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Immunotherapy for the treatment of programmed death-ligand 1 (PD-L1) positive locally advanced or metastatic triple negative breast cancer may benefit patients with metaplastic breast cancer (MpBC). Previous study of PD-L1 in MpBC scored tumor cells (TCs), different from Food and Drug Administration-approved scoring methods. We sought to define PD-L1 expression in MpBCs and to evaluate concordance of 3 PD-L1 assays. Primary, treatment naive MpBC treated at our Center from 1998 to 2019 were identified. PD-L1 expression was assessed using SP142, E1L3n, and 73-10. We evaluated PD-L1 expression on tumor infiltrating immune cells (IC) and also in TCs. For each assay, we scored PD-L1 expression using ≥1% IC expression according to the IMpassion130 trial criteria and using combined positive score (CPS) ≥10 according to the KEYNOTE-355 trial cutoff. A total of 42 MpBCs were identified. Most MpBC had PD-L1 positivity in ≥1% IC with all 3 assays (95%, 95%, 86%) in contrast to a maximum 71% with a CPS ≥10. PD-L1 IC expression was comparable between the SP142 and 73-10 assays and was lowest with E1L3n. PD-L1 TC expression was lowest using SP142. The overall concordance for IC scoring was 88% while 62% had concordant CPS. For each assay, the results of the 2 scoring algorithms were not interchangeable. The SP142 assay showed distinct expression patterns between IC (granular, dot-like) and TC (membranous) while 73-10 and E1L3n showed membranous and/or cytoplasmic expression in both IC and TC. Most MpBC in our cohort were positive for PD-L1 indicating eligibility for anti-PD-L1/programmed death-1 immunotherapy.

Purpose: Activating mutations in PIK3CA promote resistance to HER2-targeted therapy in breast cancer; however, inhibition of PI3K alone leads to escape via feedback upregulation of HER3. Combined inhibition of HER2, HER3, and PI3K overcomes this mechanism preclinically. Patients and Methods: This phase I study investigated the MTD of alpelisib given in combination with trastuzumab and LJM716 (a HER3-targeted antibody) in patients with PIK3CA-mutant HER2-positive (HER2+) metastatic breast cancer (MBC) using the continual reassessment method. Secondary analyses included efficacy and exploratory correlative studies. Results: Ten patients were treated initially with daily alpelisib (arm A). Grade ≥3 adverse events seen in ≥2 patients included diarrhea (n = 6), hypokalemia (n = 3), abnormal liver enzymes (n = 3), hyperglycemia (n = 2), mucositis (n = 2), and elevated lipase (n = 2). The MTD of alpelisib in arm A was 250 mg daily. This prompted the opening of arm B in which 11 patients received intermittently dosed alpelisib. Grade ≥3 adverse events seen in ≥2 patients included diarrhea (n = 5), hypokalemia (n = 3), and hypomagnesemia (n = 2). The MTD of alpelisib in arm B was 350 mg given 4 days on, 3 days off. Among 17 patients assessed, 1 had a partial response, 14 had stable disease, and 2 had disease progression at best response. Five patients had stable disease for >30 weeks. mRNA profiling of pre- and on-treatment tissue demonstrated PIK3CA target engagement by alpelisib via induction of downstream signaling and feedback pathways. Conclusions: Combination treatment with alpelisib, trastuzumab, and LJM716 was limited by gastrointestinal toxicity. Further efforts are warranted to target the PI3K pathway in HER2+ MBC.

Background: Metastatic renal cell carcinoma (mRCC) management guidelines recommend brain imaging if clinically indicated and the rate of occult central nervous system (CNS) metastasis is not well-defined. Early detection could have major therapeutic implications, because timely interventions may limit morbidity and mortality. Patients and Methods: A retrospective review was performed to characterize patients with mRCC incidentally diagnosed with asymptomatic brain metastases during screening for clinical trial participation at Gustave Roussy and Memorial Sloan Kettering Cancer Center. Descriptive statistics and time-to-event methods were used to evaluate the cohort. Results: Across 68 clinical trials conducted between 2001 and 2019 with a median 14.1-month follow-up, 72 of 1,689 patients (4.3%) with mRCC harbored occult brain metastases. The International Metastatic RCC Database Consortium (IMDC) risk status was favorable (26%), intermediate (61%), and poor (13%), and 86% of patients had ≥2 extracranial sites of disease, including lung metastases in 92% of patients. CNS involvement was multifocal in 38.5% of patients, and the largest brain metastasis was >1 cm in diameter in 40% of the cohort. Localized brain-directed therapy was pursued in 93% of patients, predominantly radiotherapy. Median overall survival was 10.3 months (range, 7.0–17.9 months), and the 1-year overall survival probability was 48% (95% CI, 37%–62%). IMDC risk and number or size of lesions did not correlate with survival (log-rank, P=.3, P=.25, and P=.067, respectively). Conclusions: This large multi-institutional mRCC cohort study identified occult brain metastasis in a notable proportion of patients (4.3%) and highlights that the risk of asymptomatic CNS involvement extends to those with favorable risk features per IMDC risk assessment. These data provide rationale for brain screening in patients with advanced RCC.

PURPOSE: Racial/ethnic minorities experience greater job loss than whites during periods of economic downturn and after a cancer diagnosis. Therefore, race/ethnicity-matched controls are needed to distinguish the impact of illness on job loss from secular trends. METHODS: Surveys were administered during and 4 months post-completion of breast cancer treatment. Patients were pre-diagnosis employed women aged 18–64, undergoing treatment for stage I-III breast cancer, who spoke English, Chinese, Korean, or Spanish. Each patient was asked to: 1) nominate peers who were surveyed in a corresponding timeframe (active controls), 2) report a friend’s work status at baseline and follow-up (passive controls). Both types of controls were healthy, employed at baseline, and shared the nominating patient’s race/ethnicity, language, and age. The primary outcome was number of evaluable patient-control pairs by type of control. A patient-control pair was evaluable if work status at follow-up was reported for both individuals. RESULTS: Of 180 patients, 25% had evaluable active controls (45 patient-control pairs); 84% had evaluable passive controls (151 patient-control pairs). Although patients with controls differed from those without controls under each strategy, there was no difference in the percentage of controls who were working at follow-up (96% of active controls; 91% of passive controls). However, only 65% of patients were working at follow-up. CONCLUSIONS: The majority of patients had evaluable passive controls. There was no significant difference in outcome between controls ascertained through either method. IMPLICATIONS FOR CANCER SURVIVORS: Passive controls are a low-cost, higher-yield option to control for secular trends in racially/ethnically diverse samples.

Background We previously reported on a phase 2 study of everolimus plus bevacizumab across various nonclear cell renal cell carcinoma (nccRCC) histologies and observed encouraging activity among patients with papillary RCC (pRCC) and unclassified RCC (uRCC) with a major papillary component. We subsequently expanded the study to enroll additional patients with pRCC variants. Methods Everolimus plus bevacizumab was administered at standard doses until disease progression or intolerance to therapy. The primary endpoint was the 6-month progression-free survival (PFS) rate; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Correlative analyses included next-generation sequencing (NGS) from tumor and germline across >341 genes of interest. Results In addition to 19 patients with pRCC variants in the original cohort, 20 patients with similar features were enrolled on the expansion cohort (uRCC with papillary features [n = 24], pRCC [n = 14], and translocation-associated RCC with papillary features [n = 1]). Among 37 evaluable patients, the 6-month PFS rate was 78%, the median PFS was 13.7 months (95% CI, 10.8-16.4 months), and the ORR was 35%. With a median follow-up of 17.6 months, the median OS was 33.9 months (95% CI, 23.3-71.9). Tolerance was consistent with prior reports for everolimus plus bevacizumab. NGS results (n = 33) identified responses in patients with a wide spectrum of genomic alterations, including ARID1A, FH, and MET mutations. Conclusion The expansion cohort results confirm robust activity of everolimus plus bevacizumab in metastatic pRCC variants, supporting this regimen as a standard option for this patient population.

BACKGROUND: A subset of TNBC expresses a luminal signature and demonstrates AR-dependence. Enzalutamide (ENZA), an AR-antagonist, has activity with metastatic AR+ TNBC, with a clinical benefit rate of 33% (Traina et al, JCO 2018). We recently demonstrated that one year (y) of adjuvant ENZA is feasible in early stage, AR+ TNBC, with no new safety signals observed (Traina ASCO 2019). Fatigue was the most common, treatment (tx)-related, adverse event of any grade according to investigator assessment (24%). Here we report per-protocol planned secondary analyses of PROs during one year of ENZA including quality of life (QoL), fatigue, and self-reported physical activity (NCT02750358). METHODS: Eligible patients have Stage I-III, ER/PR RESULTS: Between 5/2016 and 6/2018, 50 patients were enrolled. As of 6/27/19, 34 patients completed 1y of ENZA; 15 patients are off tx: recurrence (3), toxicity (5), nonadherence (4), and consent withdrawal (3). Patients evaluable for PRO (N): baseline (50), 12 weeks (43) and 52 weeks (34). Median scores on FACT-B and fatigue scales remained stable over the course of adjuvant ENZA in the 1st year of therapy (Table). Self-reported exercise increased during this period. Table. Median scores (range) for PROs during 1 year of adjuvant ENZATime PointBaselineWeek 12Week 52FACT-G88.0 (53.5-105.0)82.0 (36.4-105.0)89.5 (58.0-105.0)Breast Cancer Subscale28.5 (15.6-39.0)29.0 (9.0-40.0)29.0 (19.0-40.0)Total118.0 (77.0-141.0)111.0 (45.4-145.0)121.0 (83.0-145.0)FACT-B trial outcome index73.0 (43.0-92.0)73.0 (25.7-96.0)76.9 (51.0-96.0)FACIT43.0 (17.0-52.0)39.0 (10.0-52.0)43.0 (11.0-52.0)Total Exercise (min/week)120 (0-1260)152 (0-3120)180 (0-2580) CONCLUSIONS: Patient reported outcomes of health related QOL remain stable when ENZA is administered for 1 year in the adjuvant setting. Self-reported time spent engaged in physical exercise increased numerically during 1y of therapy. During presentation, additional analyses will be reported including QOL at additional time points, relationship of FACT-B score with FACIT fatigue score and exercise, and QOL changes in relation to relative dose intensity of ENZA, toxicity and off study reason. Citation Format: Tiffany A Traina, Lee W Jones, Victoria Blinder, Jessica Scott, Leigh Ann Boyle, Artavazd Arumov, Tina Alano, Sujata Patil, Patricia DeFusco, Nicholas Lamparella, Mark Robson, Ayca Gucalp. Patient-reported outcomes (PROs) during one year of adjuvant enzalutamide for the treatment of early stage androgen receptor positive (AR+) triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-09.

