Boughey, Judy C.

Abstract Purpose: We hypothesized that integrated analysis of cancer types from different lineages would reveal novel molecularly defined subgroups with unique therapeutic vulnerabilities. On the basis of the molecular similarities between subgroups of breast and ovarian cancers, we analyzed these cancers as a single cohort to test our hypothesis. Experimental Design: Identification of transcriptional subgroups of cancers and drug sensitivity analyses were performed using mined data. Cell line sensitivity to Hsp90 inhibitors (Hsp90i) was tested in vitro. The ability of a transcriptional signature to predict Hsp90i sensitivity was validated using cell lines, and cell line- and patient-derived xenograft (PDX) models. Mechanisms of Hsp90i sensitivity were uncovered using immunoblot and RNAi. Results: Transcriptomic analyses of breast and ovarian cancer cell lines uncovered two mixed subgroups comprised primarily of triple-negative breast and multiple ovarian cancer subtypes. Drug sensitivity analyses revealed that cells of one mixed subgroup are significantly more sensitive to Hsp90i compared with cells from all other cancer lineages evaluated. A gene expression classifier was generated that predicted Hsp90i sensitivity in vitro, and in cell line- and PDXs. Cells from the Hsp90i-sensitive subgroup underwent apoptosis mediated by Hsp90i-induced upregulation of the proapoptotic proteins Bim and PUMA. Conclusions: Our findings identify Hsp90i as a potential therapeutic strategy for a transcriptionally defined subgroup of ovarian and breast cancers. This study demonstrates that gene expression profiles may be useful to identify therapeutic vulnerabilities in tumor types with limited targetable genetic alterations, and to identify molecularly definable cancer subgroups that transcend lineage.

Background: Surgical-site infection after implant-based breast reconstruction adversely affects surgical outcomes and increases health care costs. This 11-year case-control study examines risk factors specific for surgical-site infection after immediate tissue expander/implant-based breast reconstruction. Methods: The authors performed a retrospective review to identify all consecutive patients with breast implant infections between 2006 and 2016. Patients who developed surgical-site infection after immediate tissue expander/implant-based breast reconstruction were included. Surgical-site infection was defined using the Centers for Disease Control and Prevention criteria; specifically, infections requiring hospital admission, intravenous antibiotics, or surgical intervention were included. The authors matched a control patient to each infection case by patient age and date of surgery. Patient demographics, medical comorbidities, and perioperative surgical variables were examined. Univariate and multivariable conditional logistic regression models were constructed. Results: A total of 270 breasts in 252 patients were evaluated. On multivariate analysis, patients with a higher body mass index (OR, 1.1 per 1 body mass index point increase; 95 percent CI, 1.0 to 1.2; p = 0.02), hypertension (OR, 6.5; 95 percent CI, 1.9 to 22.3; p = 0.002), neoadjuvant chemotherapy (OR, 2.6; 95 percent CI, 1.0 to 6.3; p = 0.04), axillary lymph node dissection (OR, 7.1; 95 percent CI, 1.7 to 29.2; p = 0.006), seroma formation (OR, 15.34; 95 percent CI, 3.7 to 62.5; p = 0.0001), and wound healing complications (OR, 23.91; 95 percent CI, 6.1 to 93.4; p < 0.0001) were significantly associated with surgical-site infection. Conclusions: Women with obesity, women with hypertension, and those treated with neoadjuvant chemotherapy are at increased risk of surgical-site infection. Further risks are also associated with postoperative seroma and wound complications. This may help patient selection and counseling, adjusted based on risk factors regarding complications of immediate implant-based breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Background and objectives: Differences in patient anatomy and physiology exist between young and older patients undergoing breast reconstruction after mastectomy. Breast cancer has been described as being more aggressive, more likely to receive radiation, contralateral mastectomy, as well as bilateral reconstruction in young patients. Our purpose is to report long-term experience on two-staged implant-based breast reconstruction (IBR) in young females, with complication sub-analysis based on obesity and adjuvant radiation. Materials and Methods: Retrospective chart review of all consecutive young patients who underwent two-staged IBR at our institution, between 2000 and 2016, was performed. Patients between 15 and 40 years old with least 1-year follow-up were included. Univariate logistic regression models and receiver operating characteristic (ROC) curves were created. Results: Overall 594 breasts met our inclusion criteria. The mean age was 34 years, and the median follow-up was 29.6 months. Final IBR was achieved in 98% of breasts. Overall, 12% of breasts had complications, leading to explantations of 5% of the devices. Adjuvant radiation was followed by higher rates of total device explantations (p = 0.003), while obese patients had higher rates of total complications (p < 0.001). For each point increase in BMI, the odds of developing complications increased 8.1% (p < 0.001); the cutoff BMI to predict higher complications was 24.81 kg/m2. Conclusions: This population demonstrates high successful IBR completion and low explantation rates. These data suggest that obese women and those with planned adjuvant radiation deserve special counseling about their higher risk of complications.

