografts (PDX) are obtained for cell sorting by DNA ploidy, aCGH, RNA and exome sequencing. Results: 140 patients have been enrolled, 104 have completed surgery and 30 unique PDX have been established corresponding to 26 patients prior to chemotherapy and 4 from residual disease at surgery. Baseline exome and RNA sequencing is complete in 140. Currently, genomic analyses of flow sorted matched baseline, surgical, PDX, and distant disease samples are available in 6 patients. Substantial genomic variation was observed in the surgical sample compared to the primary tumor including gain of oncogenic drivers (EGFR) and loss of negative regulators (ATG5) (Table). The PDX recapitulated these events with excellent fidelity compared to the corresponding human tumor. In patients with TNBC, RNA seq obained from matched samples demonstrated changes in immune related pathways. Evaluation of drug targets/pathways identified in the resistant tumors are ongoing using the PDX and sequencing of the remaining matched baseline/surgical disease will be reported. Clonal changes occurring over time in patients with residual disease or disease recurrence after NACTumor SubtypeResidual Cancer BurdenDisease StatusClonal Aberration Changes (baseline and post NAC)TNBC (AR subtype)3Contralateral lymph node recurrence at 150 days2p25.2 - p25.1 amplicon lost at recurrence; 6p21.32 -p21.31 amplicon lost at recurrenceTNBC (BL 1)3Bone/liver/lymph node recurrence at 135 days5q11.2 amplicon gained at surgery; 12p13.33 - p13.2 amplicon gained at surgeryTNBC (BL 1)3Disease-free at day 1506q21 amplicon lost at sugeryTNBC (BL 2)0Brain recurrence at 390 daysChr 2 chromothripsis at surgeryLuminal B3Progression during chemotherapy7p12.1 - p11.2 amplicon gained at surgeryLuminal HER23Disease-free at day 3609q33.2 amplicon lost at surgery; 15q13.1 - q13.3 amplicon lost at surgery; 15q22.2 - q24.1 amplicon lost at surgery Conclusions: We observed substantial evolutionary changes in residual breast tumors remaining after NAC. Our findings suggest that a comprehensive assessment of the mutational landscape that has evolved during NAC can inform drug development in high risk breast cancer patients. Citation Format: Matthew P Goetz, Michael T Barrett, Krishna R Kalari, Vera J Suman, Sarah A McLaughlin, Alvaro Moreno-Aspitia, Ann M Moyer, Donald W Northfelt, Richard J Gray, Jason Sinnwell, Douglas Mahoney, Poulami Barman, Peter Vedell, Xiaojia Tang, Kevin Thompson, Travis Dockter, Katie Jones, Sara J Felten, Amy Conners, Jeanette Eckel-Passow, Hughes Sicotte, Steven N Hart, Jia Yu, Daniel W Visscher, Eric D Wieben, Cloann Schultz, Minetta C Liu, James N Ingle, Liewei Wang, Richard W Weinshilboum, Judy C Boughey. Impact of neoadjuvant chemotherapy on the clonal composition of breast cancer [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 PD3-3.

