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Current systemic therapy guidelines for patients with HER2 + breast cancer brain metastases (BCBrM) diverge based on the status of extracranial disease (ECD). An in-depth understanding of the impact of ECD on outcomes in HER2 + BCBrM has never been performed. Our study explores the implications of ECD status on intracranial progression-free survival (iPFS) and overall survival (OS) after first incidence of HER2 + BCBrM and radiation.A retrospective analysis was performed of 151 patients diagnosed with initial HER2 + BCBrM who received radiation therapy to the central nervous system (CNS) at Duke between 2008 and 2021. The primary endpoint was iPFS defined as the time from first CNS radiation treatment to intracranial progression or death. OS was defined as the time from first CNS radiation or first metastatic disease to death. Systemic staging scans within 30 days of initial BCBrM defined ECD status as progressive, stable/responding or none (isolated brain relapse).In this cohort, 70% of patients had controlled ECD with either isolated brain relapse (27%) or stable/responding ECD (44%). OS from initial metastatic disease to death was markedly worse for patients with isolated intracranial relapse (median = 28.4 m) compared to those with progressive or stable/responding ECD (48.8 m and 71.5 m, respectively, p = 0.0028). OS from first CNS radiation to death was significantly worse for patients with progressive ECD (16.9 m) versus stable/responding (36.6 m) or isolated intracranial relapse (28.4 m, p = 0.007). iPFS did not differ statistically based on ECD status. Receipt of systemic therapy after first BCBrM significantly improved iPFS (HR 0.45, 95% CI: 0.25-0.81, p = 0.008) and OS (HR: 0.43 (95% CI: 0.23-0.81); p = 0.001).OS in patients with HER2 + isolated BCBrM was inferior to those with concurrent progressive or stable/responding ECD. Studies investigating initiation of brain-penetrable HER2-targeted therapies earlier in the disease course of isolated HER2 + intracranial relapse patients are warranted.

CYTOF Panel

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SPADE tree generated by CYTOF analysis

Supplementary Figure 4

Purpose: We conducted a phase I study of dasatinib, an oral SRC-family tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in the treatment of advanced and recurrent epithelial ovarian cancer.Experimental Design: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included defining toxicity, response rate (RR), pharmacokinetics, and pharmacodynamics. Using a “3+3” design, cohorts of three to six patients received paclitaxel (175 mg/m2) and carboplatin (AUC 6) every 3 weeks with escalating doses of dasatinib (100, 120, and 150 mg daily), followed by an eight-patient expansion cohort.Results: Twenty patients were enrolled between June 2007 and December 2009. The median age was 61 years (range: 42–82) with a median of 2 prior regimens (range: 0–6), and 71% had platinum-sensitive disease. There were three to six patients in each cohort, and eight in the expansion cohort. Pharmacokinetics were observed over the first two cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia). Other toxicities in all cycles included neutropenia (95% grade 3–4; 91% in the 150 mg dosing cohort), thrombocytopenia (35% grade 3–4), and fatigue (10% grade 3). The RR was 40% [three complete responses, (15%); five partial responses, (25%)],10 patients (50%) had stable disease, and two were not evaluable. The PFS6-month actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively.Conclusions: Due to the high incidence of myelosuppression with subsequent cycles, the recommended phase II dose of dasatinib is 150 mg daily in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity. Clin Cancer Res; 18(19); 5489–98. ©2012 AACR.

Supplementary Table 1

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Purpose:Despite promising advances in breast cancer immunotherapy, augmenting T-cell infiltration has remained a significant challenge. Although neither individual vaccines nor immune checkpoint blockade (ICB) have had broad success as monotherapies, we hypothesized that targeted vaccination against an oncogenic driver in combination with ICB could direct and enable antitumor immunity in advanced cancers.Experimental Design:Our models of HER2+ breast cancer exhibit molecular signatures that are reflective of advanced human HER2+ breast cancer, with a small numbers of neoepitopes and elevated immunosuppressive markers. Using these, we vaccinated against the oncogenic HER2Δ16 isoform, a nondriver tumor-associated gene (GFP), and specific neoepitopes. We further tested the effect of vaccination or anti–PD-1, alone and in combination.Results:We found that only vaccination targeting HER2Δ16, a driver of oncogenicity and HER2-therapeutic resistance, could elicit significant antitumor responses, while vaccines targeting a nondriver tumor-specific antigen or tumor neoepitopes did not. Vaccine-induced HER2-specific CD8+ T cells were essential for responses, which were more effective early in tumor development. Long-term tumor control of advanced cancers occurred only when HER2Δ16 vaccination was combined with αPD-1. Single-cell RNA sequencing of tumor-infiltrating T cells revealed that while vaccination expanded CD8 T cells, only the combination of vaccine with αPD-1 induced functional gene expression signatures in those CD8 T cells. Furthermore, we show that expanded clones are HER2-reactive, conclusively demonstrating the efficacy of this vaccination strategy in targeting HER2.Conclusions:Combining oncogenic driver targeted vaccines with selective ICB offers a rational paradigm for precision immunotherapy, which we are clinically evaluating in a phase II trial (NCT03632941).

