Citations

Abstract Background: Despite the well-established survival benefit associated with adjuvant hormonal treatment, younger women with hormone receptor positive (HR+) breast cancer (BC) are less adherent to endocrine therapy (ET) as prescribed, compared to their older counterparts, and may have unique issues that contribute to ET non-adherence. In an effort to identify factors that can be targeted to improve ET uptake and adherence, we sought to evaluate ET initiation in young women with BC. Methods: As part of a multi-center, prospective cohort enrolling women with newly diagnosed BC at age ≤40 years between 2006-2016, we identified 657 women with HR+, Stage 0-III BC. Participants complete serial surveys that included questions about socio-demographics, fertility concerns, and treatment. Women who did not report taking tamoxifen or an aromatase inhibitor (AI) at least once in the 18 months after diagnosis (dx) were classified as non-initiators. Variables significant at p<0.20 in univariable models were entered into a multivariable logistic regression model to identify independent (p<0.05) predictors of non-initiation. Results: By 18 months post-dx, 15% (99/657) had not initiated ET; among women with Stage 0 BC, 77% (51/66) had not initiated vs 8% (48/591) with invasive BC (p<0.0001). Among initiators (N=558), 93% were on tamoxifen, with 7% reporting AI alone or in addition to tamoxifen; 97% started ET within 12 months of dx. Among women with invasive BC (Table), non-initiation was associated with having less than a college degree (OR: 2.49 95% CI: 1.25-4.94), non-Caucasian race (OR: 2.58 95% CI: 1.18-5.64) and non-receipt of radiation (OR: 0.40 95% CI: 0.21-0.75).Age at dx, marital status, having children, employment, perceived financial comfort, fertility concern, stage, surgery, and chemotherapy were not significantly associated with non-initiation. Conclusion: Most young women with HR+ DCIS do not take adjuvant ET despite the potential benefits (substantially reduced risk of local recurrence and contralateral BC) and very low risk of serious toxicity. Among young women with invasive HR+ BC, a significant minority fails to start ET within 18 months of dx. Adjuvant ET non-initiation may contribute in part to the racial and SES outcomes disparities that have been observed. Further study is needed to elucidate barriers to initiation with the goal of developing targeted interventions that will enhance ET initiation and adherence in general. Table. Predictors of ET non-initiation in women with invasive BC (N=577*) Univariable Multivariable Median (range)OR (95% CI)pOR (95% CI)ppAge at dx (years)36 (17-40)1.08 (0.99-1.18)0.07 N (%) Financial comfort300 (51)0.88 (0.49-1.60)0.68 Non-white59 (10)2.68 (1.25-5.71)0.012.58 (1.18-5.64)0.02Full employment282 (48)0.76 (0.42-1.39)0.38 Less than college graduate95 (16)2.61 (1.36-5.02)0.0042.49 (1.25-4.94)0.009Married/living as married452 (77)0.79 (0.41-1.55)0.50 Children pre-diagnosis369 (62)1.11 (0.60-2.05)0.75 Fertility concern234 (40)0.92 (0.50-1.70)0.80 Stage (ref=3) 1244 (41)1.22 (0.47-3.15)0.68 2259 (44)1.27 (0.50-3.24)0.62 Mastectomy vs lumpectomy335 (57)1.16 (0.64-2.12)0.63 Radiation therapy331 (56)0.40 (0.21-0.73)0.0030.40 (0.21-0.75)0.004Chemotherapy411 (70)0.66 (0.36-1.22)0.18 *multivariable analytic cohort Citation Format: Rosenberg SM, Gelber S, Ruddy KJ, Tamimi RM, Schapira L, Borges VF, Come S, Meyer ME, Partridge AH. Drugs don't work if people don't take them: Non-initiation of endocrine therapy in young women [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-07.

Microdeletions involving chromosome 2p15-16.1 are a rare genetic abnormality and have been reported in 18 separate patients, mainly children, since 2007. This microdeletion syndrome is characterised by a heterogeneous expression of intellectual impairment, dysmorphic facies, musculoskeletal abnormalities and potential neurodevelopmental anomalies. We report the first case of natural progression in an adult patient who died at a young age of metastatic esophageal adenocarcinoma. Important learning points include the variable phenotypic expression of this microdeletion syndrome and the fact that clinicians must be thorough in investigating objective discrepancies in patients who cannot endorse classical symptoms.