Abstract Background: Guidelines recommend germline mutation testing of breast cancer predisposition genes in triple negative (TN) breast cancer cases with a family history of breast or ovarian cancer or when diagnosed under age 60. However, the prevalence of mutations in these genes among TN cases unselected for family history of breast or ovarian cancer is not known. Methods: To assess the frequency of mutations in 16 predisposition genes in TN cases we screened a large cohort of TN patients (n=1824) unselected for family history of breast or ovarian cancer from 12 centers and 824 study matched unaffected controls for mutations using a panel-based sequencing approach. Results: Deleterious mutations were identified in 15% of TN patients: 8.5% had BRCA1, 2.7% had BRCA2, and 3.6% had mutations in 12 other genes. Mutations in non-BRCA1/2 genes encoding proteins implicated in homologous recombination repair of DNA double strand breaks were detected at the same frequency as in breast cancer families. TN cases with mutations had high-grade tumors and were diagnosed at an earlier age than non-mutated cases. However, 10% of TN cases diagnosed at ≥60 years and 5% with no family history of cancer were also found to carry mutations. Inactivating mutations in non-BRCA1/2 predisposition genes were associated with moderate to high risks of TN breast cancer. Conclusions: National Comprehensive Cancer Network (NCCN) guidelines support clinical genetic testing of breast cancer predisposition genes in 95% of TN breast cancer patients carrying mutations in susceptibility genes. In contrast, National Institute of Health and Care Excellence (NICE) guidelines in the U.K. do not support genetic testing of a substantial proportion of TN patients with predisposing alleles. Frequency tables for inherited mutations in known predisposition genes based on age of diagnosis and family history of cancer will allow for selection of TN patients most likely to carry mutations in the predisposition genes. Citation Format: Fergus J Couch, Steven N Hart, Priyanka Sharma, Amanda Ewart Toland, Penelope Miron, Janet E Olson, Andrew Godwin, Vernon S Pankratz, Curtis Olswold, Seth Slettedahl, Lucia Guidugli, Matthias W Beckmann, Brigitte Rack, Arif B Ekici, Irene Konstantopoulou, Florentia Fostira, George Fountzilas, Liisa M Pelttari, Song Yao, Judy Garber, Angela Cox, Hiltrud Brauch, Christine Ambrosone, Heli Nevanlinna, Drakoulis Yannoukakos, Susan L Slager, Celine M Vachon, Diana M Eccles, Peter A Fasching. Triple-negative breast cancer: Frequency of inherited mutations in breast cancer susceptibility genes [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 P4-12-03.

Abstract Background: Further stratification of the 70-gene MammaPrintTM signature into ‘high’ and ‘ultra-high’ risk groups may help predict chemo-sensitivity. In I-SPY 2, patients were classified as MammaPrint High1 (MP1) or MammaPrint (ultra) High2 (MP2), with MP2 defined as MP_score <-0.154. MP1/MP2 classification was added to HR and HER2 to define the cancer subtypes used in the I-SPY 2 adaptive randomization engine. Neratinib (N), one of the experimental agents evaluated in I-SPY 2, graduated in the HR-HER2+ signature. All patients received at least standard chemotherapy (paclitaxel followed by doxorubicin/cyclophosphamide; T->AC). HER2- patients were randomized to receive N+T- >AC vs. T->AC. For HER2+ patients, neratinib was administered in place of trastuzumab (N+T->AC vs. H+T->AC). Here, we assess the performance of MP1/MP2 class as a specific biomarker of neratinib response. Methods: 115 patients in the neratinib arm and 76 concurrently randomized controls had Agilent 44K microarrays and pCR data available for analysis. We assess association between MP1/MP2 and response in the neratinib and control arms alone using Fisher’s exact test, and relative performance between arms (biomarker x treatment interaction, likelihood ratio p < 0.05) using a logistic model. This analysis is also performed adjusting for HR status as a covariate, and in receptor subsets. Our study is exploratory with no claims for generalizability of the data. Statistical calculations are descriptive (e.g. p-values are measures of distance with no inferential content). Our analyses do not adjust for multiplicities of other biomarkers in the trial but outside this study. Results: There are 133 MP1 patients (neratinib: 74, Control: 59) and 58 MP2 patients (neratinib: 41, Control: 17), 84% (49) of which are Her2-. The distribution of pCR rates among MP1/MP2 dichotomized groups are summarized in Table 1. Neratinib (n=115)Control (n=76)MP1 (n=74)MP2 (n=41)MP1 (n=59)MP2 (n=17)HER2- (n=105)0 / 1715 / 337 / 395 / 16HER2+ (n=86)22 / 574 / 85 / 200 / 1 MP2, one of the 10 eligible signatures, did not meet the graduation threshold; and MP1/MP2 did not show a significant biomarker x treatment interaction (OR in neratinib relative to control arm = 1.25). The MP1/MP2 x treatment interaction remains non-significant after adjustment for HR and HER2 status (p=0.54). In HER2- patients receiving neratinib, 45% (15/33) of MP2 patients achieved a pCR, compared to 0% (0/17) of MP1 patients. In the HER2- controls, there is a 31% pCR rate in MP2 (5/16) vs. 18% in MP1 (7/39) patients (OR=2.14). This difference in performance between treatment arms appears significant (p=0.041). 