Supplementary methods

Purpose:Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T-cell infiltration of tumors include vaccines targeting established oncogenic drivers such as the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2).Patients and Methods:In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and antitumor function were evaluated. We tested VRP-HER2 in a phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of 3 doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy.Results:Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was 1 partial response and 2 patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n = 4) and 32.7 months in cohort 2 (n = 18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS.Conclusions:VRP-HER2 increased HER2-specific memory CD8 T cells and had antitumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T-cell activity by combining with anti-PD-1.

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Although breast reconstruction after bilateral mastectomies including a contralateral prophylactic mastectomy is known to have a higher overall complication profile, whether reconstructive complication rates differ between the therapeutic mastectomy and contralateral prophylactic mastectomy sides remains unclear.Women undergoing bilateral mastectomies with autologous or implant-based breast reconstruction for a unilateral breast cancer at a single institution were identified (2009 to 2019). Postoperative complications were stratified by laterality (therapeutic mastectomy versus contralateral prophylactic mastectomy). Paired data were analyzed to compare the risks of complications between prophylactic and therapeutic reconstruction sides in the same patient.A total of 130 patients (260 reconstructions) underwent bilateral autologous or implant-based reconstruction. Although most women underwent a simple mastectomy, a higher proportion of therapeutic mastectomies were modified radical mastectomies including axillary lymph node dissections compared to contralateral prophylactic mastectomies (15.4 percent versus 0 percent). Forty-four percent of women completed postmastectomy radiation therapy of the therapeutic side before definitive reconstruction. Overall, both therapeutic and prophylactic reconstructions had a similar incidence of reconstructive failure (p = 0.57), return to the operating room (p = 0.44), mastectomy skin flap necrosis (p = 0.32), seroma (p = 0.82), fat necrosis (p = 0.16), wound infection (p = 0.56), and cellulitis (p = 0.56). Nearly one-fifth of patients experienced complications limited to the prophylactic side [contralateral prophylactic mastectomy reconstruction complications, n = 26 (20.0 percent); therapeutic mastectomy reconstruction complications, n = 15 (11.5 percent)].Despite a history of local radiation therapy and more extensive oncologic surgery on the therapeutic side, there are no significant differences in the incidence of postsurgical complications on the therapeutic mastectomy and contralateral prophylactic mastectomy sides after bilateral reconstruction.Risk, II.

Background: Fam-trastuzumab deruxtecan (DS-8201) was recently approved in patients with advanced/metastatic HER2 positive breast cancer who have received two or more prior HER2-based regimens. In DESTINY-Breast01, an unprecedented response rate was observed in 61% of heavily pretreated patients; however, all-grade interstitial lung disease (ILD) developed in almost 14% of patients, which led to death in 2% of patients. Additionally, patients with a medical history of clinically significant lung disease were excluded which is not consistent with the standard community patient population that may receive fam-trastuzumab deruxtecan. Currently, there are no recommended protocols in place or guidance for monitoring patients for interstitial lung disease/pneumonitis while on fam-trastuzumab deruxtecan. This is a retrospective chart review to assess the feasibility of implementing an ILD monitoring protocol in a cohort of patients receiving treatment with fam-trastuzumab deruxtecan at the Duke Cancer Institute. Methods: Patients with HER2-positive or HER2-low metastatic breast cancer who received ≥five cycles of fam-trastuzumab deruxtecan between Jan 1, 2020-June 30, 2020 were included. Chest imaging and pulmonary function testing with diffusing capacity for carbon monoxide (DLCO) were performed at baseline prior to initiation and every six weeks prior to cycle 3 and cycle 5 of fam-trastuzumab deruxtecan to monitor for ILD. DLCO was corrected for hemoglobin. Patients that experienced more than a 10% decrease in corrected DLCO (DLCOc) were recommended to have a pulmonology consult in which DLCOc was reviewed in combination with chest imaging and clinical history to evaluate for ILD and recommend continuance or cessation of the drug. Clinical pulmonary symptoms to include cough, shortness of breath, dyspnea, and new or worsening respiratory symptoms were monitored per chart review. Results: Seven patients with HER2-positive (N=6) and HER2-low (N=1) metastatic breast cancer were monitored per predefined ILD monitoring protocol with 100% completion of chest imaging and pulmonary function testing at baseline and prior to cycle 3 and cycle 5 indicating feasibility. There were no confirmed cases of ILD/pneumonitis within the patient cohort. Two patients (28.6%) experienced DLCOc decreases >10% warranting a pulmonology consult. Upon further assessment, ILD/pneumonitis was ruled out based on chest imaging and/or asymptomatic presentation and both patients continued therapy without treatment delay or development of pneumonitis to date. Both patients with DLCOc decrease >10% had a history of lung disease or significant metastatic disease involvement including asthma and lymphangitic carcinomatosis, respectively. In these patients, DLCOc, imaging and clinical history were able to safely rule out ILD. . Conclusion: Implementation of a comprehensive protocol to monitor and assess for ILD associated with fam-trastuzumab deruxtecan is feasible for patients receiving this therapy and may prevent treatment delay in patients with suspected ILD. In this small cohort, stable DCLOc suggests the absence of ILD onset in patients treated with fam-trastuzumab deruxtecan. DLCOc monitoring may be a reasonable measure to assess for ILD-related changes in patients. Further data collection is underway to understand the value of a comprehensive ILD monitoring protocol. Citation Format: Heather Moore, Scott Shofer, Amy Guisinger, Gloria Broadwater, Jeremy Force, Sarah Sammons, Carey Anders, Kelly Westbrook. Feasibility of a comprehensive monitoring protocol for the prevention and treatment of interstitial lung disease in patients undergoing treatment with fam-trastuzumab deruxtecan [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-33.

