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ExteNET showed that neratinib, an irreversible pan-HER tyrosine ki- nase inhibitor, given for 1 year after trastuzumab-based therapy significantly improved inva- sive disease-free survival in women with early-stage HER2-positive breast cancer. We report the final analysis of overall survival in ExteNET.

PURPOSEThe Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007, provide standardized definitions of adjuvant breast cancer clinical trial end points. Given the evolution of breast cancer clinical trials and improvements in outcomes, a panel of experts reviewed the STEEP criteria to determine whether modifications are needed.METHODSWe conducted systematic searches of ClinicalTrials.gov for adjuvant systemic and local-regional therapy trials for breast cancer to investigate if the primary end points reported met STEEP criteria. On the basis of common STEEP deviations, we performed a series of simulations to evaluate the effect of excluding non–breast cancer deaths and new nonbreast primary cancers from the invasive disease–free survival end point.RESULTSAmong 11 phase III breast cancer trials with primary efficacy end points, three had primary end points that followed STEEP criteria, four used STEEP definitions but not the corresponding end point names, and four used end points that were not included in the original STEEP manuscript. Simulation modeling demonstrated that inclusion of second nonbreast primary cancer can increase the probability of incorrect inferences, can decrease power to detect clinically relevant efficacy effects, and may mask differences in recurrence rates, especially when recurrence rates are low.CONCLUSIONWe recommend an additional end point, invasive breast cancer–free survival, which includes all invasive disease–free survival events except second nonbreast primary cancers. This end point should be considered for trials in which the toxicities of agents are well-known and where the risk of second primary cancer is small. Additionally, we provide end point recommendations for local therapy trials, low-risk populations, noninferiority trials, and trials incorporating patient-reported outcomes.

PURPOSETo develop guideline recommendations concerning optimal neoadjuvant therapy for breast cancer.METHODSASCO convened an Expert Panel to conduct a systematic review of the literature on neoadjuvant therapy for breast cancer and provide recommended care options.RESULTSA total of 41 articles met eligibility criteria and form the evidentiary basis for the guideline recommendations.RECOMMENDATIONSPatients undergoing neoadjuvant therapy should be managed by a multidisciplinary care team. Appropriate candidates for neoadjuvant therapy include patients with inflammatory breast cancer and those in whom residual disease may prompt a change in therapy. Neoadjuvant therapy can also be used to reduce the extent of local therapy or reduce delays in initiating therapy. Although tumor histology, grade, stage, and estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) expression should routinely be used to guide clinical decisions, there is insufficient evidence to support the use of other markers or genomic profiles. Patients with triple-negative breast cancer (TNBC) who have clinically node-positive and/or at least T1c disease should be offered an anthracycline- and taxane-containing regimen; those with cT1a or cT1bN0 TNBC should not routinely be offered neoadjuvant therapy. Carboplatin may be offered to patients with TNBC to increase pathologic complete response. There is currently insufficient evidence to support adding immune checkpoint inhibitors to standard chemotherapy. In patients with hormone receptor (HR)-positive (HR-positive), HER2-negative tumors, neoadjuvant chemotherapy can be used when a treatment decision can be made without surgical information. Among postmenopausal patients with HR-positive, HER2-negative disease, hormone therapy can be used to downstage disease. Patients with node-positive or high-risk node-negative, HER2-positive disease should be offered neoadjuvant therapy in combination with anti-HER2-positive therapy. Patients with T1aN0 and T1bN0, HER2-positive disease should not be routinely offered neoadjuvant therapy. Additional information is available at www.asco.org/breast-cancer-guidelines .