Background: Trastuzumab and pertuzumab (HP) with standard chemotherapy is approved for use in the neoadjuvant setting. We performed a retrospective analysis of patients (pts) treated with dose-dense doxorubicin and cyclophosphamide (AC) → paclitaxel, trastuzumab, pertuzumab (THP) in the neoadjuvant setting followed by adjuvant anti-HER2 therapy. Here we report the invasive disease-free survival (iDFS) rate, defined as the time from surgery to the first documented event of ipsilateral invasive local recurrence, ipsilateral locoregional invasive recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause Methods: We abstracted medical records of patients who were treated with pertuzumab-based therapy in the neoadjuvant setting from September 1, 2013 to March 1, 2016. Charts were analyzed for pt demographics, stage of breast cancer, surgical data, pathologic complete response (pCR)(ypT0/is ypN0) and information on systemic therapy. Results: Charts from 236 pts were reviewed. One patient was excluded as she developed metastatic disease during NAC and did not have surgery. Median follow up was 3.8 years. Median age was 49 years (range 26-79 years). Of 235 pts, 215 (91%) had operable breast cancer (T1-3, N0-1, M0) of which 10 (4%) had clinical stage I disease (T1N0)]; 225 (96%) had stage II/III (T2-4d N0-3 M0); 18 (8%) had locally advanced disease (T2-3, N2-3, M0 or T4a-c, any N, M0), and 9 (3.8%) had inflammatory breast cancer (T4d, any N, M0). 153 (65%) and 82 (35%) had hormone receptor (HR)-positive and negative diseases, respectively. All patients had HER2-positive breast cancer defined as immunohistochemistry (IHC) 3+ and/or fluorescent in-situ hybridization (FISH) of ≥ 2.0. Median number of preoperative HP cycles was 5.5 (range 1-9). 121pts (51%) underwent mastectomy, 113 pts (48%) underwent lumpectomy, 1 patient underwent axillary dissection only. Out of 235 evaluable pts, 146 (62%) had pCR; 80/153 (52%) with HR-positive and 65/82 (78%) with HR-negative diseases had pCR, respectively. After a median follow-up of 3.8 years, there were 21 iDFS events and 10 OS events (n=9-Breast cancer, n=1-Acute Myeloid Leukemia). The 3-year iDFS was 91% (95% C.I. 88-95%) for all, 94% (95% C.I. 90-98%) for pts w/ pCR, and 87% (95% C.I. 80-95%) for pts w/ non pCR (p-value=0.051). The 3-year OS was 96% (95% C.I. 94-99%) for all, 98% (95% C.I. 95-100%) for pts w/ pCR, and 93% (95% C.I. 88-99%) for pts w/ non pCR (p-value=0.12) Conclusions: At our single center experience, the iDFS and OS for patients who received neoadjuvant ddACTHP followed by adjuvant anti-HER2 treatment was 91% and 96%, respectively. Patients with pCR had better outcomes than those with residual disease. Citation Format: Jasmeet C Singh, Sujata Patil, Larry Norton, Mark Robson, Chau Dang. Disease free survival rate with dose dense Doxorubicin and Cyclophosphamide followed by weekly Paclitaxel with Trastuzumab and Pertuzumab (ddACTHP) in patients with HER2-positive early stage breast cancer: A single institution experience [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-10.

Summary Background Obesity is associated with an increased risk of developing clear cell renal cell carcinoma (RCC) but, paradoxically, obesity is also associated with improved oncological outcomes in this cancer. Because the biological mechanisms underlying this paradoxical association are poorly understood, we aimed to identify transcriptomic differences in primary tumour and peritumoral adipose tissue between obese patients and those at a normal weight. Methods In this cohort study, we assessed data from five independent clinical cohorts of patients with clear cell RCC aged 18 years and older. Overweight patients were excluded from each cohort for our analysis. We assessed patients from the COMPARZ phase 3 clinical trial, a cohort from the Cancer Genome Atlas (TCGA), and a Memorial Sloan Kettering (MSK) observational immunotherapy cohort for their inclusion into our study. We assessed overall survival in obese patients (those with a body-mass index [BMI] ≥30 kg/m2) and in patients with a normal weight (BMI 18·5–24·9 kg/m2, as per WHO's BMI categories), defined as the time from treatment initiation (in the COMPARZ and MSK immunotherapy cohorts) or surgery (in the TCGA cohort) to the date of any-cause death or of censoring on the day of the last follow-up. We also evaluated and validated transcriptomic differences in the primary tumours of obese patients compared with those of a normal weight. We compared gene-expression differences in peritumoral adipose tissue and tumour tissue in an additional, prospectively collected cohort of patients with non-metastatic clear cell RCC (the MSK peritumoral adipose tissue cohort). We analysed differences in gene expression between obese patients and those at a normal weight in the COMPARZ, TCGA, and peritumoral adipose tissue cohorts. We also assessed the tumour immune microenvironment in a prospective cohort of patients who had nephrectomy for localised RCC at MSK. Findings Of the 453 patients in the COMPARZ trial, 375 (83%) patients had available microarray data, pretreatment BMI measurements, and overall survival data for analyses, and we excluded 119 (26%) overweight patients, leaving a final cohort of 256 (68%) patients from this study for our analyses. From 332 patients in the TCGA cohort, we evaluated clinical and demographic data from 152 (46%) patients with advanced (ie, stages III and IV) clear cell RCC treated by nephrectomy; after exclusion of 59 (39%) overweight patients, our final cohort consisted of 93 (61%) patients. After exclusion of 74 (36%) overweight patients from the initial MSK immunotherapy study population of 203 participants, our final cohort for overall survival analysis comprised 129 (64%) participants. We found that overall survival was longer in obese patients than in those with normal weight in the TCGA cohort, after adjustment for stage or grade (adjusted HR 0·41, 95% CI 0·22–0·75), and in the COMPARZ clinical trial after adjustment for International Metastatic RCC Database (IMDC) risk score (0·68, 0·48–0·96). In the MSK immunotherapy cohort, the inverse association of BMI with mortality (HR 0·54, 95% CI 0·31–0·95) was not significant after adjustment for IMDC risk score (adjusted HR 0·72, 95% CI 0·40–1·30). Tumours of obese patients showed higher angiogenic scores on gene-set enrichment analysis-derived hallmark gene set angiogenesis signatures than did those of patients at a normal weight, but the degree of immune cell infiltration did not differ by BMI. We found increased peritumoral adipose tissue inflammation in obese patients relative to those at a normal weight, especially in peritumoral fat near the tumour. Interpretation We found aspects of the tumour microenvironment that vary by BMI in the tumour and peritumoral adipose tissue, which might contribute to the apparent survival advantage in obese patients with clear cell RCC compared with patients at a normal weight. The complex interplay between the clear cell RCC tumour and peritumoral adipose tissue microenvironment might have clinical relevance and warrants further investigation. Funding Ruth L Kirschstein Research Service Award, American Society of Clinical Oncology Young Investigator Award, MSK's Ludwig Center, Weiss Family Kidney Research Fund, Novartis, The Sidney Kimmel Center for Prostate and Urologic Cancers, and the National Institutes of Health (National Cancer Institute) Cancer Center Support Grant.

Background Despite guidelines recommending genetic counseling for patients with early-onset renal cell carcinoma (RCC), studies interrogating the spectrum of germline mutations and clinical associations in patients with early-onset RCC are lacking. Objective To define the germline genetic spectrum and clinical associations for patients with early-onset RCC diagnosed at age ≤46 yr who underwent genetic testing. Design, setting, and participants We retrospectively identified patients with early-onset RCC who underwent germline testing at our institution from February 2003 to June 2020. Outcome measurement and statistical analysis The frequency and spectrum of pathogenic/likely pathogenic (P/LP) variants were determined. Clinical characteristics associated with mutation status were analyzed using two-sample comparison (Fisher’s exact or χ2 test). Results and limitations Of 232 patients with early-onset RCC, 50% had non–clear-cell histology, including unclassified RCC (12.1%), chromophobe RCC (9.7%), FH-deficient RCC (7.0%), papillary RCC (6.6%), and translocation-associated RCC (4.3%). Overall, 43.5% had metastatic disease. Germline P/LP variants were identified in 41 patients (17.7%), of which 21 (9.1%) were in an RCC-associated gene and 20 (8.6%) in a non–RCC-associated gene, including 17 (7.3%) in DNA damage repair genes such as BRCA1/2, ATM, and CHEK2. Factors associated with RCC P/LP variants include bilateral/multifocal renal tumors, non–clear-cell histology, and additional extrarenal primary malignancies. In patients with only a solitary clear-cell RCC, the prevalence of P/LP variants in RCC-associated and non–RCC-associated genes was 0% and 9.9%, respectively. Conclusions Patients with early-onset RCC had high frequencies of germline P/LP variants in genes associated with both hereditary RCC and other cancer predispositions. Germline RCC panel testing has the highest yield when patients have clinical phenotypes suggestive of underlying RCC gene mutations. Patients with early-onset RCC should undergo comprehensive assessment of personal and family history to guide appropriate genetic testing. Patient summary In this study of 232 patients with early-onset kidney cancer who underwent genetic testing, we found a high prevalence of mutations in genes that increase the risk of cancer in both kidneys and other organs for patients and their at-risk family members. Our study suggests that patients with early-onset kidney cancer should undergo comprehensive genetic risk assessment.