Background: CDK 4/6 inhibitors in patients (pts) with HR+/HER2- ABC has led to significant improvements in clinical outcomes, however our understanding of the impact of these treatments on CV health is unknown. Gains in overall survival should not be offset by increased CV morbidity and mortality; a particular concern given the shared risk factors for both breast cancer and CV disease. Objective: The aim of this study was to describe patient characteristics, treatment patterns and cardiovascular risk factors and disease in pts with ABC treated with endocrine therapy (ET) or ET + CDK 4/6 inhibitor. Methods: We retrospectively studied pts with HR+/HER2- ABC who were receiving first line endocrine therapy. Post-menopausal (PM) women, pre-menopausal women on ovarian suppression (OS), and men were included. Two cohorts were included: Group A - treated with ET alone (2012-2014; prior to US approval of CDK 4/6 inhibitors) and Group B - treated with ET+ CDK 4/6 inhibitor (2015-2017). The following data was extracted from Duke University Health System’s electronic medical record (EPIC) and entered into a REDCap database: demographics, baseline cardiovascular risk factors, and co-morbidities. Pt characteristics are summarized using medians and interquartile ranges for continuous variables and categorical descriptions are summarized using frequencies and percentages. Results: In total 103 patients were included with 57 in Group A (ET alone) and 46 in Group B (ET + CDK 4/6 inhibitor). Median age was 62.0 and 63.5 years in Group A and B, respectively. Fifty-three (93%) of pts in Group A were PM women compared to 37 (80%) PM women and 1 (3%) male in Group B. The groups seemed to be similar in terms of race (white 70% vs 72%), baseline body mass index (28.2 vs 27.6), baseline systolic blood pressure (132.0 vs 135.5) and diastolic blood pressure (79.0 vs 77.5). Similarly, the groups seemed to be similar in baseline hypertension (68% vs 62%); diabetes (23% vs 24%); Hemoglobin A1c (7.2% vs 6.4%) or family history of CV disease (56% vs 55%), Group A versus Group B, respectively. There were slightly more current/past smokers in Group B than Group A (48% vs 35%) and more pts in Group A with a history of hyperlipidemia relative to Group B (52% vs 31%). Conclusions: In this retrospective descriptive cohort study there seemed to be no differences in demographics or baseline CV risk factors between the ET and ET + CDK 4/6 inhibitor cohorts with the exception of more baseline hyperlipidemia in the ET cohort. This might suggest that baseline CV risk factors did not dissuade practioners from prescribing ET + CDK 4/6 inhibitor therapy. We plan to expand our cohort to collect information on type and duration of ET and CDK 4/6 inhibitors, reason for treatment discontinuation, and CV events (eg heart failure, arrhythmias, stroke, myocardial infarction), to better understand the impact that cardiovascular risk factors have on outcomes in breast cancer patients taking ET+ CDk 4/6 inhibitor. Table 1: Demographics and CV risk factors in ABC patients treated with ET or ET + CDK4/6 inhibitor Median (IQR) unless otherwise indicatedGroup A ET (n=57)Group B ET+ CDK 4/6 inhibitor (n=46)Age median (range)62.0 (27-84)63.5 (30-82)Menopausal status, n (%) Post menopausal Premenopausal + OS Male53 (93) 4 (7) 037 (80) 8 (17) 1 (3)Race, n (%) White Other40 (70) 17 (30)33 (72) 13 (28)Type of Insurance, n (%) Private Medicare Medicare and Private Medicaid Medicaid and Medicare Vererans Sponsored Self-Pay Unknown19 (33) 14 (25) 16 (28) 1 (2) 4 (7) 0 3 (5) 019 (41) 4 (9) 15 (33) 1 (2) 4 (9) 1 (2) 0 2 (4)BMI (kg/m2)28.2 (24.9, 30.6)27.6 (24.4, 34.5)Baseline BP (mmHg) Systolic Diastolic132.0 (118.0, 145.0) 79.0 (73.0, 84.0)135.5 (124.0, 149.0) 77.5 (72.0, 84.0)HgbA1c (%)7.2 (6.4, 7.4)6.4 (5.4, 6.4)CVRF, n (%) Hypertension Diabetes FH CVD Current/past smokers Hyperlipidemia36 (68) 13 (23) 28 (56) 20 (35) 29 (52)28 (62) 11 (24) 22 (55) 22 (48) 14 (31)OS = ovarian suppression; BMI = body mass index; BP = blood pressure; HgbA1c = hemoglobin A1c; CVRF = cardiovascular risk factors; FH = family history; CVD = cardiovascular disease; IQR = Interquartile range Citation Format: Susan Dent, Gloria Broadwater, Terry Hyslop, Kevin Oeffinger, Michel Khouri, Sanjeev Balu, Gretchen Kimmick. Cardiovascular (CV) risk profile in patients with estrogen receptor (ER) positive HER2 negative advanced breast cancer (ABC): A retrospective cohort study (CAREB) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-48.