90% of HER2+ patients are MP1, thus MP1/MP2 status x treatment interaction within the HER2+ subtype cannot be evaluated. Conclusion: Within the I-SPY 2 population as a whole, MP1/MP2 stratification does not appear to be a specific biomarker of response to neratinib relative to the control arm. The number of HER2- patients is small and precludes any definitive conclusion, but these data motivate further investigation of the biological mechanisms distinguishing MP1 from MP2 to better understand chemotherapy and/or neratanib responsiveness. Citation Format: Christina Yau, Denise M Wolf, Ashish Sanil, Jo Chien, Anne Wallace, Judy Boughey, Doug Yee, Debu Tripathy, Angela DeMichele, Rita Nanda, Steven Chiu, Claudine Isaacs, Kathy Albain, Hank Kaplan, Stacey Moulder, Rebecca Viscusi, Donald Northfelt, Kirsten Edmiston, Anthony Elias, Toncred Styblo, Barbara Haley, Lamorna Brown-Swigart, Susan Flynn, Gillian L Hirst, Meredith Buxton, Nola Hylton, Melissa Paoloni, W Fraser Symmans, Laura Esserman, Don Berry, Minetta C Liu, John W Park, Laura van 't Veer. MammaPrint High1/High2 risk class as a biomarker of response to neratinib plus standard neoadjuvant therapy for breast cancer in the I-SPY 2 TRIAL [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 P3-06-29.

Abstract Background: We hypothesize that response to the pan-ERBB inhibitor, neratinib (N), may be predicted by pre-treatment HER2-EGFR signaling. In the I-SPY 2 TRIAL, N graduated in the HR-/HER2+ signature. All patients received at least standard chemotherapy. For HER2+ patients, N was administered in place of trastuzumab. We evaluated 18 HER family signaling proteins as biomarkers of N response using reverse phase protein microarray (RPMA) data from pre-treatment LCM purified tumor epithelium. Methods: 168 patients (N: 106, concurrent controls: 62) had RPMA and pCR data. 18 biomarkers relating to HER family signaling were evaluated: AKT S473, AKT T308, EGFR, EGFR Y1068, EGFR Y1148, EGFR Y1173, EGFR Y992, ERBB2, ERBB2 Y1248, ERBB3 total, ERBB3 Y1289, ERK1/2 T202/Y204, Heregulin, mTOR, mTOR S2448, PI3K p85 Y458/p55 Y199, PTEN S380, and SHC Y317. We assessed association between biomarker and response in the N and control arms alone (likelihood ratio test), and relative performance between arms (biomarker x treatment interaction) using a logistic model. Analysis was also performed adjusting for HR/HER2 status. In an exploratory analysis, we selected the marker with the greatest interaction (phosphorylated EGFR (Y1173)) to dichotomize patients optimally based on the data and assessed it in the context of the graduating signature by adding the EGFR Y1173-High patients to the HR-/HER2+ subtype and evaluating the treatment effect in this ‘biomarker-positive’ group. Our study is exploratory with no claims for generalizability of the data and does not account for multiplicities. Statistical calculations are descriptive (e.g. p-values are measures of distance with no inferential content). Results: 7 HER pathway markers (EGFR Y1068, EGFR Y1173, EGFR Y992, ERBB2 total, ERBB2 Y1248, ERBB3 Y1289, SHC Y317) are associated with response in the N but not the control arm. However, the difference in performance between arms did not reach significance by permutation testing. Adjusting for HR/HER2 status, EGFR Y1173 shows a significant biomarker x treatment interaction (p = 0.049). In an exploratory analysis, we dichotomized patients by their EGFR Y1173 levels and evaluated the distribution of pCR rates (Table 1). Neratinib (n=106)Control (n=62)EGFR Y1173 Low (n=31)EGFR Y1173 High (n=75)EGFR Y1173 Low (n=29)EGFR Y1173 High (n=33)HR-/HER2+ (n=28)0 / 412 / 181 / 11 / 5Not HR-/HER2+ (n=140)3 / 2724 / 575 / 285 / 28Table 1 OR between EGFR Y1173 groups in the N relative to control arm is 10.1. When EGFR Y1173 High patients are added to the graduating HR-/HER2+ subset, the OR associated with treatment is 3.2 and is comparable to that in the HR-/HER2+ signature (OR: 2.1), while increasing the prevalence of biomarker-positive patients by ∼50%. Evaluation of EGFR Y1173 under the I-SPY 2 Bayesian model is pending. Conclusion: Our sample size is too small to draw definitive conclusions. Our exploratory analysis reveals that HER family phosphoproteins associate with response to N, but only phosphorylated EGFR Y1173 appears to add value to the graduating signature. Given that this biomarker would expand the patient population that may benefit, it merits evaluation in other ongoing trials of neratinib. Citation Format: Julia D Wulfkuhle, Christina Yau, Denise M Wolf, Rosa I Gallagher, Ashish Sanil, Lamorna Brown-Swigart, Susan Flynn, Gillian Hirst, I-SPY 2 TRIAL Investigators, Meredith Buxton, Angela DeMichele, Nola Hylton, William F Symmans, Laura van't Veer, Douglas Yee, Melissa Paoloni, Laura Esserman, Donald Berry, Minetta C Liu, John W Park, Emanuel F Petricoin III. Evaluation of HER family protein signaling network as a predictive biomarker for pCR for breast cancer patients treated with neratinib in the I-SPY 2 trial [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 P3-06-15.