Background: The persistent effects on skin hydration and elasticity resulting from cytotoxic and endocrine agents used in early stages of breast cancer are poorly understood. The objective of this preliminary analysis of the CHANCE study is to describe the pattern of persistent biomechanical skin changes in non-metastatic breast cancer patients treated with cytotoxic chemotherapies and/or endocrine therapies. Methods: This is an ongoing single-center, prospective, longitudinal cohort study of non-metastatic breast cancer patients treated with cytotoxic chemotherapies and/or endocrine therapies. Objective skin hydration and elasticity measurements of the forearm were measured using Tewameter® (TM 300; Courage & Khazaka) and Cutometer® (MPA 580; Courage & Khazaka) devices under a controlled ambient environment at baseline and 6 months after chemotherapy completion, or one year after initiation of endocrine therapy. Results: A total of 107 patients were assessed at baseline and follow-up for transepidermal water loss (TEWL) (median age 53, range 26-82) and 106 patients for skin elasticity (median age 53.5, range 26-82). Fifty-three healthy controls were evaluated at baseline with median age 47 (range, 22-73). The mean TEWL at baseline and follow-up among patients were 6.922 g/h/m2 and 8.521 g/h/m2, respectively (p Conclusions: An increase in TEWL was observed in patients receiving cytotoxic and endocrine therapies, suggesting a deterioration of the protective skin barrier possibly attributed to these therapies. No significant changes in skin firmness or elasticity were found in this preliminary analysis. Further studies are needed to elucidate the pathophysiologic mechanisms involved in persistent skin changes after systemic breast cancer therapies. Objective skin hydration and elasticity in patients receiving breast cancer therapy Control (n=53)Baseline (n=107)Follow-Up (n=107)p-value*TEWL (g/h/m2)9.4626.9228.521 Citation Format: Lacouture ME, Phillips GS, Freites-Martinez A, Patil S, Samuels A, Shapiro J, Kukoyi O, Goldfarb S. The CHANCE study: Mechanical skin changes among women with non-metastatic breast cancer receiving chemotherapy and endocrine therapy [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 P4-16-07.

BACKGROUND: Pathologic complete response (pCR) is associated with better prognosis and guides management for patients with advanced rectal cancer. Response rates vary between series for unclear reasons. We examine whether the thoroughness of pathologic assessment explains differences in pCR rates. METHODS: We retrospectively reviewed pathology reports from patients with stage II/III rectal cancer who underwent chemoradiation and resection in a prospective, multicenter trial. We utilized a novel measure for the thoroughness of pathologic assessment by dividing residual tumor size by the number of cassettes evaluated (tumor size to cassette ratio, TSCR), and evaluated whether TSCR is associated with pCR. We validated our findings using a separate cohort. RESULTS: From the trial cohort, 71 of 247 (29%) patients achieved pCR. The pCR rate ranged from 0 to 45% and mean TSCR ranged 0.29 to 0.87 across 12 institutions. Within each institution, a lower TSCR was associated with pCR, demonstrating a higher degree of thoroughness used for tumors that achieved pCR. Moreover, across all samples, low TSCR was independently associated with pCR on multivariable analysis. This finding was corroborated in a separate cohort of 201 tumors evaluated by five pathologists; each pathologist had a lower mean TSCR for pCR calls compared with non-pCR calls. However, the mean TSCR for an institution was not associated with its overall pCR rate. CONCLUSIONS: Pathologists assess rectal cancers that have responded significantly to neoadjuvant therapy more thoroughly. Thoroughness does not appear to explain differences in pCR rates between institutions. Our results suggest pCR is not a sampling artifact.

Background Favorable progression-free survival (PFS) and overall survival (OS) results were previously reported on a phase II trial of patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC), treated with weekly paclitaxel in combination with trastuzumab and pertuzumab in the first- and second-line setting, with a median follow-up of 33 months. Here, we report updated PFS and OS results with more than 2 years of additional follow-up. Materials and methods In this phase II study, adult patients with HER2-positive MBC who received no or one prior therapy received intravenous paclitaxel (80 mg/m2 weekly) with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks) and pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks), administered in 21-day cycles. Primary endpoint was 6-month PFS, and secondary endpoints included median PFS and OS. Results From January 2011 to December 2013, 69 patients were enrolled: 51 (74%) and 18 (26%) were treated in first- and second-line metastatic settings, respectively. As of August 21, 2017, the median follow-up was 59 months (range, 20-75 months; 67 [97%] patients were evaluable for efficacy). The 6-month PFS was 86% (95% confidence interval [CI] 0.76-0.93). The median PFS was 24.2 months (95% CI 17-35) for the overall population; it was 25.7 months (95% CI 17.0 to not reached) and 20.1 months (95% CI 8.5-33.0) for patients with no and one prior treatment, respectively. The median OS was not reached for the overall group; it was not reached and 39.7 months (95% CI 32.9-66.7) for patients with no and one prior treatment, respectively. Treatment was well tolerated with no additional safety concerns. Conclusion With a longer follow-up of almost 5 years, combination of weekly paclitaxel, trastuzumab, and pertuzumab remains effective with a favorable median PFS and a median OS not reached. Implications for practice The combination of weekly paclitaxel, trastuzumab, and pertuzumab has been endorsed by the National Comprehensive Cancer Network as one of the first-line treatment options in patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, the long-term safety and efficacy are still unknown. Findings from this phase II study provide favorable preliminary data on the safety and efficacy of trastuzumab and pertuzumab in combination with weekly paclitaxel at 5-year follow-up, and it remains an effective first-line treatment option for patients with HER2-positive MBC.

Background Locally advanced and metastatic breast cancer remains a challenge to treat. With emerging study results, it is important to interpret the available clinical data and apply the evidence offering the most effective treatment to the right patient. Poly(ADP Ribose) Polymerase (PARP) inhibitors are a new class of drug and their role in the treatment of locally advanced and metastatic breast cancer is being established. Objectives To determine the efficacy, safety profile, and potential harms of Poly(ADP-Ribose) Polymerase (PARP) inhibitors in the treatment of patients with locally advanced or metastatic breast cancer. The primary outcome of interest was overall survival; secondary outcomes included progression-free survival, tumour response rate, quality of life, and adverse events. Search methods On 8 June 2020, we searched the Cochrane Breast Cancer Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via OvidSP, Embase via OvidSP, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) search portal and ClinicalTrials.gov. We also searched proceedings from the major oncology conferences as well as scanned reference lists from eligible publications and contacted corresponding authors of trials for further information, where needed. Selection criteria We included randomised controlled trials on participants with locally advanced or metastatic breast cancer comparing 1) chemotherapy in combination with PARP inhibitors, compared to the same chemotherapy without PARP inhibitors or 2) treatment with PARP inhibitors, compared to treatment with other chemotherapy. We included studies that reported on our primary outcome of overall survival and secondary outcomes including progression-free survival, tumour response rate, quality of life, and adverse events. Data collection and analysis We used standard methodological procedures defined by Cochrane. Summary statistics for the endpoints used hazard ratios (HR) with 95% confidence intervals (CI) for overall survival and progression-free survival, and odds ratios (OR) for response rate (RR) and toxicity. Main results We identified 49 articles for qualitative synthesis, describing five randomised controlled trials that were included in the quantitative synthesis (meta-analysis). A sixth trial was assessed as eligible but had ended prematurely and no data were available for inclusion in our meta-analysis. Risk of bias was predominately low to unclear across all studies except in regards to performance bias (3/5 high risk) and detection bias for the outcomes of quality of life (2/2 high risk) and reporting of adverse events (3/5 high risk). High-certainty evidence shows there may be a small advantage in overall survival (HR 0.87, 95% CI 0.76 to 1.00; 4 studies; 1435 patients). High-certainty evidence shows that PARP inhibitors offer an improvement in PFS in locally advanced/metastatic HER2-negative, BRCA germline mutated breast cancer patients (HR 0.63, 95% CI 0.56 to 0.71; 5 studies; 1474 patients). There was no statistical heterogeneity for these outcomes. Subgroup analyses for PFS outcomes based on trial level data were performed for triple-negative breast cancer, hormone-positive and/or HER2-positive breast cancer, BRCA1 and BRCA2 germline mutations, and patients who had received prior chemotherapy for advanced breast cancer or not. The subgroup analyses showed a persistent PFS benefit regardless of the subgroup chosen. Pooled analysis shows PARP inhibitors likely result in a moderate improvement in tumour response rate compared to other treatment arms (66.9% vs 48.9%; RR 1.39, 95% CI 1.24 to 1.54; 5 studies; 1185 participants; moderate-certainty evidence). The most common adverse events reported across all five studies included neutropenia, anaemia and fatigue. Grade 3 or higher adverse events probably occur no less frequently in patients receiving PARP inhibitors (59.4% for PARP arm versus 64.5% for non-PARP arm, RR 0.98, 95% CI 0.91 to 1.04; 5 studies; 1443 participants; moderate-certainty evidence). Only two studies reported quality of life outcomes so this was not amenable to meta-analysis. However, both studies that did assess quality of life showed PARP inhibitors were superior compared to physician's choice of chemotherapy in terms of participant-reported outcomes. Authors' conclusions In people with locally advanced or metastatic HER2-negative, BRCA germline mutated breast cancer, PARP inhibitors offer an improvement in progression-free survival, and likely improve overall survival and tumour response rates. This systematic review provides evidence supporting the use of PARP inhibitors as part of the therapeutic strategy for breast cancer patients in this subgroup. The toxicity profile for PARP inhibitors is probably no worse than chemotherapy but more information is required regarding quality of life outcomes, highlighting the importance of collecting such data in future studies. Future studies should also be powered to detect clinically important differences in overall survival and could focus on the role of PARP inhibitors in other relevant breast cancer populations, including HER2-positive, BRCA-negative/homologous recombination repair-deficient and Programmed Death-Ligand 1 (PDL1) positive.

Background Systemic responses to cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) are variable and difficult to anticipate. The authors aimed to determine the association of CN with modifiable International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors and oncological outcomes. Methods Consecutive patients with mRCC referred for potential CN (2009-2019) were reviewed. The primary outcome was overall survival (OS); variables of interest included undergoing CN and the baseline number of modifiable IMDC risk factors (anemia, hypercalcemia, neutrophilia, thrombocytosis, and reduced performance status). For operative cases, the authors evaluated the effects of IMDC risk factor dynamics, measured 6 weeks and 6 months after CN, on OS and postoperative treatment disposition. Results Of 245 treatment-naive patients with mRCC referred for CN, 177 (72%) proceeded to surgery. The CN cases had fewer modifiable IMDC risk factors (P = .003), including none in 71 of 177 patients (40.1%); fewer metastases (P = .011); and higher proportions of clear cell histology (P = .012). In a multivariable analysis, surgical selection, number of IMDC risk factors, metastatic focality, and histology were associated with OS. Total risk factors changed for 53.8% and 57.2% of the patients from the preoperative period to 6 weeks and 6 months after CN, respectively. Adjusted for preoperative IMDC risk scores, an increase in IMDC risk factors at 6 weeks and 6 months was associated with adverse OS (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.13-2.19; P = .007; HR, 2.52; 95% CI, 1.74-3.65; P Conclusions IMDC risk factors are dynamic clinical variables that can improve after upfront CN in select patients, and this suggests a systemic benefit of cytoreduction, which may confer clinically meaningful prognostic implications.