Abstract INTRODUCTION: Breast cancer is the most common invasive cancer and the second leading cause of cancer death in women. Approximately 20% of breast cancer tumors overexpress human epidermal growth factor receptor 2 (HER2), which is associated with an aggressive clinical phenotype and with a poorer prognosis. The development of trastuzumab, an immunoglobulin G monoclonal antibody directed against HER2, has changed the treatment paradigm for this disease. However, approximately 15-20% still does not respond to anti-HER2 therapy. Furthermore, despite advances in the management of metastatic HER2-positive breast cancer, response rate varies greatly, with most patients eventually succumbing to their disease. It is crucial to develop additional therapeutic strategies to improve outcomes for HER2 positive patients, especially those with tumors that do not respond to anti-HER2 therapy. METHODS and RESULTS: Using HER2+ breast cancer cell lines, we found that an USP7 inhibitor, P5091, dramatically sensitized cancer cells to HER2 inhibitor, trastuzumab treatment. To confirm it in vivo, we tested the drug combination in BT474 xenografts and found P5091 and trastuzumab synergistically suppressed tumor growth. Furthermore, using trastuzumab resistant HER2+ breast cancer cell line, we found that USP7 inhibitor, P5091, can dramatically re-sensitize trastuzumab-resistant BT474 cell line to trastuzumab treatment both in vitro and in vivo. More importantly, using patient derived xenograft (PDX) HER2+ models, we confirmed the synergistic combination effect of P5091 and trastuzumab. Mechanistically, USP7 inhibitor, P5091 led to significantly increased degradation of all four HER family members (HER1-4). When we knocked down USP7 by RNA interference or small hairpin RNA (shRNA), we observed similar substantial decrease in HER family member proteins. CONCLUSIONS: We have demonstrated the feasibility of using USP7 inhibitor P5091 to sensitize HER2+ breast cancers to trastuzumab treatment. These results provide a rationale for the use of combination therapy of USP7 inhibitors and HER2 inhibitors to treat HER2+ breast cancer. This combination therapy might also be effective in other cancers with upregulated HER signaling, such as GI cancer, lung cancer or ovarian cancer. Citation Format: Jia Yu, Bo Qin, Judy Boughey, Matthew Goetz, Liewei Wang. The role of USP7 and USP7 inhibitor in HER2+ breast cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2980.

Abstract Background: I-SPY2 is a multicenter, Phase II trial using response-adaptive randomization within biomarker subtypes to evaluate novel agents as neoadjuvant therapy for high-risk at least T2N0 breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. The goal is to identify regimens that have ≥ 85% Bayesian predictive probability of success in a 300-patient phase 3 neoadjuvant trial defined by hormone-receptor (HR) and HER2 status, and MammaPrint (MP). Regimens may leave the trial for futility (&lt; 10% probability of success), maximum sample size accrual (with probability of success ≥ 10% and &lt; 85%), or as recommended by the independent DSMB. For HER2- subjects the control arm is weekly paclitaxel x12 then doxorubicin & cyclophosphamide (AC) q2-3 weeks x4. For this arm, paclitaxel was omitted and replaced with maximum tolerated dose PARPi talazoparib with synergy dosed irinotecan (25mg/m2). Paclitaxel could be given adjuvantly for these subjects and non-responding subjects could be taken off of experimental therapy. Methods: Women with tumors ≥ 2.5cm were eligible for screening. MP low/HR+ tumors were ineligible. MRI scans (baseline, 3 cycles after start of therapy, prior to AC, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients. Talazoparib was given at 1mg daily with 25mg/m2 irinotecan q2wks. Analysis was intention to treat. Subjects who switched to non-protocol therapy count as non-pCR. Subjects on experimental therapy at time of arm closure are non-evaluable. Talazoparib/irinotecan (TI) was open only to HER2- tumors and eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-/HER2-. Results: TI did not meet criteria for graduation and was stopped at the recommendation of the DSMB based on expectations of limited activity beyond that seen with standard treatment. Maximum sample size had been reached at the time of this recommendation and subjects currently receiving TI were allowed to continue or change to standard therapy. Exploratory “as treated” analysis for response in gBRCA mutation carriers showed 6/10 gBRCA carriers attained a pCR in the TI arm. Except for 1 patient these gBRCA pCR subjects had &gt;90% tumor reduction by MRI after TI and prior to AC (range: 68-96%). In the TI arm pCR rates were also higher in subjects with a PARPi7-High/MP2 gene expression signature (0.344 vs 0.146). Expected differences in toxicity were seen between arms including g3/4 peripheral neuropathy on control therapy which included paclitaxel (2.6% vs none) and g3/4 neutropenia with TI (30.2% vs 8.2%). Notably gBRCA mutation carriers receiving TI had higher rates of g3/4 neutropenia (60% vs 25.9%). Conclusion: The I-SPY2 study finds the probability that investigational regimens will be successful in a Phase III neoadjuvant trial; TI did not reach the efficacy threshold of 85% probability of success in Phase III in any of the 3 signatures. However by adding talazoparib with synergy dosed irinotecan we were able to omit paclitaxel and observe similar estimated pCR rates. This informs current work to evolve the I-SPY2 trial design to reduce toxicity without compromising outcomes and develop successful combinations targeted to biology, including DNA repair deficiency. Citation Format: Richard Schwab, Amy S. Clark, Christina Yau, Nola Hylton, Wen Li, Denise Wolfe, A Jo Chien, Anne M. Wallace, Andres Forero-Torres, Erica Stringer-Reasor, Rita Nanda, Nora Jaskowiak, Judy Boughey, Tufia Haddad, Heather S. Han, Catherine Lee, Kathy Albain, Claudine Isaacs, Anthony D. Elias, Erin D. Ellis, Payal Shah, Julie E. Lang, Janice Lu, Debasish Tripathy, Kathleen Kemmer, Douglas Yee, Barbara Haley, Melanie Majure, Erin Roesch, Christos Vaklavas, Cheryl Ewing, Teresa Helsten, W Fraser Symmans, Jane Perlmutter, Hope S. Rugo, Michelle Melisko, Amy Wilson, Ruby Singhrao, Laura van 't Veer, Angela DeMichele, Smita Asare, Don Berry, Laura J. Esserman. Evaluation of talazoparib in combination with irinotecan in early stage, high-risk HER2 negative breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT136.