Abstract Background: Overexpression of COX-2 has been associated with worse outcome in NSCLC. In C30203, we found that administration of the selective COX-2 inhibitor celecoxib in addition to chemotherapy in advanced NSCLC improved outcome (progression free and overall survival, PFS, OS) in pts with moderate to high COX-2 expression by immunohistochemistry (IHC). C30801 was designed to prospectively confirm that finding. Patients and Methods: Pts with NSCLC (stage IIIb with pleural effusion, IV 6th ed) were pre-registered and biopsy specimens analyzed for COX-2 by IHC. Pts with COX-2 expression > or = 2, PS 0-2 and normal organ function were eligible. Chemotherapy was determined by histology: carboplatin (AUC = 6), pemetrexed (500 mg/m2) d 1, q21 days for pts with non-squamous NSCLC; carboplatin(AUC=5.5) d1, gemcitabine (1000 mg/m2) d 1,8 for pts with squamous histology. Randomization was to celecoxib (400 mg bid) (Arm A) or placebo (Arm B). The primary endpoint was to demonstrate improvement in PFS in patients with COX-2 index >=4 with hazard ratio of 0.645. Results: The study was halted by the DSMB for futility after 312 of the planned 322 pts were randomized. The current analysis is based upon the first 300 pts. There were no significant differences between the groups (Table). There was a possible harmful effect for COX-2 inhibition in the COX-2 2-3 subset (OS HR = 1.75, p =.0977). Toxicity was similar for both arms. Subset analyses evaluating histology, chemotherapy regimen, incremental COX-2 expression did not demonstrate any advantage for COX-2 inhibition. Conclusions: 1. COX-2 expression by IHC failed to select pts who could benefit from selective COX-2 inhibition. 2. COX-2 inhibition did not significantly increase toxicity associated with chemotherapy or increase cardiovascular morbidity. 3. We will evaluate other possible determinants of toxicity and response to COX-2 inhibition. OutcomeArm AArm BCOX-2 2-3 (n=37)COX-2 > or = 4 (n=111)COX-2 2-3 (n=46)COX-2 > or = 4 (n=106)PFS (months)4.404.934.606.11OS (months)9.0310.5814.8512.68 Citation Format: Martin J. Edelman, Xiaofei Wang, Lydia Hodgson, Richard T. Cheney, Maria Baggstrom, Thomas Sachdev, Ajeet Gajra, Erin Bertino, Karen Reckamp, Julian Molina, Joan Schiller, Kisha Mitchell-Richards, Paula Friedman, Jon Ritter, Everett Vokes, Alliance for Clinical Trials in Oncology. Phase III randomized, placebo controlled trial of COX-2 inhibition in addition to standard chemotherapy for advanced non-small cell lung cancer (NSCLC):CALGB 30801 (Alliance). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT238. doi:10.1158/1538-7445.AM2014-CT238

Abstract Background: I-SPY 2 is a multicenter, phase II neoadjuvant trial in women with high-risk stage II/III breast cancer using adaptive randomization within biomarker subtypes to evaluate novel agents added to standard chemotherapy. Primary endpoint is pathologic complete response (pCR). Goal is to identify regimens that meet a high Bayesian predictive probability of statistical significance in a neoadjuvant 300-patient phase III trial defined by hormone-receptor (HR), HER2 status, and MammaPrint (MP). Experimental regimens may “graduate” in 1 of 10 signatures, with a maximum of 120 patients. We report efficacy results for neratinib (N). Methods: Tumors ≥2.5cm by clinical exam & ≥2cm by imaging are eligible for screening. MP low risk/HR+/HER2- tumors are ineligible for randomization. Patients receive chemotherapy (paclitaxel qwk x 12, doxorubicin and cyclophosphamide q2-3 wk x 4, T->AC). HER2- pts were randomized to N+T->AC vs. T->AC and HER2+ pts to N+T->AC vs. trastuzumab+T->AC. Analysis is intent-to-treat with pts who switch to non-protocol therapy regarded as non-pCRs. We provide estimated pCR rates (95% Bayesian probability intervals), probabilities of superiority of neratinib over control, and Bayesian predictive