Patients selected to receive neoadjuvant chemotherapy (NAC) are usually those at higher risk of relapse, and there is a need to find better therapeutic options for these patients.To determine the efficacy and safety outcomes for patients with hormone receptor (HR)-positive, ERBB2 (formerly HER2)-, high-risk early breast cancer enrolled in the randomized clinical trial monarchE who received NAC.The monarchE randomized clinical trial was a multicenter, phase 3, open-label study that evaluated adjuvant treatment with abemaciclib plus endocrine therapy (ET) compared with ET alone in patients with HR+, ERBB2-, and node-positive early breast cancer who were at high risk of recurrence. Patients were recruited between July 2017 and August 2019 from 603 sites in 38 countries. This subgroup analysis was performed with primary outcome data, with a cutoff date of July 8, 2020.Enrolled patients were randomized (1:1) to receive standard of care ET for at least 5 years with or without treatment with abemaciclib (150 mg, twice daily) for 2 years (treatment period) or until criteria were met for discontinuation.Prior chemotherapy (NAC vs adjuvant vs none) was a stratification factor in monarchE, and and a prespecified exploratory analysis included outcomes in patients who received NAC. The data presented in this article are from the primary outcome analysis (395 invasive disease-free survival [IDFS] events; cutoff date, July 8, 2020; median follow-up 19 months [IQR, 15.6-23.9 months]). Invasive disease-free survival (the primary end point of monarchE) and distant relapse-free survival (DRFS) were evaluated using the Cox proportional hazard model and Kaplan-Meier method.Of the 5637 patients (mean [SD] age, 49.9 [10.6] years; 2046 women [99.5%]; 462 Asian [22.8%], 54 Black [2.7%], and 1473 White participants [70.8%]) enrolled in monarchE, 2056 (37%) received treatment with NAC. In this subgroup, treatment with abemaciclib and ET demonstrated clinically meaningful benefit in IDFS (hazard ratio, 0.61; 95% CI, 0.47-0.80) and DRFS (hazard ratio, 0.61; 95% CI, 0.46-0.81), which corresponded with an absolute improvement of 6.6% in 2-year IDFS rates and 6.7% in 2-year DRFS rates. A consistent treatment benefit was observed across subgroups of pathological breast tumor size or number of positive lymph nodes at surgery.In the randomized clinical trial monarchE, treatment with adjuvant abemaciclib combined with ET demonstrated a clinically meaningful improvement in IDFS and DRFS for patients with HR+, ERBB2-, node-positive, high-risk early breast cancer who received NAC before trial enrollment.ClinicalTrials.gov Identifier: NCT03155997.

Background: Invasive lobular carcinoma (ILC) is the second most common type of invasive breast cancer and accounts for 10-15% of all cases. Though ILC has distinct clinical, prognostic and molecular features, studies are limited and include few patients. ILCs show a decreased response to neoadjuvant chemotherapy and an increased resistance to endocrine therapy. Thus, there is a great need to identify alternative therapies, such as immunotherapy, that could improve overall survival. Success of immunotherapy largely depends on tumor immunogenicity which varies with histologic type. Determination of predictive and prognostic biomarkers for ILC will help determine who can benefit the most. Our study investigates canonical markers of immunogenicity - PD-L1 expression and Tumor Mutational Burden (TMB) - in patients with ILC compared to invasive ductal carcinoma (IDC). We further correlate these markers in different subtypes i.e. hormone receptor positive (HR+), HER2 positive (HER2+), and in triple negative breast cancers (TNBC). We also analyze differences in immune cell profiles constituting the tumor microenvironment (TME) and differences in genomic alterations between ILC and IDC. Methods: A retrospective data analysis was performed to identify breast cancer