Background Psychosocial distress, depression, or anxiety can occur in up to 50% of women after a breast cancer diagnosis and mastectomy. The purpose of this study was to assess the potential benefit of lavender oil as a perioperative adjunct to improve anxiety, depression, pain, and sleep in women undergoing microvascular breast reconstruction. Methods This was a prospective, single-blinded, randomized, controlled trial of 49 patients undergoing microvascular breast reconstruction. Patients were randomized to receive lavender oil or placebo (coconut oil) throughout their hospitalization. The effect of lavender oil on perioperative stress, anxiety, depression, sleep, and pain was measured using the hospital anxiety and depression scale, Richards–Campbell Sleep Questionnaire, and the visual analogue scale. Results Twenty-seven patients were assigned to the lavender group and 22 patients were assigned to the control group. No significant differences were seen in the perioperative setting between the groups with regard to anxiety (p = 0.82), depression (p = 0.21), sleep (p = 0.86), or pain (p = 0.30) scores. No adverse events (i.e., allergic reaction) were captured, and no significant differences in surgery-related complications were observed. When evaluating the entire cohort, postoperative anxiety scores were significantly lower than preoperative scores (p Conclusion In the setting of microvascular breast reconstruction, lavender oil and aromatherapy had no significant adverse events or complications; however, there were no measurable advantages pertaining to metrics of depression, anxiety, sleep, or pain as compared with the control group.

BACKGROUND Pelvic washings for patients with endometrial cancer is recommended but not used for staging. The International System for Reporting Serous Fluid Cytology (TIS) has standardized diagnostic categories, but the criteria remain incomplete. The 3 primary goals of this study were to 1) investigate features that distinguish atypical/indeterminate from malignant specimens, 2) measure the level of agreement between chart and reviewer diagnoses, and 3) determine whether the number of years in practice had an effect on the diagnoses rendered. METHODS Pelvic washings and surgical pathology specimens for 52 patients with a chart diagnosis of atypical/indeterminate, suspicious, or malignant cytology and 52 age-matched controls with a negative chart diagnosis were included, reviewed blindly by 2 cytopathologists, and assigned a study diagnosis. Morphologic features were assessed. Agreement between original chart diagnoses and reviewer diagnoses were assessed as well as effect of years in practice. RESULTS The overall cellularity in cell block (CB) slides for the malignant category was significantly increased compared with the atypical/indeterminate category (P < .0001). In addition, the number of atypical groups in ThinPrep for malignant washings was significantly increased compared with the atypical category (P < .001) and the negative and suspicious categories (P < .0001) in the CB. Overall agreement between the original and adjudicated diagnoses was high (γ = 0.983). There was no significant difference between diagnoses rendered and years in practice. CONCLUSION The overall cellularity and number of atypical cells can be used to distinguish between malignant and atypical pelvic washing specimens. There is high reproducibility in the diagnostic categories and high agreement among pathologists, regardless of practice experience. These findings can help refine the criteria for TIS.

Recent advances in next-generation sequencing have allowed for an increase in molecular tumor profiling. We sought to assess the actionability and clinical utilization of molecular tumor profiling results obtained via Foundation Medicine tumor sequencing tests in uterine and ovarian cancers. We performed a single-institution retrospective chart review to obtain demographic and clinical information in patients with uterine and ovarian cancer whose tumors were submitted to Foundation Medicine for molecular tumor profiling over a 7-year period. Alterations identified on testing were stratified according to the OncoKB database actionability algorithm. Descriptive statistics were primarily used to analyze the data. Tumors from 185 women with gynecologic cancer were submitted for molecular tumor profiling between 2013 and 2019. The majority of tests (144/185; 78%) were ordered after a diagnosis of recurrence. In 60 (32%), no actionable molecular alteration was identified. Thirteen (7%) identified an alteration that directed to a US Food and Drug Administration-approved therapy in that tumor type, while 112 (61%) had alterations with investigational or hypothetical treatment implications. In patients with any actionable finding, treatment was initiated in 27 (15%) based on these results. The majority of uterine and ovarian cancers (93%) did not have molecular alterations with corresponding Food and Drug Administration-approved treatments. Even in patients with a potentially actionable alteration, gynecologic oncologists were more likely to choose an alternative therapy. Further investigation is warranted to determine which patients with uterine and ovarian cancer are most likely to benefit from molecular tumor profiling and the ideal timing of testing. The potential to identify effective therapeutic options in a minority of patients needs to be balanced with the current limited clinical applicability of these results in most cases.