Background The National Comprehensive Cancer Network recommends either three cycles of bleomycin, etoposide, and cisplatin or four cycles of etoposide and cisplatin (EPx4) as initial chemotherapy for the treatment of good-risk germ cell tumors (GCTs). To assess the response, toxicity, and survival outcomes of EPx4, we analyzed our experience. Material and Methods Response and survival outcomes, selected toxicities, and adherence to chemotherapy dose and schedule were assessed in patients with good-risk GCT who received EPx4 at Memorial Sloan Kettering Cancer Center between 1982 and 2016. The results were compared with our past results and published data. Results Between 1982 and 2016, 944 patients with GCT were treated with EPx4, 289 who were previously reported plus 655 treated between January 2000 and August 2016. A favorable response was achieved in 928 of 944 patients (98.3%). Five-year progression-free, disease-specific, and overall survival rates were 93.9%, 98.6%, and 97.9%, respectively. Median follow-up was 7.3 years (range, 2.8 months to 35.5 years). Viable, nonteratomatous malignant GCT was present in 3.5% of 432 postchemotherapy retroperitoneal lymph node dissection specimens from patients with nonseminomatous GCT. Febrile neutropenia and thromboembolic events occurred in 16.0% and 8.9%, respectively, with one treatment-related death. In the more recent 655-patient cohort, full-dose EPx4 was administered to 631 (96.3%), with deviations from planned treatment driven mainly by vascular (n = 13), hematologic (n = 11), renal (n = 7), or infectious (n = 5) events. Conclusion EPx4 is highly effective and well tolerated in patients with good-risk GCTs and remains a standard of care. Implications for Practice Four cycles of etoposide and cisplatin (EPx4) is a standard-of-care regimen for all patients with good-risk germ cell tumors with a favorable response rate and disease-specific survival of 98%. Full-dose administration of etoposide and cisplatin and complete resection of residual disease lead to optimal outcomes. EPx4 should be the recommended regimen in active smokers, patients with reduced or borderline kidney function, and patients aged 50 years or older, which are patient groups at increased risk for bleomycin pulmonary toxicity. Because of a risk of acquired severe pulmonary illness, EPx4 may also be favored for patients who vape or use e-cigarettes and during ongoing transmission of severe acute respiratory syndrome coronavirus 2.

Sorafenib has demonstrated anti-tumor efficacy and radiosensitizing activity preclinically and in breast cancer. We examined sorafenib in combination with whole brain radiotherapy (WBRT) and explored the [18F] 3′deoxy-3′-fluorothymidine (FLT)-PET as a novel brain imaging modality in breast cancer brain metastases. A phase I trial of WBRT + sorafenib was conducted using a 3 + 3 design with safety-expansion cohort. Sorafenib was given daily at the start of WBRT for 21 days. The primary endpoints were to determine a maximum tolerated dose (MTD) and to evaluate safety and toxicity. The secondary endpoint was CNS progression-free survival (CNS-PFS). MacDonald Criteria were used for response assessment with a correlative serial FLT-PET imaging study. 13 pts were evaluable for dose-limiting toxicity (DLT). DLTs were grade 4 increased lipase at 200 mg (n = 1) and grade 3 rash at 400 mg (n = 3). The MTD was 200 mg. The overall response rate was 71%. Median CNS-PFS was 12.8 months (95%CI: 6.7-NR). A total of 15 pts (10 WBRT + sorafenib and 5 WBRT) were enrolled in the FLT-PET study: baseline (n = 15), 7–10 days post WBRT (FU1, n = 14), and an additional 12 week (n = 9). A decline in average SUVmax of ≥ 25% was seen in 9/10 (90%) of WBRT + sorafenib patients and 2/4 (50%) of WBRT only patients. Concurrent WBRT and sorafenib appear safe at 200 mg daily dose with clinical activity. CNS response was favorable compared to historical controls. This combination should be considered for further efficacy evaluation. FLT-PET may be useful as an early response imaging tool for brain metastases. Trial registration numbers and dates: NCT01724606 (November 12, 2012) and NCT01621906 (June 18, 2012).

Aim Neoadjuvant therapy and total mesorectal excision (TME) for rectal cancer are associated with bowel dysfunction symptoms known as low anterior resection syndrome (LARS). Our study compared the only two validated instruments-the LARS Questionnaire (LARS-Q) and the Memorial Sloan Kettering Bowel Function Instrument (MSK-BFI)-in rectal cancer patients undergoing sphincter-preserving TME. Methods One hundred and ninety patients undergoing sphincter-preserving TME for Stage I-III rectal cancer completed the MSK-BFI and LARS-Q simultaneously at a median time of 12 (range 1-43) months after restoration of bowel continuity. Associations between the MSK-BFI total/subscale scores and the LARS-Q score were investigated using Spearman rank correlation (r s ). Discriminant validity for the two questionnaires was assessed, and the questionnaires were compared with the European Quality of Life Instrument. Results Major LARS was identified in 62% of patients. The median MSK-BFI scores for no LARS, minor LARS and major LARS were 76.5, 70 and 57, respectively. We found a strong association between MSK-BFI and LARS-Q (r s -0.79). The urgency/soilage subscale (r s -0.7) and the frequency subscale (rs -0.68) of MSK-BFI strongly correlated with LARS-Q. Low correlation was observed between the MSK-BFI diet subscale and LARS-Q (r s -0.39). On multivariate analysis, both questionnaires showed worse bowel function in patients with distal tumours. A low to moderate correlation with the European Quality of Life Instrument was observed for both questionnaires. Conclusions The MSK-BFI and LARS-Q showed good correlation and similar discriminant validity. As the LARS-Q is easier to complete, it may be considered the preferred tool to screen for bowel dysfunction.

Background Several phase 3 studies reported positive results for combinations of Immune-Oncology (IO) and Vascular Endothelial Growth Factor (VEGF) targeted therapies in patients with metastatic clear cell Renal Cell Carcinoma (ccRCC). However, there are limited data on outcomes to systemic therapy after IO-VEGF combinations. Methods A retrospective analysis was performed on patients with metastatic ccRCC treated at the Memorial Sloan Kettering Cancer Center and Cleveland Clinic who initiated systemic therapy post IO-VEGF including combinations with VEGF receptor (VEGFR) tyrosine kinase inhibitors (IO-TKI) and combinations with the anti-VEGF monoclonal antibody bevacizumab (IO-Bev). The study objectives were to evaluate the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) on systemic therapy post IO-VEGF. RECIST v1.1 criteria were used to determine radiological responses and progression. Survival estimates were evaluated with the Kaplan-Meier methods and the log-rank test from the start of systemic therapy post IO-VEGF to the event of interest. Results A total of fifty-nine patients were treated post discontinuation of IO-VEGF regimens which included IO-Bev (n = 35; 59%) and IO-TKI (n = 24; 41%). Fifty-eight patients (98%) received IO-VEGF regimens as part of a clinical trial. Subsequent therapies included cabozantinib (n = 22; 37%), axitinib (n = 18; 31%), pazopanib (n = 4; 7%), lenvatinib and everolimus (n = 4; 7%), mTOR inhibitor monotherapy (n = 3; 5%), axitinib and dalantercept (n = 2; 3%), sunitinib (n = 1; 2%), sorafenib (n = 1; 2%), and treatment with agents on unreported clinical trials (n = 4; 7%). Patients treated on unreported clinical trials were excluded from the efficacy analysis. Post IO-VEGF, the ORR was 25% and median PFS was 12.0 months (95% CI, 8.2–24.5). Median OS was 24.5 months (95% CI, 12–NE) and 12 months OS rate was 63.3% (95% CI, 48.6–74.9). We observed no differences post IO-VEGF OS when comparing IO- TKI vs IO-Bev (Log-rank p = 0.73). Conclusions Post IO-VEGF, most patients received VEGFR-TKIs. In this setting, VEGFR-TKIs demonstrated clinical activity and remain a viable option for salvage therapy after progression on IO-VEGF.

The Ventana PD-L1 SP142 immunohistochemistry (IHC) assay is the FDA-approved companion diagnostic assay for atezolizumab therapy selection for patients with PD-L1-positive locally advanced or metastatic triple-negative breast carcinoma (TNBC). We aimed to elucidate clinical, pathologic, and molecular features associated with PD-L1 expression in TNBCs. Clinical, pathologic, and next-generation sequencing (NGS)-based molecular data for TNBCs tested with PD-L1 (SP142) IHC at our institution between 11/2018 and 12/2019 were retrieved and reviewed. PD-L1 positivity was defined as ≥1% IC staining. Patients with metastatic TNBC treated at first line with atezolizumab regimens were evaluated for treatment response and for time to treatment failure (TTF). Among 156 TNBCs, PD-L1 was positive in 47.4% of cases. Primary TNBCs were significantly more frequently PD-L1 positive, compared with recurrent/metastatic samples (p = 0.002). PD-L1-positive TNBCs had increased stromal IC, compared with PD-L1-negative samples (p

PURPOSE The relapse rate after primary retroperitoneal lymph node dissection (RPLND) for patients with pathologic stage (PS) IIA nonseminomatous germ cell tumors (NSGCTs) is 10%-20% but increases to ≥ 50% for PS IIB disease. We report our experience with 2 cycles of adjuvant etoposide plus cisplatin (EP×2) after therapeutic primary RPLND. PATIENTS AND METHODS All patients with PS II NSGCT seen at Memorial Sloan Kettering Cancer Center from March 1989 to April 2016 and who were planned to receive EP×2 were included. Each cycle consisted of cisplatin 20 mg/m2 and etoposide 100 mg/m2 on days 1 through 5 at 21-day intervals. Demographic characteristics, histopathologic features, therapeutic and survival outcomes were recorded. RESULTS Of 156 patients, 30 (19%) had pathologic N1, 122 (78%) had pathologic N2 (pN2), and 4 (3%) had pathologic N3 (pN3) disease. The median number of involved lymph nodes was 3 (range, 1-37 nodes), and the median size of the largest involved node was 2.0 cm (range, 0.4-7.0 cm); extranodal extension was present in 69 patients (45%). Embryonal carcinoma was the most frequent RPLND histology, present in 143 patients (92%). One hundred fifty patients (96%) received EP×2, five received EP×1 and one received EP×4. With a median follow-up of 9 years, 2 patients (1.3%; 1 patient each with pN2 and pN3 disease) experienced relapse; both patients remain continuously disease free at more than 5 and 22 years after salvage chemotherapy. Three patients died, all unrelated to NSGCT, yielding 10-year disease-specific, relapse-free, and overall survival rates of 100%, 98%, and 99%, respectively. CONCLUSION Adjuvant EP×2 for PS II NSGCT is highly effective, has acceptable toxicity, and incurs less drug cost than 2 cycles of bleomycin, etoposide, and cisplatin. Inclusion of bleomycin in this setting is not necessary.