probabilities of success in an equally randomized phase III trial. Results: Neratinib met the predictive probability criterion in HR-/HER2+, “graduated”, and accrual ceased [115 N patients (65 HER2+), 78 concurrently randomized controls (22 HER2+)]. The table shows results for all 10 signatures. Two patients (1 N and 1 control) withdrew consent and are not included. Conclusion: I-SPY 2's standing trial mechanism efficiently evaluates agents in biomarker-defined patient subsets. In a modest number of patients, adaptive randomization successfully identified a biomarker signature (HR-/HER2+) for neratinib's further development. All HER2+ and MP+ tumors may also benefit from this regimen, consistent with preclinical data. Evaluation in I-SPY 3, a phase III registration trial, is planned. SignatureEstimated pCR Rate (95% probability interval)Probability NeratinibIs Superior to ControlPredictive Probability of Success in Phase IIINeratinibControlALL32% (28-36%)23% (19%-28%)92%44%HR+23% (18%-28%)17% (11%-22%)81%40%HR-43% (37%-49%)31% (24%-38%)89%53%HER2+39% (33%-45%)23% (15%-30%)95%73%HER2-26% (21%-32%)24% (18%-29%)63%20%MP+*45% (38%-53%)29% (20%-39%)91%66%HR-/HER2-36% (29%-43%)30% (23%-38%)72%34%HR-/HER2+55% (46%-64%)32% (22%-43%)94%78%HR+/HER2+31% (24%-37%)17% (10%-24%)91%65%HR+/HER2-14% (8%-19%)16% (10%-21%)39%12%* MammaPrint 44K Array Low/High score was adjusted to MammaPrint High1 (MP-) or High2 (MP+), using a pre-defined median cut-point of I-SPY 1 participants, who fit the eligibility criteria of I-SPY 2. Citation Format: John W. Park, Minetta C. Liu, Douglas Yee, Angela DeMichele, Laura van 't Veer, Nola Hylton, Fraser Symmans, Meredith B. Buxton, A. Jo Chien, Amy Wallace, Michelle Melisko, Richard Schwab, Judy Boughey, Debashish Tripathy, Hank Kaplan, Rita Nanda, Stephen Chui, Kathy S. Albain, Stacy Moulder, Anthony Elias, Julie E. Lang, Kirsten Edminston, Donald Northfelt, David Euhus, Qamar Khan, Julia Lyandres, Sarah E. Davis, Christina Yau, Ashish Sanil, Laura J. Esserman, Donald A. Berry. Neratinib plus standard neoadjuvant therapy for high-risk breast cancer: Efficacy results from the I-SPY 2 TRIAL. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT227. doi:10.1158/1538-7445.AM2014-CT227

Abstract Purpose: The purpose of this study was to evaluate oncologists' preferences for methods to increase delivery of tobacco cessation support to cancer patients. Methods: An email list of 6844 physicians at NCI Designated Cancer Centers was generated using publically available online resources. An online survey was conducted in the fall of 2013 to assess tobacco assessment and cessation practices by physicians, barriers to providing cessation support, and methods to improve access to cessation services for cancer patients. Results of this survey are compared to similar survey findings by the American Society of Clinical Oncology (ASCO) and the International Association for the Study of Lung Cancer (IASLC). Results: Of 6844 electronically delivered survey invitations, we received 887 responses (13%). Consistent with previously published ASCO and IASLC surveys, 90% of physicians agreed that tobacco use by patients affects cancer treatment outcomes (vs. 87-92% in ASCO/IASLC), 90% of respondents reported that they ask patients about their tobacco use (vs. 90% in ASCO/IASLC), and 83% routinely advise tobacco users to quit (vs. 80-82% in ASCO/IASLC). However, only 37% of respondents regularly discussed medications, and 35% actively treated patients (vs. 39-44% in ASCO/IASLC). Most (71%) responding oncologists preferred cessation support be provided at the initial patient consult, and few (11%) were concerned about the use of tobacco cessation medications. Lack of time and lack of available resources were the dominant barriers to the administration of tobacco cessation support to cancer patients by oncologists. Only 10% of