Dietary zinc increases susceptibility to Clostridium difficile infection following antibiotic use in mice.

Purpose The purpose of this research note is to identify and prioritize diseases important for detection in adult hearing health care delivery systems. Method Through literature review and expert consultation, the authors identified 195 diseases likely to occur in adults complaining of hearing loss. Five neurotologists rated the importance of disease on 3 dimensions related to the necessity of detection prior to adult hearing aid fitting. Results Ratings of adverse health consequences, diagnostic difficulty, and presence of nonotologic symptoms associated with these diseases resulted in the identification of 104 diseases potentially important for detection prior to adult hearing aid fitting. Conclusions Current and evolving health care delivery systems, including direct-to-consumer sales, involve inconsistent means of disease detection vigilance prior to device fitting. The first steps in determining the safety of these different delivery methods are to identify and prioritize which diseases present the greatest risk for poor health outcomes and, thus, should be detected in hearing health care delivery systems. Here the authors have developed a novel multidimensional rating system to rank disease importance. The rankings can be used to evaluate the effectiveness of alternative detection methods and to inform public health policy. The authors are currently using this information to validate a consumer questionnaire designed to accurately identify when pre- fitting medical evaluations should be required for hearing aid patients.

Abstract Previous preclinical studies and a phase I clinical trial suggested that myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia. Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once a day for 2 weeks, and then twice a day for 6 months. The primary endpoint was change in dysplasia rate after 6 months of intervention on a per-participant basis. Other trial endpoints reported herein include Ki-67 labeling index, blood and bronchoalveolar lavage fluid (BAL) levels of proinflammatory, oxidant/antioxidant biomarkers, and an airway epithelial gene expression signature for PI3K activity. Seventy-four (n = 38 myo-inositol and n = 36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (P = 0.76). Compared with placebo, myo-inositol intervention significantly reduced IL6 levels in BAL over 6 months (P = 0.03). Among those with a complete response in the myo-inositol arm, there was a significant decrease in a gene expression signature reflective of PI3K activation within the cytologically normal bronchial airway epithelium (P = 0.002). The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent. Cancer Prev Res; 9(12); 906–14. ©2016 AACR.

Purpose To provide guidance to clinicians regarding the use of neoadjuvant chemotherapy and interval cytoreduction among women with stage IIIC or IV epithelial ovarian cancer. Methods The Society of Gynecologic Oncology and the American Society of Clinical Oncology convened an Expert Panel and conducted a systematic review of the literature. Results Four phase III clinical trials form the primary evidence base for the recommendations. The published studies suggest that for selected women with stage IIIC or IV epithelial ovarian cancer, neoadjuvant chemotherapy and interval cytoreduction are noninferior to primary cytoreduction and adjuvant chemotherapy with respect to overall and progression-free survival and are associated with less perioperative morbidity and mortality. Recommendations All women with suspected stage IIIC or IV invasive epithelial ovarian cancer should be evaluated by a gynecologic oncologist prior to initiation of therapy. The primary clinical evaluation should include a CT of the abdomen and pelvis, and chest imaging (CT preferred). Women with a high perioperative risk profile or a low likelihood of achieving cytoreduction to < 1 cm of residual disease (ideally to no visible disease) should receive neoadjuvant chemotherapy. Women who are fit for primary cytoreductive surgery, and with potentially resectable disease, may receive either neoadjuvant chemotherapy or primary cytoreductive surgery. However, primary cytoreductive surgery is preferred if there is a high likelihood of achieving cytoreduction to < 1 cm (ideally to no visible disease) with acceptable morbidity. Before neoadjuvant chemotherapy is delivered, all patients should have confirmation of an invasive ovarian, fallopian tube, or peritoneal cancer. Additional information is available at www.asco.org/NACT-ovarian-guideline and www.asco.org/guidelineswiki .