Background Overexpression and activation of tyrosine kinase Src has been linked to breast carcinogenesis and bone metastases. We showed the feasibility of combining the SRC inhibitor dasatinib with weekly paclitaxel in patients with metastatic breast cancer (MBC) and herein report the subsequent phase II trial. Patients and Methods Patients had received ≤ 2 chemotherapy regimens for measurable, HER2-negative MBC. Patients received paclitaxel and dasatinib (120 mg daily) and were assessed according to Response Evaluation Criteria in Solid Tumors for overall response rate (ORR), the primary end point. Secondary end points included progression-free survival (PFS) and overall survival (OS). A 30% ORR (n = 55) was deemed worthy of further investigation. Exploratory biomarkers included N-telopeptide (NTX) and plasma vascular epidermal growth factor (VEGF) receptor 2 as predictors of clinical benefit. Results From March 2010 to March 2014, 40 patients, including 2 men enrolled. The study was stopped early because of slow accrual. Overall, 32 patients (80%) had estrogen receptor-positive tumors and 23 (58%) had previously received taxanes. Of the 35 assessable patients, 1 (3%) had complete response and 7 (20%) partial response, resulting in an ORR of 23%. The median PFS and OS was 5.2 (95% confidence interval [CI], 2.9-9.9) and 20.6 (95% CI, 12.9-25.2) months, respectively. As expected, fatigue (75%), neuropathy (65%), and diarrhea (50%) were common side effects, but were generally low-grade. Median baseline NTX was similar in patients who had clinical benefit (8.2 nmol BCE) and no clinical benefit (10.9 nmol BCE). Similarly, median baseline VEGF levels were similar between the 2 groups; 93.0 pg/mL versus 83.0 pg/mL. Conclusion This phase II study of dasatinib and paclitaxel was stopped early because of slow accrual but showed some clinical activity. Further study is not planned.

Guidelines concur that postmastectomy radiation therapy (PMRT) in T1-2 tumors with one to three positive (+) lymph nodes (LNs) decreases locoregional recurrence (LRR) but advise limiting PMRT to patients at highest risk to balance against potential harms. In this study, we identify the risks of LRR after mastectomy in patients with T1-2N1 disease, treated with modern chemotherapy, and identify predictors of LRR when omitting PMRT. Patients with T1-2N1 breast cancer undergoing mastectomy between 1995 and 2006 were categorized by receipt of PMRT. The Chi square test compared the clinicopathologic features between both groups, and Kaplan–Meier and Cox regression analysis was used to determine the rates of LRR, recurrence-free survival (RFS), and overall survival (OS). Overall, 1087 patients (924 no PMRT, 163 PMRT) were included in the study, with a median follow-up of 10.8 years (range 0–21). We identified 63 LRRs (56 no PMRT, 7 PMRT), and 10-year rates of LRR with and without PMRT were 4.0% and 7.0%, respectively. Patients receiving PMRT were younger (p = 0.019), had larger tumors (p = 0.0013), higher histologic grade (p = 0.029), more positive LNs (p

Background Renal medullary carcinoma (RMC) is a rare and aggressive type of kidney cancer that primarily affects young adults with sickle cell trait; outcomes are poor despite treatment. Identifying molecular features of this tumor could provide biologic rationale for novel targeted therapies. The objective was to report on clinical outcomes with systemic therapy and characterize molecular features. Patients and Methods This was a retrospective analysis on 36 patients given a pathologic diagnosis of RMC at one institution from 1995 to 2015. Tumors were analyzed for expression of SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1 (SMARCB1) through immunohistochemistry and for genomic alterations with fluorescence in situ hybridization for SMARCB1, and targeted next-generation sequencing. Time from initiation of therapy to progression of disease and overall survival were calculated using the Kaplan–Meier method. Results The median age in the cohort was 28 (range, 12-72) years, and all patients tested had sickle cell trait. Overall survival was 5.8 months (95% confidence interval [CI], 4.1-10.9) and for 12 patients who received platinum-based therapy, median progression-free survival was 2.5 months (95% CI, 1.2-not reached). A total of 10 available tumors underwent analysis with fluorescence in situ hybridization for SMARCB1; this revealed loss of heterozygosity with concurrent translocation in 8, and biallelic loss in 2. Next-generation targeted sequencing showed no recurring mutations. Conclusions Outcome was generally poor in this cohort of patients with RMC. Uniform loss of SMARCB1 is a key molecular feature in this tumor and mechanism of loss appears to be mostly through translocations and deletions.

PURPOSE: HER2 copy number by fluorescence in situ hybridization (FISH) is typically reported relative to the centromere enumeration probe 17 (CEP17). HER2/CEP17 ratio could be impacted by alterations in the number of chromosome 17 copies. Monosomy of chromosome 17 (m17) is found in ~1,900 cases of early stage HER2-positive breast cancer annually in the United States, however the efficacy of HER2-directed trastuzumab therapy in these patients is not well characterized. Here we retrospectively identified HER2-amplified, stage I-III breast cancers with m17 and characterized the impact of trastuzumab treatment. METHODS: From January 1, 2000 to June 1, 2011 we identified 99 women with HER2-amplified m17 breast cancers, as defined by a CEP17 signal of

Women with ductal carcinoma in situ (DCIS) are increasingly choosing bilateral mastectomy. We sought to quantify rates of contralateral breast cancer (CBC) and ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) for DCIS, and to compare risk factors for CBC and IBTR. From 1978 to 2011, DCIS patients undergoing BCS with a contralateral breast at risk were identified from a prospectively maintained database. The association of clinicopathologic and treatment factors with CBC and IBTR were evaluated using Kaplan–Meier analysis, multivariable Cox regression, and competing risk regression (CRR). Of 2759 patients identified, 151 developed CBC and 344 developed IBTR. Five- and 10-year Kaplan–Meier CBC rates were 3.2 and 6.4%. Overall, 10-year IBTR rates were 2.5-fold higher than CBC rates, and, without radiation, 4-fold higher. On CRR, 5- and 10-year rates were 2.9 and 5.8% for CBC, and 7.8 and 14.5% for IBTR. CBC risk and invasive CBC risk were not significantly associated with age, family history, presentation, nuclear grade, year of surgery, or radiation. By multivariable Cox regression, endocrine therapy was associated with lower CBC risk (hazard ratio 0.57, p = 0.03). Ten-year risk of subsequent CBC in the subset of patients who developed IBTR was similar to the cohort as a whole (8.1 vs. 6.4%). CBC rates were low across all groups, including those who experienced IBTR. CBC was not associated with factors that increase IBTR risk. While factors associated with IBTR risk are important in decision making regarding management of the index DCIS, they are not an indication for contralateral prophylactic mastectomy.

Background: Mutations in VHL, PBRM1, SETD2, BAP1, and KDM5C are common in clear cell renal cell carcinoma (ccRCC), and presence of certain mutations has been associated with outcomes in patients with non-metastatic disease. Limited information is available regarding the correlation between genomic alterations and outcomes in patients with metastatic disease, including response to VEGF-targeted therapy. Objective: To explore correlations between mutational profiles and cancer-specific outcomes, including response to standard VEGF-targeted agents, in patients with metastatic cc RCC. Methods: A retrospective review of 105 patients with metastatic ccRCC who had received systemic therapy and had targeted next-generation sequencing of tumors was conducted. Genomic alterations were correlated to outcomes, including overall survival and time to treatment failure to VEGF-targeted therapy. Results: The most frequent mutations were detected in VHL (83%), PBRM1 (51%), SETD2 (35%), BAP1 (24%), KDM5C (16%), and TERT (14%). Time to treatment failure with VEGF-targeted therapy differed significantly by PBRM1 mutation status (p = 0.01, median 12.0 months for MT versus 6.9 months for WT) and BAP1 mutation status (p = 0.01, median 6.4 months for MT versus 11.0 months for WT). Shorter overall survival was associated with TERT mutations (p = 0.03, median 29.6 months for MT versus 52.6 months for WT) or BAP1 mutations (p = 0.02, median 28.7 months for MT versus not reached for WT). Conclusions: Genomic alterations in ccRCC tumors have prognostic implications in patients with metastatic disease. BAP1 and TERT promoter mutations may be present in higher frequency than previously thought, and based on this data, deserve further study for their association with poor prognosis.

Randomized trials demonstrate equivalent locoregional control with sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) for T1–2 micrometastatic breast cancer, but include few mastectomy patients. Consensus is lacking on indications for post-mastectomy radiotherapy (PMRT) in this population. Herein, we evaluate locoregional recurrence (LRR) in an unselected, modern cohort of T1–2 breast cancer patients with micrometastases or isolated tumor cells (ITCs; N0i+/N1mi) having a mastectomy. We identified patients with T1–2N0i+/N1mi breast cancer treated with mastectomy from January 2006 to December 2011. Recurrent, bilateral, and neoadjuvant cases were excluded. The primary outcome of interest was LRR. Overall, 352 patients [211 (60%) with ITCs and 141 (40%) with micrometastases] were identified. 162 (46%) patients had SLNB alone and one node was positive in 295 (84%) cases; 31 (9%) patients had PMRT and 95% had systemic therapy. At a median 6 years of follow-up, the overall crude LRR rate was 2.8% (n = 9), with no axillary recurrences, and the crude LRR rate was 3.9% among those who had SNB alone. Those with LRR had a median age of 55 years, median tumor size of 1.7 cm, and ductal histology; the majority were high-grade (89%) and estrogen receptor positive (78%), with one positive node (89%). There was no association between LRR and receipt of PMRT (p = 0.4), SLNB versus ALND (p = 0.2), or number of positive nodes (p = 0.7) using the log-rank test. LRR was infrequent among T1–2N0i+/N1mi patients treated with mastectomy without PMRT, with no axillary failures, suggesting that PMRT or nodal radiotherapy are not routinely indicated in this population.