Unintentional falls and breast cancer are common among older women, but the associations between them are understudied. We aimed to identify factors associated with falls in older women with breast cancer. We retrospectively reviewed clinical records of older women with breast cancer at Duke Medical Center who had completed the Senior Adult Oncology Program geriatric assessment. Characteristics were compared between women had had at least one fall in the past year and those who did not. Pearson’s Chi-square tests and t tests were used for comparison of groups’ characteristics. Logistic regression determined factors associated with falling. We identified 425 women, age 76.2 years (range 65–89 years), at the time of the assessment. 118 (27.8%) women reported a fall in the prior year. Age, race, ethnicity, and time since diagnosis (all p > 0.05) were similar between groups. In univariate analyses, metastatic disease (p = 0.023) and history of endocrine therapy (p = 0.042) were more common among women who fell. Women who fell had lower systolic (p = 0.001), diastolic (p

BACKGROUND Enhanced recovery after surgery (ERAS) initiatives improve postoperative function and expedite recovery, leading to a decrease in length of stay. The authors noted a high rate of postoperative symptomatic hypotension in patients undergoing abdominal free flap breast reconstruction and wished to explore this observation. METHODS Subjects undergoing abdominal free flap breast reconstruction at the authors' institution from 2013 to 2017 were identified. The ERAS protocol was initiated in 2015 at the authors' hospital; thus, 99 patients underwent traditional management and 138 patients underwent ERAS management. Demographics and perioperative data were collected and analyzed. Postoperative symptomatic hypotension was defined as mean arterial pressure below 80 percent of baseline with symptoms requiring evaluation. RESULTS A significantly higher rate of postoperative symptomatic hypotension was observed in the ERAS cohort compared with the traditional management cohort (4 percent versus 22 percent; p < 0.0001). Patients in the ERAS cohort received significantly less intraoperative intravenous fluid (4467 ml versus 3505 ml; p < 0.0001) and had a significantly increased amount of intraoperative time spent with low blood pressure (22 percent versus 32 percent; p =0.002). Postoperatively, the ERAS cohort had significantly lower heart rate (77 beats per minute versus 88 beats per minute; p < 0.0001) and mean arterial pressure (71 mmHg versus 78 mmHg; p < 0.0001), with no difference in urine output or adverse events. CONCLUSIONS The authors report that ERAS implementation in abdominal free flap breast reconstruction may result in a unique physiologic state with low mean arterial pressure, low heart rate, and normal urine output, resulting in postoperative symptomatic hypotension. Awareness of this early postoperative finding can help better direct fluid resuscitation and prevent episodes of symptomatic hypotension. CLINICAL QUESTION/LEVEL OF EVIDENCE Therapeutic, III.

OBJECTIVES: Racial disparities in survival from endometrial cancer (EC) are well known. Cancer distress has also been associated with worse clinical outcomes. We characterized the association between race/ethnicity, patient distress reported on the National Comprehensive Cancer Network Distress Thermometer and Problem List (NCCN DT & PL), referral to support services, time to surgery, and acceptance of adjuvant therapy in patients with EC. METHODS: We included patients presenting at an academic gynecologic oncology practice from 1/2013–6/2020 who had not received prior EC-directed treatment. Demographics, NCCN DT scores, and treatment details were abstracted from the electronic medical record. Difference in initial DT scores by race/ethnicity and treatment type was tested using general linear modeling. The significance of interaction effects was tested using linear mixed models and logistic regression. RESULTS: 393 non-Hispanic White (NHW) and 134 non-Hispanic Black (NHB) patients were included. Median distress scores were higher in NHW patients compared to NHB patients (4 vs. 2, p 0.25). CONCLUSIONS: An observed difference in NCCN DT leads to racial disparities in referral to support services. The NCCN DT may not adequately measure distress in NHB women with EC.