oncologists believed they were adequately trained to counsel patients on smoking cessation, but 55% reported that training for someone else in their clinic would increase tobacco cessation support. When asked what provider they prefer to administer cessation support to cancer patients, 16% reported a primary care physician, 18% reported a mid-level (nurse practitioner or physician assistant), 50% reported any other clinical staff, and only 1% preferred to personally provide cessation support. Whereas most (58%) oncologists preferred to have dedicated cessation services within their institution, 38% reported they would use dedicated services either within, or outside their institution. Conclusions: Most oncologists at NCI Designated Cancer Centers recognize the importance of tobacco cessation, but prefer to have tobacco cessation support for cancer patients provided by another trained professional. Citation Format: Alix Pommerenke, Anthony Alberg, Thomas H. Brandon, Ivana Croghan, Michael K. Cummings, Carolyn Dresler, Ellen R. Gritz, Roy Herbst, Scott Leischow, James R. Marshall, Benjamin Toll, Graham Warren. Physician preferences in tobacco cessation support for cancer patients: A survey of physicians at National Cancer Institute Designated Cancer Centers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5049. doi:10.1158/1538-7445.AM2014-5049

Abstract Recent studies have shown that associations between common genetic variation and gene expression in breast tumors provide insight into the functional mechanisms underlying breast cancer risk loci. However, the relationship between genetic variation, gene expression, and risk of triple negative (TN) breast cancer remains largely unexplored. We performed a genome-wide expression quantitative trait locus (eQTL) analysis of TN breast cancer using 668 formalin-fixed paraffin embedded TN tumors from the Triple Negative Breast Cancer Consortium (TNBCC) to identify novel genes relevant to TN breast cancer risk and to further explore the biology underlying known TN risk loci. Cis-eQTLs were defined as correlations between single nucleotide polymorphisms (SNP) and expression of genes within 1Mb, and trans-eQTLs were defined as the remainder of all SNP-gene correlations. In a genome-wide analysis, we identified 68,012 cis-eQTLs, representing correlations between 42,193 SNPs and 2,092 genes that were significant at a 10% false discovery rate (FDR). We also identified 70 trans-eQTLs across two unique genes at the same FDR threshold. Five cis-eQTLs involved SNPs previously associated with TN breast cancer risk (p<5.0x10-5) in 3,700 TN cases and 4,700 controls from the TNBCC. Three of these, located on chromosomes 5p (cis-eQTL p=4.8x10-34; risk p=1.1x10-7), 7p (cis-eQTL p=6.1x10-10; risk p=1.3x10-7), and 17q (cis-eQTL p=1.8x10-15; risk p=2.9x10-7), have previously been reported in public databases of normal tissue. The remaining two TN breast cancer cis-eQTLs, located on chromosomes 8q (cis-eQTL p=6.3x10-6, risk p=8.3x10-6) and 14q (cis-eQTL p=3.1x10-6, risk p=1.2x10-5), have not been reported as eQTLs in other tissues. In addition, 12 of 25 known TN breast cancer risk loci (PEX14, MDM4, 2q31.1, ESR1, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, 19p13.1, MLK1), contained at least one significant cis-eQTL. In summary, we have identified five cis-eQTLs that may identify novel risk loci for TN breast cancer. Citation Format: Kristen S. Purrington, Drakoulis Yannoukakos, Jane Carpenter, Heli Nevanlinna, Angela Cox, Gianluca Severi, Christine Ambrosone, Amanda Ewart Toland, Andrew K. Godwin, Hiltrud Brauch, Peter A. Fasching, Penelope Miron, Jenny Chang-Claude, Nicholas G. Martin, Grant W. Montgomery, Vessela Kristensen, Hoda Anton-Culver, Paul Goodfellow, Janet E. Olson, Hugues Sicotte, Naresh Prodduturi, Daniel W. Visscher, Jeanette E. Eckel-Passow, S. Keith Anderson, Seth Slettedahl, Curtis Olswold, Xianshu Wang, V. Shane Pankratz, Susan Slager, Wei Zheng, Arto Mannermaa, Ute Hamann, Diana M. Eccles, Celine M. Vachon, Fergus J. Couch. Expression quantitative trait locus analysis of triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3266. doi:10.1158/1538-7445.AM2014-3266