6526 Background: Most patients diagnosed with breast cancer turn to the Internet to learn about their diagnosis; however, information online is often generic, challenging to navigate, and not expert-curated. To facilitate patient education and engagement in our breast clinic, we piloted the implementation of pre-visit education via brief microlearning videos organized within an online platform. Methods: Seventeen videos of 2-4 minute duration were developed by multidisciplinary content experts. Videos covered a variety of educational topics relevant to breast cancer, including treatment options. Patients received a link via email to create an account, which provided access to the platform. Aggregate viewing data and optional patient surveys (online after viewing 3 videos and at the clinical appointment) were used to assess opt-in rates, engagement, and satisfaction. Results: Between September 2018 and January 2019, 57.4% (240/418) of women with biopsy proven breast cancer who were sent an email invitation registered on the platform. On average, patients watched 11 of the 17 videos, with 93.7% of users (225/240) viewing at least one. Overall, 85% (168/198) of women recommend the microlearning format for patient education. The most-viewed video topics included types of breast cancer, breast abnormality and biopsy, understanding biopsy results, tumor markers, and staging. Seventy-eight percent (154/198) of women reported that they planned to share the videos with family or caregivers, and 67% (133/198) felt that the educational content increased their satisfaction with their overall experience. Barriers to video access were emails marked as junk, not having an email address, and difficulties with videos loading. Conclusions: The majority of patients participating in this pilot registered on the platform and watched pre-visit microlearning educational videos. These expert-curated videos contributed to high levels of satisfaction and engagement. Strategies to overcome barriers to access will be developed to expand the reach of this new valuable component of breast cancer care.

Background: Two-staged implant-based reconstruction (IBR) is the most common breast reconstructive modality. Recently, technological and surgical advances have encouraged surgeons to revisit prepectoral IBR. Data comparing prepectoral against subpectoral IBR in women under the age of 40 are lacking. Methods: Retrospective chart review of patients under the age of 40 years old, who underwent immediate 2-staged IBR at our institution, was performed. Patient’s demographics, clinical characteristics, operative details, and early surgical outcomes of prepectoral and subpectoral reconstruction were compared. Data with values of P < 0.05 were considered statistically significant. Results: Between 2012 and 2016, 100 patients (187 breasts) who underwent prepectoral and 69 patients (124 breasts) who underwent subpectoral IBR were included. Median follow-up was 17.9 and 17.5 months in the prepectoral and subpectoral groups, respectively. Total number of complications including both stages of reconstruction was 20 (10.7%) and 19 (15.3%) in the prepectoral and subpectoral groups, respectively (P = 0.227). Specific complications, including hematoma, seroma, skin flap necrosis, wound dehiscence, and breast infections, were not significantly different among groups. Ten (5.4%) devices, including implants and tissue expander, required explantation in the prepectoral group and 8 (6.5%) in the subpectoral group (P = 0.683). Explantation was most commonly due to infection (n = 14), and all of them occurred during the first stage (P < 0.001). Conclusions: Early complications and implant explantation rates are comparable among prepectoral and subpectoral breast reconstruction in women under 40 years old. Based on these results, we believe that prepectoral IBR is a safe, reliable, and promising reconstructive option.