BACKGROUND Patients undergoing mastectomy may not be candidates for immediate free-flap breast reconstruction because of medical comorbidities or postmastectomy radiation therapy. In this setting, flap reconstruction may be intentionally delayed or staged with tissue expander placement ("delayed-immediate" reconstruction). The optimal reconstructive choice and incidence of complications for these approaches remain unclear. METHODS The authors retrospectively identified patients who underwent delayed [n = 140 (72 percent)] or staged [n = 54 (28 percent)] abdominal free-flap breast reconstruction between 2010 and 2018 and compared the incidence of postoperative complications. RESULTS Patients undergoing staged reconstruction had a higher overall incidence of perioperative complications, including surgical-site infection (40.7 percent versus 6.5 percent; p < 0.001), wound healing complications (29.6 percent versus 12.3 percent; p = 0.004), hematoma (11.1 percent versus 0.7 percent; p < 0.001), and return to the operating room (27.8 percent versus 4.4 percent; p < 0.0001). These complications occurred predominately during the expansion stage, resulting in an 18.5 percent (n = 10) rate of tissue expander failure. Mean time from mastectomy to flap reconstruction was 476.8 days (delayed, 536.4 days; staged, 322.4 days; p < 0.001). At the time of flap reconstruction, there was no significant difference in the incidence of complications between the staged cohort versus the delayed cohort, including microsurgical complications (1.9 percent versus 4.3 percent; p = 0.415), total flap loss (0 percent versus 2.1 percent; p = 0.278), or fat necrosis (5.6 percent versus 5.0 percent; p = 0.875). CONCLUSIONS The aesthetic and psychosocial benefits of staged free-flap breast reconstruction should be balanced with the increased risk of perioperative complications as compared to a delayed approach. Complications related to definitive flap reconstruction do not appear to be affected by the approach taken at the time of mastectomy. . CLINICAL QUESTION/LEVEL OF EVIDENCE Therapeutic, III.

Simple Summary Uterine cancer is the most common gynecologic cancer. The treatment for women with a newly diagnosed uterine cancer is surgery to remove the uterus, fallopian tubes, ovaries, and lymph nodes. For women who desire future pregnancy or are not healthy enough to undergo surgery with hysterectomy, treatment with hormonal therapy, using the levonorgestrel intrauterine device (IUD), is an option. Response rates to this type of therapy are promising and range between 50% and 88%. This project explores a molecular classification scheme and applies it to women with uterine cancer and pre-cancer who opt for treatment with an IUD. Evaluating the genetic alterations underlying tumor development can identify patients who would be more or less likely to respond to treatment with IUDs. Additionally, this knowledge can help physicians counsel women with uterine cancer who may be interested in non-surgical options about her odds of having her cancer respond to a hormonal treatment. Abstract Background: The aim of this study was to evaluate whether molecular classification prognosticates treatment response in women with endometrial cancers and endometrial intraepithelial neoplasia (EIN) treated with levonorgestrel intrauterine system (LNG-IUS). Methods: Patients treated with LNG-IUS for endometrial cancer or EIN from 2013 to 2018 were evaluated. Using immunohistochemistry and single gene sequencing of POLE, patients were classified into four groups as per the Proactive Molecular Risk Classifier for Endometrial cancer (ProMisE): POLE-mutated, mismatch repair-deficient (MMRd), p53 wild type (p53wt), and p53-abnormal (p53abn). Groups were assessed relative to the primary outcome of progression or receipt of definitive treatment. Results: Fifty-eight subjects with endometrioid endometrial cancer or EIN treated with LNG-IUS were included. Of these, 22 subjects (37.9%) had endometrial cancer and 36 subjects (62.1%) had EIN. Per the ProMisE algorithm, 44 patients (75.9%) were classified as p53wt, 6 (10.3%) as MMRd, 4 (6.9%) as p53abn, and 4 (6.9%) as POLE-mutated. Of the 58 patients, 11 (19.0%) progressed or opted for definitive therapy. Median time to progression or definitive therapy was 7.5 months, with p53abn tumors having the shortest time to progression or definitive therapy. Conclusions: Molecular classification of endometrial cancer and EIN prior to management with LNG-IUS is feasible and may predict patients at risk of progression.

Introduction Identification of geriatric syndromes is important for determining functional age and optimizing care for people with cancer. Based on administration of a geriatric screening tool, we aimed to describe needed resources for geriatric syndromes, including lack of social support, depressed mood, deficits in instrumental and activities of daily living (IADL/ADL), falls, nutritional issues, polypharmacy, ability to pay for medications, and memory deficits, in a population of patients with breast cancer. Methods Consecutive medical oncology patients with breast cancer age 65 years and older, seen at a tertiary care center, completed a screening tool, adapted from Overcash 2006, consisting of a nurse-administered memory assessment and a one-page, self-administered questionnaire. Responses identified geriatric syndromes. Demographics and clinical information were retrospectively gathered. Frequencies and means were used to describe data. Results From January 2012 through July 2014, patients (n = 429) completed the screening tool as part of routine care. Study group had mean age 76 years (range 65–89), mean time since diagnosis 6.5 years, 91% non-metastatic disease, mean Charlson Comorbidity score 1.8 (range 0–10). Treatment included partial mastectomy (49%), adjuvant radiation (43%), chemotherapy (25%), and endocrine therapy (61%). The screening tool identified need for social support (8%); depression (31%); mobility issues (20%); falls (28%); nutritional needs (33%); polypharmacy (83%); and memory deficit (19%). Conclusion This screening tool identified geriatric syndromes requiring attention in many patients with breast cancer presenting for medical oncology appointments. In oncology practice, need for referral networks to address geriatric syndromes should be assessed.