Purpose To validate the finding of an association between single nucleotide polymorphisms (SNPs) and toxicity during chemoradiotherapy (CRT) in rectal cancer patients, in an independent population. Methods and Materials The cohort consisted of 165 patients who received CRT for rectal cancer from 2006 to 2012. Prospectively recorded toxicity information, graded according to the Common Terminology Criteria for Adverse Events version 3.0, was retrieved from the medical record. Additionally, a subset of 52 patients recorded their gastrointestinal symptoms weekly during CRT, using the 7-item Bowel Problems Scale. Deoxyribonucleic acid was extracted from normal tissue in the proctectomy specimens and screened for 3 SNPs: XRCC1 R399Q, XPD K751Q, and TGFβ1 R25P. Univariable and multivariable logistic regression models were constructed. Results The median radiation dose was 50.4 Gy, and all patients received concurrent chemotherapy. Toxicities measured by the Common Terminology Criteria for Adverse Events were closely associated with patient-reported outcomes for the patients who completed the 7-item Bowel Problems Scale. Grade ≥3 toxicity occurred during CRT in 14 patients (8%). All 14 patients had either XRCC1 R399Q or TGFβ1 R25P polymorphisms. The TGFβ1 R25P polymorphism was significantly associated with grade ≥3 toxicity (odds ratio [OR] 3.47, P =.04) and, in patients who completed the Bowel Problems Scale, with grade ≥4 toxicity (OR 5.61, P =.02). The latter finding persisted in a multivariable logistic regression model controlling for ethnicity, age, and sex (adjusted OR 1.83, P =.02). Conclusions We have validated the correlation between the TGFβ1 R25P SNP and acute toxicity during CRT in an independent cohort using both clinician- and patient-reported toxicity. The information from our study could be used as a basis to formulate a prospective trial testing the utility of this SNP as a biomarker of acute toxicity during neoadjuvant treatment in locally advanced rectal cancer.

BACKGROUND Indications for postmastectomy radiotherapy (PMRT) in patients with T1 to T2, lymph node-negative (N0) breast cancer with “high-risk” features are controversial. The European Organization for Research and Treatment of Cancer (EORTC) 22922 and National Cancer Institute of Canada Clinical Trials Group MA20 trials reporting improved 10-year disease-free survival with lymph node irradiation included patients with high-risk N0 disease, but, to the authors’ knowledge, benefits in patients receiving modern systemic therapy are uncertain. METHODS The authors retrospectively identified patients with T1 to T2N0 disease who were treated with mastectomy from January 2006 through December 2011. High-risk features included age .05). Receipt of systemic therapy decreased the LRR rate (hazard ratio, 0.40; P = .03). Although crude LRR rates increased from 3.8% to 9.4% with 1 versus ≥ 4 high-risk features, the number of risk factors was not found to be significantly associated with LRR (P = .54). CONCLUSIONS In the current study, a low crude LRR rate (4.7%) was observed in a large unselected cohort of patients with T1 to T2N0 breast cancer with high-risk features who were treated with mastectomy and systemic therapy without PMRT. Although increasing tumor size and the omission of systemic therapy were found to be predictive, other features did not confer a higher LRR risk either independently or together, and do not by themselves mandate the use of PMRT in this patient population. Cancer 2017;123:2626-33. © 2017 American Cancer Society.

Objectives Trastuzumab (H) and pertuzumab (P) with standard chemotherapy is approved for use in the neoadjuvant setting for human epidermal growth receptor 2 -positive patients. A retrospective analysis was performed of patients treated with dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T), trastuzumab, and pertuzumab (THP) in the neoadjuvant setting. Here, the pathologic complete response (pCR) rates are reported. Methods An electronic medical record review was conducted of patients treated with HP-based therapy in the neoadjuvant setting from September 1, 2013, to March 1, 2015. Data on patient demographics, stage of breast cancer, pathology reports, surgical data, and information on systemic therapy were collected. The pCR was defined as total (tpCR, ypT0/is ypN0), German Breast Group (GBG) pCR (ypT0 ypN0), breast pCR (bpCR) with in situ disease (ypT0/is) and without in situ disease (ypT0), and explored axillary pCR (ypN0). Results Charts from 66 patients were reviewed, and 57 patients were evaluable for pCR. Median age was 46 years (range 26-68 years). Median tumor size was 4 cm. Of 57 patients, 53 (93%) had operable breast cancer (T1-3, N0-1, M0). Three patients (5.3%) had locally advanced disease (T2-3, N2-3, M0 or T4a-c, any N, M0), and 1 (1.7%) had inflammatory breast cancer (T4d, any N, M0). Overall, 44 (77%) and 13 (23%) had hormone receptor (HR)-positive and negative diseases, respectively. Median numbers of cycles of neoadjuvant treatment were as follows: AC (4, range 1-4), T (4, range 1-4), trastuzumab (6, range 3-8), and pertuzumab (6, range 2-8). In these 57 patients, the rates of tpCR and bpCR with in situ disease were demonstrated in 41/57 (72%) patients, and the rates of GBG pCR and bpCR without in situ disease were found in 30/57 (53%) patients. Of 26 patients with biopsy-proven lymph nodal involvement, axillary pCR occurred in 22 (85%) patients. Conclusion At a single center, the tpCR and GBG pCR rates of dd AC followed by THP are high at 72% and 53%, respectively. The Oncologist 2017;22:139-143Implications for Practice: This is the first study describing the role of doxorubicin and cyclophosphamide followed by paclitaxel and dual anti-HER2 therapy with trastuzumab and pertuzumab (ACTHP) in patients with early stage HER2-positive breast cancer. Total (breast + lymph node) pathological complete remission (pCR) remission (ypT0/is ypN0) and German Breast Group pCR rates (ypT0/ ypN0) were high at 72% and 53%, respectively, with the ACTHP regimen. Rate of axillary clearance in patients with known axillary involvement was high at 85%, which may translate into less extensive axillary surgeries in this subset in the future.

Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation, and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic, or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients’ tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.

PURPOSE In men with metastatic germ cell tumors (GCTs), risk-directed treatment is determined, in part, by a distinction between seminoma and nonseminomatous GCT (NSGCT). The importance of NSGCT cell type is uncertain. We evaluated the long-term impact of teratoma on survival in patients with NSGCT. METHODS Prechemotherapy, primary tumors from patients who received platinum-based chemotherapy were studied, and the histology was confirmed by a genitourinary pathologist. The cumulative incidence of disease-related death (CIDD) was the primary end point, and a competing-risk analysis was performed. RESULTS Tumors were available from 232 patients, including 193 with NSGCT. An element of teratoma was present in 82 NSGCT primary tumors (42%). With a median follow-up of 17 years (range, 0.3 to 35 years), 58 patients with NSGCT died, 47 as a result of GCT and 11 as a result of other causes. Most GCT deaths occurred within the first 5 years and were associated with pretreatment risk status ( P < .001). Death as a result of other causes rose steadily after 15 years and was not associated with risk status ( P = .66). A higher CIDD was observed in patients who had NSGCT with teratoma than those with NSGCT without teratoma and seminoma (5-year CIDD rate, 27.4%, 17.4%, and 10.3%, respectively; P = .03). A higher CIDD was observed in patients who had NSGCT with mature teratoma compared with those with either NSGCT with immature teratoma or NSGCT without teratoma (5-year CIDD rate, 38.1%, 19.9%, and 17.4%, respectively; P = .01). CONCLUSION The presence of teratoma, particularly mature teratoma, in an NSGCT primary tumor is associated with a higher CIDD, consistent with the hypothesis that differentiation is associated with adverse outcomes. Death as a result of non-GCT causes is not associated with risk status and must be separated from GCT death when evaluating long-term survival.

Purpose: Lapatinib and capecitabine cross the blood–tumor barrier in breast cancer brain metastasis but have modest clinical efficacy. Administration of high-dose tyrosine kinase inhibitor has been evaluated in brain metastases and primary brain tumors as a strategy to improve drug exposure in the central nervous system (CNS). We derived a rational drug scheduling of intermittent high-dose lapatinib alternating with capecitabine based on our preclinical data and Norton–Simon mathematical modeling. We tested this intermittent, sequential drug schedule in patients with breast cancer with CNS metastasis. Patients and Methods: We conducted a phase I trial using an accelerated dose escalation design in patients with HER2-positive (HER2+) breast cancer with CNS metastasis. Lapatinib was given on day 1–3 and day 15–17 with capecitabine on day 8–14 and day 22–28 on an every 28-day cycle. Lapatinib dose was escalated, and capecitabine given as a flat dose at 1,500 mg BID. Toxicity and efficacy were evaluated. Results: Eleven patients were enrolled: brain only (4 patients, 36%), leptomeningeal (5 patients, 45%), and intramedullary spinal cord (2 patients, 18%). Grade 3 nausea and vomiting were dose-limiting toxicities. The MTD of lapatinib was 1,500 mg BID. Three patients remained on therapy for greater than 6 months. Conclusions: High-dose lapatinib is tolerable when given intermittently and sequentially with capecitabine. Antitumor activity was noted in both CNS and non-CNS sites of disease. This novel administration regimen is feasible and efficacious in patients with HER2+ breast cancer with CNS metastasis and warrants further investigation.

5017 Background: HDCT/ASCT represents a curative salvage treatment for patients with GCT but is rarely used for other solid tumors. Patients undergoing HDCT/ASCT for hematologic neoplasms require revaccination for their childhood immunizations. Whether this is necessary in patients with GCT is unknown. Methods: In this prospective longitudinal study, patients with GCT undergoing HDCT-ASCT from 11/2010 to 5/2018 had serologies for Measles, Mumps, Rubella, Diphtheria, Tetanus, Polio, and Varicella Zoster measured before HDCT and at 3, 6, and in a subset, 12+ months after the last HDCT with results at these timepoints compared using descriptive statistics. In addition, titer levels at ≥6 months post-transplant were matched 1:1 for age and gender with HL patients who underwent HDCT/ASCT during the same time period. Immunity was compared between cohorts using the Cochran-Mantel-Haenszel test. Results: Of 80 patients with GCT (median age 30, 84% nonseminoma), 91% received 3 sequential transplants and 68 had repeat titers at ≥6 months. Immunity at baseline was >95% for Diphtheria, Tetanus and Polio and 89% for Varicella Zoster but lower for Measles (74%), Mumps (85%), and Rubella (83%) (Table). Compared to baseline, proportional immunity for all infections was similar at 3, 6, and 12 months post-transplant in the GCT population (≥6 months shown in Table). Matching resulted in 58 GCT-HL pairs. One-year immunity was numerically lower for most infections in the HL vs. GCT patients and significantly decreased for Measles and Rubella (Table). Conclusions: To our knowledge, this is the first study to assess vaccine titers following HDCT/ASCT for GCT. We demonstrate that HDCT/ASCT does not result in loss of immunity to childhood vaccines and that GCT patients retain protective titers more frequently than those with HL. However, 15-31% of GCT patients lack MMR immunity at baseline and at 1-year post-ASCT. Therefore, we recommend checking MMR titers at 1-year post-ASCT with revaccination of those lacking immunity. Titer evaluation and revaccination is not necessary for other childhood immunizations.[Table: see text]