tumors with ILC or IDC histology profiled at Caris Life Sciences (Phoenix, AZ) that were tested for PD-L1 by SP142 assay and had whole transcriptome sequencing data available. ILC and IDC cases were further subtyped as HR+ and HER2+ and TNBC. PD-L1 expression in immune cell was assessed using Ventana PD-L1 (SP142) histochemical assay and PD-L1 expression in tumor cell was assessed by laboratory developed test using SP142 clone with staining higher than 2+ considered positive. TMB was measured by counting somatic non-synonymous missense mutations on the 592 gene panel (Nextseq) next generation sequencing (NGS) assay, and ≥ 10 mutations/megabase (mut/Mb) was considered high. Using the whole transcriptome RNA sequencing (NovaSeq) data we analyzed the difference in immune cell profiles constituting the TME using a computational RNA deconvolution approach. NGS was used to identify significant differences in genomic alterations between ILC and IDC. Results: We identified 1,359 breast cancer patients (ILC: 194 vs IDC: 1,165). Among ILC, 79% were HR +, 11% TNBC, 10% ILC: 1% vs. IDC: 5% p=0.017). PD-L1 expression in tumor cells was also lower in ILC (ILC 1% vs IDC 5%; p =0.0136). All subtypes of ILC had lower PD-L1 expression in immune and tumor cells when compared to IDC. TMB was similar and comparable in IDC and ILC (median TMB 7 mut/Mb). Assessment of TME showed a significantly increased abundance of cytotoxic lymphocytes and monocytic cells in IDC, and stromal endothelial cells in ILC. Androgen receptor (AR) expression, and mutations in CDH1 (ILC 76% vs IDC 2%) and PIK3CA (ILC 44% vs IDC 30%) were more common in ILC. CDH1 mutation was significantly higher in both TN ILC (ILC 60% vs IDC 1%; p Citation Format: Upama Giri, Joanne Xiu, Tatiana Karadimitriou, Sofi Castanon, Foluso Ademuyiwa, Paula Pohlmann, Elias Obeid, Jasgit Sachdev, Elisa Krill-Jackson, Michael Simon, Antoinette Tan, Neelima Denduluri, Lee Schwartzberg, Michael Korn, Evanthia T Roussos Torres. Molecular evaluation of immunogenicity and genomic alterations in invasive lobular breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-27.

Background Trastuzumab deruxtecan (T-DXd, DS-8201) is an antibody-drug conjugate with a HER2 antibody, tetrapeptide-based cleavable linker, and a novel topoisomerase I inhibitor payload. DESTINY-Breast01 (NCT03248492) is an open-label, international, multicenter, phase 2 study of T-DXd in patients with HER2 positive metastatic breast cancer (MBC) and supported regulatory approval in the US and Japan. Updated longer-term safety and efficacy results are presented here. Methods All patients were required to have MBC that progressed on or after T-DM1. 253 patients were enrolled and 184 received T-DXd 5.4 mg/kg, representing the primary analysis set. The primary endpoint was ORR. Additional endpoints included duration of response, PFS, and OS. Results Patients had received a median of 6 previous lines of treatment for MBC. In this updated data cutoff (8 June 2020) compared to the prior data cutoff (1 Aug 2019), median duration of follow-up has increased from 11.1 to 20.5 mo; 37 patients (20.1%) remain on treatment. Confirmed ORR was 61.4% (12 CRs) with a median duration of response of 20.8 mo; the disease control rate was 97.3% (95% CI, 93.8-99.1). The updated mPFS was 19.4 mo (95% CI, 14.1 mo-NE). Estimated OS was 85% (95% CI, 79%-90%) at 12 months and 74% (95% CI, 67%-80%) at 18 months. The preliminary mOS is 24.6 mo (estimated at 35% maturity with only 17 patients at risk at 24 months). The safety profile of T-DXd was similar as that previously reported; with an additional 9 mo follow-up, only 3 new cases of T-DXd-related interstitial lung disease (ILD) were reported. Results are summarized in the table below. Conclusion Consistent with prior results, T-DXd demonstrated high rates of durable responses in a heavily pretreated population of patients with MBC. From this