Bevacizumab provides benefit in epithelial ovarian cancer (EOC), yet resistance to bevacizumab often occurs. We determined if nintedanib, a tyrosine kinase inhibitor of VEGF, FGF, and PDGF receptors has antitumor activity in bevacizumab-resistant recurrent EOC, tubal, and peritoneal cancer.This phase II study evaluated nintedanib 200 mg/day until disease progression or unacceptable toxicity. The primary objective was 6-month progression free survival (PFS6m). Secondary objectives were response rate and toxicity. Simon two-stage optimal design was used. Baseline angiogenic plasma biomarkers were measured.27 patients were enrolled evaluable for PFS; 26 were evaluable for PFS6m. The median age was 65 years (range 44-73); 89.9% had high-grade serous EOC; 70% received at least2 prior chemotherapies; and 81% (22/27) had chemoresistant disease. With median follow up of 15.6 months (range 2-38) the PFS6m rate was 11.5% (3/26). Three participants had long duration of disease control (8-16 months). Median PFS and overall survival were 1.8 and 16 months, respectively. Response rate was 7.4% (2/27 PR). Thirty-seven percent (10/27) had stable disease, while 56% (15/27) had progressive disease. Adverse events included Grade 3 liver enzyme elevation (15%), Grade 3 diarrhea (7%), Grade 2 fatigue (7%), and Grade 2 nausea/vomiting (15%). PD patients exhibited higher levels of CD73, IL6, and VEGFD (p0.05) compared to PR/SD patients. IL6 was associated with worse PFS (p = 0.03).Single-agent nintedanib has minimal activity in an unselected bevacizumab-resistant EOC population. Nintedanib was tolerable and toxicities were manageable. Plasma CD73, IL6, and VEGFD were identified as prognostic markers for progressive disease, and IL6 was associated with worse PFS confirming similar observations made in patients treated with other anti-angiogenic agents.

Purpose: Immune-based therapy for metastatic breast cancer has had limited success, particularly in molecular subtypes with low somatic mutations rates. Strategies to augment T-cell infiltration of tumors include vaccines targeting established oncogenic drivers such as the genomic amplification of HER2. We constructed a vaccine based on a novel alphaviral vector encoding a portion of HER2 (VRP-HER2). Patients and Methods: In preclinical studies, mice were immunized with VRP-HER2 before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and antitumor function were evaluated. We tested VRP-HER2 in a phase I clinical trial where subjects with advanced HER2-overexpressing malignancies in cohort 1 received VRP-HER2 every 2 weeks for a total of 3 doses. In cohort 2, subjects received the same schedule concurrently with a HER2-targeted therapy. Results: Vaccination in preclinical models with VRP-HER2 induced HER2-specific T cells and antibodies while inhibiting tumor growth. VRP-HER2 was well tolerated in patients and vaccination induced HER2-specific T cells and antibodies. Although a phase I study, there was 1 partial response and 2 patients with continued stable disease. Median OS was 50.2 months in cohort 1 (n = 4) and 32.7 months in cohort 2 (n = 18). Perforin expression by memory CD8 T cells post-vaccination significantly correlated with improved PFS. Conclusions: VRP-HER2 increased HER2-specific memory CD8 T cells and had antitumor effects in preclinical and clinical studies. The expansion of HER2-specific memory CD8 T cells in vaccinated patients was significantly correlated with increased PFS. Subsequent studies will seek to enhance T-cell activity by combining with anti-PD-1.

Objective The primary aim of this study was to pilot the use of an objective measurement technique to prospectively evaluate the incidence of lower extremity lymphedema (LEL) after minimally invasive staging surgery for endometrial cancer. Secondary objectives included observation of changes in lower extremity function and quality of life in this patient population. Methods A prospective evaluation of LEL was performed in 97 women who underwent minimally invasive staging surgery for endometrial cancer using comparative circumferential volume measurements. Postoperative changes in lower extremity function and global quality of life were also assessed using patient-reported outcome measures. Results Ninety-seven patients were included for lymphedema analysis. The rate of LEL was 25% at 4–6 weeks, 19% at 6–9 months, and 27% at 12–18 months postoperatively. The presence of LEL was associated with a significant worsening from baseline Lower Extremity Functional Scale (LEFS) scores at 4–6 weeks (−27.0% vs −3.7%, p = 0.02) and 6–9 months (−13.0% vs 0%, p = 0.01). LEL was not associated with a change in patient-reported global quality of life. Conclusions Up to one in four women experience lymphedema following surgical staging for endometrial cancer, and its presence is associated with diminished lower extremity function. Larger, prospective trials using the objective methodology piloted in this study should better clarify risk factors and long-term outcomes of this morbidity.

Background Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37 298 (93%) of 40 070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28·0% vs 31·4%; RR 0·86, 95% CI 0·82–0·89; p Interpretation Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes.