3509 Background: Clinical response following neoadjuvant therapy is paramount to identifying locally advanced rectal cancer (LARC) patients suitable for Watch and Wait (WW). A 3-tier schema was devised to stratify clinical response. Patients with a complete clinical response (cCR) are considered for WW, while those with an incomplete clinical response (iCR) are recommended for total mesorectal excision (TME). A near complete response (nCR) tier captures patients with significant, but not complete, response to be considered for WW. This schema’s efficacy has yet to be validated. We investigated survival and organ preservation (OP) rates based on this 3-tier clinical response assessment in patients with LARC who underwent total neoadjuvant therapy (TNT) in a prospective, multi-center clinical trial. Methods: Patients with MRI stage II and III rectal adenocarcinoma were randomized to either induction chemotherapy (FOLFOX or CAPEOX) followed by chemoradiation or chemoradiation followed by consolidation chemotherapy (FOLFOX or CAPEOX). At 8+/-4 weeks following TNT, response on digital rectal and endoscopic examinations was evaluated by the 3-tier schema. The date of this restaging clinical response assessment was used as time zero. The endpoints of rate of OP, disease-free survival (DFS), TME-free DFS, and overall survival (OS) were evaluated using the Kaplan-Meier method with differences analyzed by the log-rank test. Results: Clinical response assessments were available for 294 patients. The median time to assessment after neoadjuvant therapy was 7.9 weeks. Based on the 3-tier schema, 124 patients were categorized as cCR, 113 as nCR, and 57 as iCR. Baseline age, sex, average distance from the anal verge, clinical T classification, and clinical N classification were similar between the response groups. The table shows the 3-year rates of OP, DFS, TME-free DFS, and OS. The median follow-up was 2.36 years. Of the patients with a nCR, the 3-year TME rate was 48% compared with 21% in the cCR group. Conclusions: The 3-tier clinical response assessment has prognostic implications for OP and DFS in patients with LARC who underwent TNT. In patients with a nCR, more than half achieved OP at 3 years. This information should be utilized to counsel patients regarding their expected outcomes. Clinical trial information: NCT02008656. [Table: see text]

386 Background: TIP was established as an effective second-line regimen in a phase II study of 46 patients (pts) with relapsed GCT and favorable risk factors (Kondagunta, JCO 2005). Here, we report long-term follow up from this trial and outcomes for additional pts who subsequently received TIP off protocol. Methods: Eligiblepts included those who received TIP on the original phase II trial (original cohort) or who received TIP following study closure but would have met the trial inclusion criteria (expansion cohort). An additional exploratory cohort was comprised of pts with unfavorable risk factors who would not have met the original trial criteria. The primary endpoint was favorable response rate (FRR), which included complete responses (CR) and partial responses with negative markers (PR-). Overall survival (OS), progression free survival (PFS), and relapse rates were also evaluated. Results: Of 204 pts who received TIP for GCT at our institution from 5/1994 to 7/2019, 87 (original cohort, n=46; expansion cohort, n=41) met the inclusion criteria and were evaluable for the main analysis. An additional 17 pts were analyzed in the exploratory cohort (unfavorable risk factor: PR- lasting

296 Background: An estimated 5% of kidney cancers are associated with hereditary RCC syndromes. Current germline genetic testing guidelines for patients with kidney cancer were developed to identify carriers of known RCC-associated genes and have evolved in the panel-testing era. We evaluated the utility of the recent National Comprehensive Cancer Network (NCCN) recommendation of testing all patients with early-onset RCC (defined as age of diagnosis ≤ 46 years) for germline variants in genes implicated in hereditary RCC syndromes. Methods: We retrospectively identified patients with RCC diagnosed at age ≤ 46 years who underwent targeted germline testing at our institution through referral to clinical genetics service (n = 68, 29%) or through broad germline testing of ≥77 cancer susceptibility genes using next generation sequencing as part of a prospective matched tumor-normal genomic profiling initiative (n = 165, 71%). Diagnostic performance of referral criteria was assessed by the presence of pathogenic/likely pathogenic (P/LP) germline variants in RCC-associated genes and incidental cancer susceptibility genes. Results: Of 233 patients, 61% were male, 74% were Caucasian, 15% had family history of RCC, 15% had RCC-syndromic features, including 9% with multifocal renal tumors. Most patients (54%) had clear cell RCC (ccRCC). P/LP germline variants were identified in 42 (18%) patients but only 21 (9%) had mutations in RCC genes (12 FH, 4 VHL, 2 SDHB, 1 each in BAP1, TSC1, and FLCN). All 21 early-onset patients with germline variants in an RCC-associated gene also had one of the following risk factors: non-ccRCC histology, family history, or syndromic features. In 91 patients (39%) with a non-RCC germline variants or no alteration, none of these three risk factors were found. Of 21 patients with non-RCC P/LP germline variants, 9 had mutations in moderate/high penetrance genes ( BRCA1 [2], ATM [2], CHEK2 [1], TP53 [2] , PALB2 [1], and RET [1]); 8/9 (89%) met standard criteria for testing for those genes independent of early-onset RCC diagnosis. Conclusions: Patients with early-onset clear cell RCC and no suspicious personal or family history are unlikely to have an RCC-associated germline mutation. RCC-gene panel testing has highest utility in early-onset patients with either non-ccRCC histology, family history of RCC, or RCC-associated syndromic features. Given the high frequency of non-RCC P/LP variants, early-onset RCC patients should be counseled regarding broader testing beyond RCC-associated genes.

323 Background: Immunotherapy improves survival in patients with advanced renal cell carcinoma (RCC), but has no established role for perioperative use in patients with localized RCC. Neoadjuvant immunotherapy is a promising strategy in several cancers, and may leverage the primary tumor as antigen source. Methods: We conducted a single institution pilot study of neoadjuvant nivolumab in patients with RCC undergoing nephrectomy with curative intent. Patients were eligible if their risk of metastatic recurrence within the first 12 years was >20% by an established nomogram. After confirmatory biopsy and renal MRI, patients were treated with standard dose nivolumab every 2 weeks for 4 treatments, with a follow-up renal MRI prior to nephrectomy. The primary end points of the study were safety and feasibility defined as being able to complete 3/4 treatments without surgical delay. We evaluated adverse events by CTCAE, surgical safety by Clavien-Dindo classification, and tumor radiographic response by RECIST 1.1. Results: Eighteen (11 men, 7 women; median age 60) were enrolled. All patients had clear cell RCC, median tumor size at baseline was 8.8cm (range 6.4-14.2cm). Median predicted 12-year probability of recurrence was 45% (range 25-71%). All received at least 1 dose of nivolumab; 16/18 patients completed all 4 doses. 17/18 (94%) patients completed at least 3 doses. No patient had notable delay in the timing of their nephrectomy. 4 patients had surgical complications per Clavien-Dindo classification, including 2 with grade 3a chylous ascites after lymphadenectomy. Two patients had nivolumab discontinued for immune-related adverse events, including grade 3 transaminitis and grade 2 arthralgias; a third patient developed grade 4 colitis 4 months after completing nivolumab. All patients had stable disease as the best response prior to surgery. Recurrence-free survival at 2 years was 0.74 (95%CI 0.45-0.90). We analyzed an additional 21 patients with metastatic RCC (20 ccRCC, 1 epithelioid AML) who subsequently had nephrectomy after standard immunotherapy. 15 patients had received ipilimumab+nivolumab, 6 received single-agent PD-1 or PD-L1 inhibitors. 3 (14%) patients achieved a near or complete pathologic response, including a patient with epithelioid AML. Analysis of radiologic and pathologic biomarkers of response are ongoing and will be presented at conference. Conclusions: In this pilot study, there were no new safety signals or delays in surgery with preoperative nivolumab. Neoadjuvant immunotherapy shows preliminary evidence of safety, feasibility and efficacy; biomarker studies may help identify individuals who may have a higher likelihood of response. Clinical trial information: NCT02595918 .

This cohort study evaluates the association of early trastuzumab interruption with clinical outcomes in patients with ERBB2-positive breast cancer.

Purpose: To assess the safety and tolerability of preoperative cryoablation-mediated tumor antigen presentation and/or ipilimumab-mediated immune modulation in women with operable breast cancer. Experimental Design: In this pilot study, 19 women with breast cancer for whom mastectomy was planned were treated with preoperative tumor cryoablation (n = 7), single-dose ipilimumab at 10 mg/kg (n = 6), or both (n = 6). The primary outcome for this pilot study was safety/tolerability as defined as freedom from delays in pre-planned, curative-intent mastectomy. Exploratory studies of immune activation were performed on peripheral blood and tumor. Results: Preoperative cryoablation and/or ipilimumab were safe and tolerable, with no delays in pre-planned surgery. Grade III toxicity was seen in 1 of 19 (unrelated rash after ipilimumab). Combination therapy was associated with sustained peripheral elevations in: Th1-type cytokines, activated (ICOS+) and proliferating (Ki67+) CD4+ and CD8+ T cells, and posttreatment proliferative T-effector cells relative to T-regulatory cells within tumor. Conclusions: Preoperative cryoablation and single-dose ipilimumab are safe alone or in combination with no surgical delays incurred. Potentially favorable intratumoral and systemic immunologic effects were observed with the combination, suggesting the possibility for induced and synergistic antitumor immunity with this strategy. Clin Cancer Res; 22(23); 5729–37. ©2016 AACR.