Abstract Background: Pathologic complete response (pCR) is an established prognostic biomarker for aggressive HER2+ breast cancer (BC). Improving pCR rates may identify new therapies that improve survival. Pertuzumab (P) has established survival benefit in the metastatic setting, and received accelerated approval in the neoadjuvant setting when combined with trastuzumab (H) and docetaxel(D) as part of a complete treatment regimen for early breast cancer. We tested its ability, when combined with standard therapy (paclitaxel, T, and H) to improve pCR (ypT0ypN0) over TH in the adaptively randomized, phase II, I-SPY 2 neoadjuvant trial. Methods: Enrolled patients (pts) had invasive BC ?2.5 cm in HER2-positive subsets. Pts were adaptively randomized to control (TH, qwk x 12) or THP (P, q3wk x 4) followed by doxorubicin/cyclophosphamide (AC) x 4 and surgery. To compare THP to TH we utilized all control pts accrued over the course of the trial, adjusting for potential differences due to time period treated, which were informed by the several other treatment arms that have been in the trial. Adaptive assignment to the experimental arms was based on current Bayesian probabilities of superiority over control. “Graduation” by signature and futility stopping were based upon Bayesian predictive probability of success in a 2-arm, N = 300 phase III randomized 1:1 trial of THP vs. TH with pCR endpoint. Results: THP met the predictive probability criterion and graduated in 3 signatures: all HER2+, HER2+/HR+, and HER2+/HR- (See Table 1). Final accrual: 44 THP and 31 TH. Safety data will be shown. Conclusions: I-SPY 2's standing platform trial efficiently evaluates agents in biomarker-defined pt subsets. THP -&gt; AC substantially improves pCR rates over standard TH -&gt; AC in all 3 HER2+ signatures, including HR+ and HR- subsets. APHINITY, a trial of adjuvant pertuzumab with a primary outcome of invasive disease-free survival, is ongoing. Table 1Signature*Estimated pCR Rate (95% probability interval)Signature*THPControl (TH)Probability THP Is Superior to ControlPredictive Probability of Success in Phase IIIHER2+54% (38%-70%)22% (5%-39%)99.8%96%HER2+/HR+44% (24%-63%)17% (0%-34%)99%91%HER2+/HR-74% (53%-95%)33% (6%-59%)99.8%98%*HR = Hormone Receptor Citation Format: Meredith Buxton, Angela M. DeMichele, Stephen Chia, Laura van't Veer, Jo Chien, Anne Wallace, Henry Kaplan, Julie Lang, Douglas Yee, Claudine Isaacs, Stacy Moulder, Kathy Albain, Judy Boughey, Kathleen Kemmer, Barbara Haley, Susan Minton, Andres Forero, Rita Nanda, Anthony Elias, Larissa Korde, Rebecca Viscuzi, Hope Rugo, Richard Schwab, Fraser Symmans, Melissa Paoloni, Nola Hylton, Michael Hogarth, Julia Lyandres, Jane Perlmutter, Ashish Sanil, Christina Yau, Laura Esserman, Don Berry, I-SPY 2 TRIAL Investigators. Efficacy of pertuzumab/trastuzumab/paclitaxel over standard trastuzumab/paclitaxel therapy for HER2+ breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT106.

Abstract Background: Pathologic complete response (pCR) is an established prognostic biomarker for aggressive HER2+ breast cancer (BC). Improving pCR rates may identify new therapies that improve survival. T-DM1 and pertuzumab have established benefits in metastatic HER2+ BC. We tested their ability when combined, without paclitaxel, to improve pCR rates (ypT0ypN0) over standard therapy in the randomized, phase 2, I-SPY 2 neoadjuvant trial. Methods: Enrolled patients (pts) had invasive breast cancer ?2.5 cm in HER2-positive subsets. Pts were adaptively randomized to 12 wkly cycles of paclitaxel+trastuzumab (TH, control) or T-DM1+pertuzumab (T-DM1+P) without T, followed by doxorubicin/cyclophosphamide (AC) x 4 and surgery. We utilized all TH control pts accrued over the course of the trial, adjusting for potential differences due to time period treated, which were informed by the several other treatment arms that have been in the trial. Adaptive assignment to the various experimental arms in the trial was based on current Bayesian probabilities of superiority vs. control. “Graduation” by signature and futility stopping were based upon Bayesian predictive probability of success in a future 2-arm, N = 300 neoadjuvant Phase 3 randomized 1:1 trial of T-DM1+P vs. control with pCR endpoint. Results: T-DM1+P met the predictive probability criterion and graduated from I-SPY 2 in 3 signatures: all HER2+, HER2+/HR+, HER2+/HR- (Table 1). Final accrual: 52 T-DM1+P and 31 TH. Safety data will be shown. Conclusions: I-SPY 2's standing platform trial mechanism efficiently evaluates agents in biomarker-defined pt subsets. T-DM1+P (w/o T) -&gt; AC substantially improves pCR rates over standard TH -&gt; AC in all 3 HER2+ signatures, including HR+ and HR- subsets. These findings warrant further investigation of these agents without paclitaxel in a neoadjuvant trial powered for survival endpoints. Table 1Signature*Estimated pCR Rate (95% probability interval)Probability T-DM1+P Is Superior to Control**Predictive Probability of Success in Phase 3T-DM1+PControl (TH)HER2+52% (36%-68%)22% (5%-39%)99.5%94%HER2+/HR+46% (26%-66%)17% (0% - 34%)99.1%93%HER2+/HR-64% (39%-88%)33% (6%-59%)98%90%*HR = Hormone Receptor Citation Format: Angela M. DeMichele, Stacy Moulder, Meredith Buxton, Douglas Yee, Anne Wallace, Jo Chien, Claudine Isaacs, Kathy Albain, Judy Boughey, Kathleen Kemmer, Barbara Haley, Julie Lang, Henry Kaplan, Susan Minton, Andres Forero, Anthony Elias, Rita Nanda, Larissa Korde, Richard Schwab, Michelle Melisko, Ashish Sanil, Michael Hogarth, Nola Hylton, Melissa Paoloni, Fraser Symmans, Jane Perlmutter, Julia Lyandres, Christina Yau, Don Berry, Laura Esserman, I-SPY 2 TRIAL Investigators. Efficacy of T-DM1+pertuzumab over standard therapy for HER2+ breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT042.