Background Granulosa cell tumors (GCT) variably express estrogen receptors (ER) and progesterone receptors (PR). The goal of this study is to evaluate the relationship between ER and PR expression patterns and clinical outcomes in women with GCT. Methods A multicenter, retrospective analysis was performed of all cases of GCT diagnosed between 1989 and 2012. Immunohistochemical staining for ER and PR was performed on formalin-fixed paraffin embedded (FFPE) tumor tissue and interpreted using a semiquantitative scoring system that incorporated tumor cell staining proportion and intensity. Demographics, disease status, and survival information were collected. Associations between ER and PR staining scores and recurrence-free and overall survival were assessed using univariate Cox proportional hazards models. Results FFPE tumor blocks were available for 149/186 GCT patients. The majority of the women had clinical stage I disease (76%). ER and PR expression was present in 52% and 98% of subjects, respectively. The median composite scores of ER and PR staining were 1 (range 0–8) and 9 (range 0–15), respectively. In univariate analysis, PR composite score >9 was strongly associated with decreased recurrence-free survival (HR = 2.9, 95% CI = 1.5–5.5) and decreased overall survival (HR = 3.7, CI 1.3–10.2). ER composite score was not a significant predictor of recurrence-free survival or overall survival (p = 0.7, HR = 1.1, 95% CI 0.6–2.0 and p = 0.06, HR = 1.1, 95% CI 0.4–2.9, respectively). Conclusions Our results reveal that high PR composite score (≥9) was associated with both decreased recurrence-free and overall survival in patients with GCT while ER expression was not associated with survival outcomes.

To evaluate surgical complexity scores (SCS) and minimally invasive surgery (MIS) at interval debulking surgery (IDS) in advanced epithelial ovarian cancer (EOC) patients receiving neoadjuvant chemotherapy (NACT).A multi-institutional study of NACT with IDS for advanced EOC was conducted. Demographic data were abstracted and SCS assigned based on IDS findings. Disease-specific overall survival (DSS) was defined as the time from completion of adjuvant chemotherapy to death due to disease. Cox proportional hazards regression models were used for univariate and multivariate survival analyses.282 patients were identified; 80.5% had high-grade serous histology and 54.6% were75 (median 63.9; range 34.1-84.8). Approximately 84% were optimally cytoreduced (61% R0; 23%1 cm). In multivariate analyses, age 75+ (p ≤ 0.001), residual disease (1 cm; p = 0.03), and SCS ≥ 3 (p = 0.04) were significantly predictive of worse DSS when morbidity and ASA score were also in the model. When optimally debulked was defined as R0, only age 75+ (0.001) was significantly associated with decreased DSS. In the R0 cohort, SCS did not significantly predict DSS. However, subset analysis defining optimal ≤1 cm, revealed higher SCS was associated with a 1.6-fold increased risk of death (p = 0.02). Fifty-one patients underwent laparoscopic IDS. Twenty-four (47%) were converted to laparotomy to achieve optimal debulking in 21 patients (87.5%); while 25 had laparoscopic optimal cytoreduction (19/25 [76%] R0).In women with advanced EOC treated with NACT, older age, SCS ≥ 3, and residual disease1 cm at IDS were predictors of worse survival. MIS appears safe and feasible with acceptable optimal cytoreduction rates.

Background: Immune-based therapy for metastatic breast cancer has had limited success. Strategies to augment adaptive immunity include vaccines targeting genomic amplifications like Human Epidermal Growth Factor Type 2 (HER2), an established driver of malignancy. Using a novel alphaviral vector, we constructed a vaccine encoding a portion of HER2 (VRP-HER2). Methods: In preclinical studies, mice were immunized before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and anti-tumor function were assessed. We then translated this vaccine into a phase I clinical trial in which subjects with advanced HER2-overexpressing breast cancers received VRP-HER2 every 2 weeks for a total of three doses (cohort 1). In cohort 2, subjects received the same dose of VRP-HER2 along with a standard HER2 targeted therapy. Results: VRP-HER2 induced HER2-specific T cell and antibody responses while controlling tumor growth in murine models. Vaccination with VRP-HER2 was well tolerated in both patient cohorts. PFS was modest, while median OS was 50.2 months in cohort 1 and 32.7 months in cohort 2. In cohort 2, there is one partial response and two patients with continued stable disease. Vaccine induced anti-HER2 antibodies and T cells were identified. Increased perforin expression by memory CD8 T cells post vaccination significantly correlated with improved PFS. Conclusions: VRP-HER2 led to an increase in perforin expressing HER2-specific memory CD8 T cells in preclinical and clinical studies, and had profound antitumor effects in murine models. The generation of HER2-specific memory CD8 T cells was significantly correlated with increased PFS in patients. Subsequent studies will seek to enhance T cell activity by combination with anti-PD-1/PD-L1 antibodies. Citation Format: Crosby EJ, Gwin WR, Chang S, Maecker HT, Lubkov V, Snyder JC, Broadwater G, Hyslop T, Osada T, Hobeika AC, Hartman ZC, Morse MA, Lyerly HK. CD8 T cells induced by novel alphaviral vector predict improved progression free survival in advanced HER2+ breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-16.