Abstract Background: Nulliparity is an established endometrial cancer risk factor, but whether this association is related to infertility is unclear. Although there are many underlying causes of infertility, few studies have assessed risk relationships according to specific causes. Despite concerns that most treatments induce ovulation and that the endometrium is highly hormonally-responsive, previous studies have provided conflicting results on treatment associations. Methods: To address these issues, we conducted a pooled analysis of 8,151 cases and12,471 controls from 2 cohort and 12 case-control studies conducted in 1982 to 2009 (N. America, Europe, Australia, Asia). All studies provided self-reported infertility, causes and treatments, except for 1 study that relied on data from national registries. Study-specific exposures and covariate data were harmonized across studies. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusted for study, age, interview year, race, parity, oral contraceptive and menopausal hormone use, and body mass index. If data were not reported for a particular variable, that study was excluded from the variable-specific analysis. Results: Nulliparous women had an elevated endometrial cancer risk compared with parous women (adjusted OR=1.73; 95% CI: 1.58-1.90).Women with self-reported infertility also had an increased risk (adjusted OR=1.22; 95% CI: 1.13-1.32) compared with those without infertility issues, even after adjusting for parity; the strongest associations was seen among studies that defined infertility as unsuccessfully trying to conceive for 2+ years (adjusted OR=1.31; 95% CI: 1.07-1.60). Infertility was associated with similar risks among nulliparous (1.22; 1.10-1.48) and parous (1.22; 1.12-1.34) women, although there was no increased risk associated with infertility among those who had given birth to 3+ children. Two infertility causes associated with risk elevation were endometriosis (adjusted OR=2.08; 95% CI: 1.46-2.95 compared with women no infertility problems) and anovulation (adjusted OR=1.40; 95% CI: 1.16-1.70). Based on relatively small numbers, none of the individual treatments (in vitro fertilization, selective estrogen response modulators, gonatropins, progestins, estrogens) were substantially related to risk. Conclusion: Based on mainly self-reported infertility data, we found that parity and infertility independently contribute to endometrial cancer risk, with parity seemingly being the predominant risk predictor. Understanding residual endometrial cancer relationships related to causes of infertility and infertility treatment may benefit from documented medical information on causes of infertility and treatment parameters. Citation Format: Hannah P. Yang, Linda S. Cook, Elisabete Weiderpass, Hans-Olov Adami, Kristin E. Anderson, Hui Cai, James R. Cerhan, Tess Clendenen, Ashley S. Felix, Christine Friedenreich, Montserrat Garcia-Closas, Marc T. Goodman, Xiaolin Liang, Jolanta Lissowska, Lingeng Lu, Anthony M. Magliocco, Susan E. McCann, Kristen B. Moysich, Sara H. Olson, Malcolm C. Pike, Silvia Polidoro, Fulvio Ricceri, Harvey Risch, Carlotta Sacerdote, V. Wendy Setiawan, Xiao Ou Shu, Amanda B. Spurdle, Britton Trabert, Penelope M. Webb, Nicolas Wentzensen, Yong-Bing Xiang, Youming Xu, Herbert Yu, Anne Zeleniuch-Jacquotte, Louise A. Brinton. Infertility and risk of incident endometrial carcinoma: a pooled analysis from the Epidemiology of Endometrial Cancer Consortium. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2167. doi:10.1158/1538-7445.AM2014-2167