BACKGROUND A 21-gene expression assay (Oncotype DX recurrence score [RS]) that uses reverse transcriptase-polymerase chain reaction is used clinically in patients with early-stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast carcinoma (ER+/HER2- BC) to determine both prognosis with tamoxifen therapy and the usefulness of adding adjuvant chemotherapy. Use of the assay is associated with reductions in overall chemotherapy use. The current study examined the treatments and outcomes in patients with low RS. METHODS The authors reviewed the institutional database to identify patients with lymph node-negative, ER+/HER2- BC who were treated at the study institution between September 2008 and August 2013 and their 21-gene RS results. RESULTS A total of 1406 consecutive patients with lymph node-negative ER+/HER2- BC and a low RS were identified (510 patients had an RS of 0-10 and 896 patients had an RS of 11-17). The median age at the time of diagnosis of BC was 56 years; 63 patients (4%) were aged

Introduction Heat shock protein (HSP) 90, a viable target for cancer treatment, mediates the maturation and stabilization of client oncoproteins. HSP90 inhibitors (HSP90i) are potentially active in a variety of tumors, but therapeutic benefit is confirmed in only a small subset. We explored potential biomarkers across multiple studies of HSP90i in advanced solid tumors. Patients and Methods Archived tumor specimens from patients treated with HSP90i in 7 different phase I/II trials at Memorial Sloan Kettering Cancer Center were identified. Tumor tissue was tested using immunohistochemistry; estrogen, progesterone, and androgen receptors ≥ 1% positive and Results Adequate tissue was available for 51 of 158 patients (32%), including 10 different solid tumors. Of these, 71% (36 of 51) and 51% (26 of 51) patients met the criteria to assess CB by best ORR or by the "8-week scan" assessment, respectively. Breast was the most frequent tumor. The mean duration of HSP90i therapy was 55 days (range, 16-411 days). There were 16 responses (4 partial response; 12 stable disease); 13 of 16 responses strongly correlated with HER2-positive status ( P = .001). Conclusion Our findings suggest HER2 as a sensitive client and perhaps the only effective biomarker for sensitivity to these HSP90i.

The American College of Surgeons Oncology Group Z0011 trial demonstrated the safety of omitting axillary lymph node dissection (ALND) for women with fewer than three positive sentinel lymph nodes (SLNs) who are undergoing breast-conservation therapy (BCT). Because most of the women were postmenopausal with estrogen receptor (ER) positive cancers, applicability of ALND for younger patients and those with triple-negative (TN) or human epidermal growth factor receptor 2 (HER2) overexpressing (HER2+) tumors remains controversial.From August 2010 to December 2015, patients undergoing BCT for cT1-2N0 disease and found to have positive SLNs were prospectively followed. Axillary lymph node dissection was indicated for more than two positive SLNs or gross extracapsular extension. Clinicopathologic characteristics, axillary surgery, nodal burden, and outcomes were compared between the high-risk patients (TN, HER2+, or age 50 years) and the remaining patients, termed average risk patients.Among 701 consecutive patients, 242 (35 %) were high risk: 31 (13 %) with TN, 48 (20 %) with HER2+, 130 (54 %) with age less than 50 years, and 33 (14 %) with more than one high-risk feature. The remaining 459 patients (65 %) were average risk. The high-risk patients were younger, had higher-grade tumors (p 0.0001), and more often had abnormal nodes imaged (p = 0.02). In this study, SLNB alone was performed for 85 % high-risk versus 82 % average-risk cases (p = 0.39). A median of four versus three SLNs were excised (p = 0.04), and both groups had a median of one positive SLN. Additional positive nodes at ALND were found in 62 % high-risk patients versus 65 % average-risk patients (p = 0.8), with a median of three positive nodes in both groups. During a median follow-up period of 31 months, no patients experienced isolated axillary recurrences.Axillary lymph node dissection was no more likely to be indicated for high-risk patients. For patients undergoing ALND, the nodal burden was similar. For patients otherwise meeting the American College of Surgeons Oncology Group (ACOSOG) Z0011 clinical eligibility criteria, ALND is not indicated on the basis of age or subtype.

Bevacizumab has shown benefit in the first-line setting in combination with interferon; however, data on use as monotherapy are limited. In this retrospective analysis of 71 patients we assessed the efficacy of bevacizumab monotherapy in patients whose disease progressed during treatment with other targeted drugs. Bevacizumab monotherapy resulted in prolonged disease control and few discontinuations for adverse events, including for patients who were heavily pretreated.Bevacizumab has shown benefit in the first-line treatment of metastatic clear cell renal cell carcinoma (ccRCC) in combination with interferon α. In this retrospective analysis we assessed the efficacy of bevacizumab monotherapy in patients whose disease progressed during treatment with vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors, and/or mammalian target of rapamycin inhibitors.A retrospective analysis was performed on metastatic ccRCC patients who received bevacizumab monotherapy after their disease progressed during treatment with previous targeted therapies. The primary objective was to assess overall survival (OS) and the secondary objectives includes progression-free survival (PFS), therapy duration, and incidence of serious adverse events assessed during visits to the Memorial Sloan Kettering Cancer Center (MSKCC) urgent care center.Seventy-one patients were treated with bevacizumab as monotherapy in the salvage setting. Most patients were heavily pretreated with 36 patients (51%) who received bevacizumab as a fourth-line or later agent, and 33 patients (46%) who received at least 2 previous VEGF targeted agents. Eighteen patients (25%) had a Karnofsky Performance Status (KPS)80%, and 20 patients (28%) were classified as poor risk according to MSKCC criteria. Median OS was 11.5 months (95% confidence interval [CI], 6.4-17.4), and median PFS was 1.9 months (95% CI, 1.7-4.1). Nine patients (13%) had a prolonged time of therapy of12 months. Four patients (6%) discontinued therapy because of adverse events. Poor KPS (80%) and MSKCC poor-risk classification were prognostic for poor OS with hazard ratios of 4.09 (P.001) and 2.84 (P = .021), respectively.Bevacizumab monotherapy resulted in prolonged disease control and few discontinuations because of adverse events in patients whose disease had progressed during treatment with other targeted therapies, including patients who were heavily pretreated.

Low-income and minority groups appear to be at increased risk of post-treatment job loss and its sequelae, including financial strain and bankruptcy. However, the drivers of disparities in job loss are not understood. We surveyed employed women aged 18-64 with stage I-III breast cancer who spoke Chinese, English, Korean, or Spanish. Baseline surveys (telephone or online) were administered during adjuvant treatment; follow-up surveys were conducted 4 months after completion of active treatment except endocrine and targeted therapy (i.e., trastuzumab with or without pertuzumab). The primary outcome was post-treatment work status (working full- or part-time vs. any other work status). We used healthy peers to control for disparities in non-cancer unemployment and multivariable analyses to identify predictors of work status in patients. Our sample (n=479) was 28% Latina, 23% black, 21% non-Latina white, 19% Chinese, and 7% Korean; 56% were foreign-born. Overall, 31% had a household income This abstract is also being presented as Poster A100. Citation Format: Victoria S. Blinder, Sujata Patil, Carolyn Eberle, Gabriel Jung, Lewis J. Kampel, Caroline Hwang, Ting Bao, Mark E. Robson, Manmeet Malik, Francesca Gany. Disparities in work status after treatment for breast cancer: A controlled, longitudinal study [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr PR03.

e12653 Background: The addition of pertuzumab in the neoadjuvant setting has become a standard of care in stage II-III HER2-positive BC. In the Katherine study the incidence of brain metastases (BM) at the follow-up of 3-years was 5.9 % in patients (pts) with residual disease who received TDM1. The aim of this study was to assess the incidence of BM in pts who received NAC with HP at a single center who were found to have pathological complete response (pCR) (ypT0/is ypN0) versus non-pCR at the time of surgery. Methods: Chart review on HER2-positive pts treated with NAC and HP between September 1, 2013 to May 1, 2018 was conducted. Only surgical specimens of pts whose pre-NAC specimens were internally reviewed for HER2 status by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were included in this analysis. Data on BM as component of distant recurrence along with invasive disease-free (IDFS) and overall survival (OS) were collected. Results: 540 pts were identified. Cases with no internally verified-HER2 status (387), equivocal status (10) and discordant internal assessment (13) were excluded. 130 pts with preoperative HER2 status confirmed by dedicated breast pathologists were included. Clinicopathological features are described in Table. pCR was achieved in 77/130 (60%) of cases, residual disease in 53/130 (40%). The median follow-up was 2.83 (0.35-5.3) years. The rate of BM as first presentation of distant disease was 3.8 % (3/77) and 3.7 % (2/53) in pts with pCR and non-pCR, respectively. Median time to development BM was 35 (13-58) months and 11.7 (9-14) months in the pCR group and non-pCR, respectively. Conclusions: In our cohort, the combination of HP was associated with a high pCR rate. At a median follow-up of 2.8 years, the incidence of BM appeared to be similar in pts who achieved pCR versus non-pCR. The data of IDFS and OS will be reported. Further data are needed to validate our findings before designing clinical trials to test prophylactic strategies to prevent BM. [Table: see text]

e17092 Background: With the approval of ipilimumab plus nivolumab (I+N) and other immune checkpoint blockade (ICB) based combinations in the first-line setting, the role of I+N for salvage is of high interest for treatment sequencing, yet data is limited. Methods: We conducted a retrospective review of mRCC patients (pts) treated with I+N in the second-line (2L) and beyond settings at MSKCC between 2013-2019. Pt demographics, treatment history and toxicity were compiled. IMDC-risk status was calculated at I+N therapy start. Time to treatment failure (TTF) was defined as earliest date of clinical progression, therapy change or death, and overall survival (OS) was estimated by Kaplan-Meier method. Results: 36 pts received I+N in the 2+L setting, including 31/36 with clear-cell histology. Evaluable IMDC-risk at I+N start was favorable in 1/35 and intermediate-poor in 34/35 pts. The most common 1L therapies were anti-VEGF (22/36) and VEGF + ICB (6/36). 11/36 pts had ICB treatment exposure prior to I+N therapy. I+N therapy in the 2L, 3L and 4L was in 21/36, 8/36 and 7/36 pts, respectively, and 7/36 pts continue I+N at data cut-off. 8/36 pts discontinued I+N due to toxicity, 20/36 pts discontinued therapy due to disease progression, and 1 pt discontinued per pt preference. Cohort median OS was 14.8 months (95%CI: 4.2-44). Overall median TTF was 5.0 months (95%CI: 2.9-14.4), and TTF per 2L, 3L and 4+L was 8.3, 8.9 and 2.5 months, respectively. The number of patients who completed all 4 I+N induction cycles in the 2L, 3L, and 4+L was 11/21 (52%), 5/8 (63%), and 1/7 (14%). The number of patients who subsequently received nivolumab maintenance therapy after induction was 16/21 (76%) in the 2L, 1/8 (13%) in the 3L, and 0/7 (0%) in 4+L. Conclusions: With emerging treatment options for mRCC, this study reveals activity and safety for I+N in 2+L settings. In this limited cohort, completion of induction ipilimumab and use of maintenance nivolumab decline in later-line settings, suggesting limitations as salvage therapy. [Table: see text]

Chemotherapy-induced peripheral neuropathy (CIPN) is the most common and debilitating long-term adverse effect of neurotoxic chemotherapy that significantly worsens cancer survivors’ quality of life. Well-tolerated, evidence-based interventions for CIPN are needed.1