Abstract Introduction: Multiple myeloma (MM) is a malignancy of plasma cells that is still considered incurable due to the 90% relapse rate in patients. Despite the advent of new agents the majority of MM patients relapse secondary to therapy resistance. The potential of reovirus (RV) as a novel therapeutic agent for MM under in vitro, in vivo and ex vivo conditions has been demonstrated by us and a phase I clinical trial of MM with RV therapy has shown indications of efficacy. Recently we have shown that RV could synergize with several standard of care MM drugs such as bortezomib (BTZ), carfilzomib (CFZ) and dexamethasone and importantly, enhance its therapeutic potential in therapy resistant human MM cell lines in vitro. Utilizing the syngeneic Vk*MYC BTZ resistant transplantable MM mouse model, we demonstrate that mice harbouring BTZ insensitive MM tumors significantly respond to RV treatment. Our data indicate that this RV treatment sensitivity is manifested via, direct oncolysis in conjunction with immune modulatory effects. Methods: Vk*MYC myeloma cells (Vk12598) were injected via tail vein (IV) into 3 groups of C57BL/6 wt recipient mice. Seven days post tumor injection, mice were treated with PBS (vehicle) or live (LV) or dead reovirus (DV) (5×10⁁8 PFU) administered IV every 6 days in a total of 5 doses. Serum gamma globulins (M-spike) were assessed weekly by serum protein electrophoresis. Mice were sacrificed on day 35 post tumour injection and their spleens and bone marrow (BM) were harvested. Splenic and BM cells were stained for CD45+/CD45R-/CD138+ (MM tumors), CD4+/CD8+ (T cells), CD3+/NKG2D+ (NKT cells), CD11b+Ly6C+ (monocytic myeloid derived suppressor cells (Mo-MDSC) and CD11b+Ly6G+ (polymorphonuclear (PMN) - MDSCs) and analyzed by flow cytometry. Results: Mice treated with RV demonstrated highly significant (P&lt;0.001) reductions in their M-spikes at 4 and 5 weeks post treatment. RV treatment led to a significant NKT cell accumulation in splenic and BM of RV treated mice in comparison to vehicle treated mice suggestive of immune activation due to RV. Further, RV treatment led to a significant increase in BM Mo-MDSC number but not PMN-MDSC numbers. Interestingly, significant down regulation of splenic PMN-MDSCs was seen with RV treatment. Conclusions: Our results indicate reovirotherapy is successful in a validated syngeneic BTZ resistant MM model. These results have important implications for future clinical trials. Currently we are conducting further experiments to assess the immune modulatory (such as T - memory and T - regulatory cells) contributions of RV in this model. Citation Format: Chandini M. Thirukkumaran, Zhong Qiao Shi, Joanne Luider, Karen Kopciuk, Marta Chesi, Leif Bergsagel, Yuan Dong, Chunfen Zhang, Ahmed Mostafa, Kathy Gratton, Satbir Thakur, Don Morris. Successful oncolytic virotherapy in a bortezomib resistant syngeneic mouse model of multiple myeloma: Implications for translational significance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 541.