single-arm, phase 2 study, the PFS and immature OS results are encouraging; these endpoints will be further evaluated in the ongoing randomized controlled studies of T-DXd. For patients who remained on treatment for this longer duration (double that of the previous report), the rate of discontinuation or ILD did not notably increase. Continued attention to pulmonary symptoms and careful monitoring is warranted. Updated Results for DESTINY-Breast011 Aug 2019 datacut8 Jun 2020 datacutPatients remaining on treatment, n/N (%)79/184 (42.9%)37/184 (20.1%)Median duration of follow-up11.1 months20.5 monthsORR60.9%61.4%CR6.0%6.5%PR54.9%54.9%SD36.4%35.9%Duration of response, median (95% CI)14.8 months (13.8-16.9)20.8 months (15.0-NE)PFS, median (95% CI)16.4 months (12.7-NE)19.4 months (14.1-NE)OSMedian (95% CI)NE (NE-NE)24.6 months (23.1-NE)Point estimate at 12 mo (95% CI)86.2% (79.8-90.7)85% (79-90)Point estimate at 18 mo (95% CI)–74% (67-80)SafetyPatients with a TEAE, n (%)183 (99.5%)183 (99.5%)Grade ≥3105 (57.1%)113 (61.4%)Associated with discontinuation28 (15.2%)34 (18.5%)Associated with death10 (5.4%)10 (5.4%)Drug-related ILD per ILD adjudication committeea25 (13.6%)28 (15.2%)Grade 5 drug-related ILD per ILD adjudication committee4 (2.2%)5 (2.7%)a1 grade 1 and 1 grade 3 event are pending adjudication and are not included. Citation Format: Shanu Modi, Cristina Saura, Toshinari Yamashita, Yeon Hee Park, Sung-Bae Kim, Kenji Tamura, Fabrice Andre, Hiroji Iwata, Yoshinori Ito, Junji Tsurutani, Joohyuk Sohn, Neelima Denduluri, Christophe Perrin, Kenjiro Aogi, Eriko Tokunaga, Seock-Ah Im, Keun Seok Lee, Sara A Hurvitz, Javier Cortes, Caleb Lee, Yali Liu, Lin Zhang, Javad Shahidi, Antoine Yver, Jose Baselga, Ian E Krop. Updated results from DESTINY-breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd ) in HER2 positive metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-06.

Background: Three CDK 4/6 inhibitors (inh) are FDA approved in combination with endocrine therapy (ET) for HR+/HER2- metastatic breast cancer (MBC), however, there are no validated predictive markers of response to this class of drugs. Approximately 30-40% of patients (pts) have little to no response to these agents, with disease progression occurring in weeks to a few months after therapy initiation. We conducted an open-label, multicenter clinical trial (NCT03195192) to utilize cutting edge proteomic technologies to map the functional activation of the signaling architecture of pre-treatment tumor tissue from HR+/HER2- MBC pts receiving first line CDK4/6 inh plus ET, and to correlate these functional phosphoprotein-based signaling patterns with 1-year progression-free survival (1-yr PFS). Methods: We enrolled 29 of 100 planned pts, then the study closed early due to slow accrual. All pts were followed up to 12 months from starting a CDK4/6 inhibitor or until disease progression if it occurred earlier. The primary objective of this trial is to assess the correlation between baseline phosphorylated Rb levels that indicate activated Rb in tumor tissue and 1-yr PFS. We hypothesized that high levels of activated Rb will identify pts who are more likely to respond to CDK4/6 inh. Secondary objective is to evaluate the correlation between 1-yr PFS and 8 pre-specified qualifying (protein/phosphoprotein CDK 4/6 kinase pathway biomarkers: total Rb, Rb (S780), total Cyclin D1, Cyclin D1 (S286), total p16INK, total p27, p27 (T187), FoxM1 (T600). Results: Pre-treatment diagnostic FFPE biopsy material available from 24 evaluable pts were analyzed by a Laser Capture Microdissection (LCM) Reverse Phase Protein Microarray (RPPA) workflow. Seventeen of 24 pts (71%) were White, 7 (29%) African American; median age 65 (range 36-79); 22 pts (92%) received an aromatase inh and 2 (8%) had fulvestrant. The primary analysis expressed the relationship between phospho-RB and 1-yr PFS as a 2x2 table of frequencies summarized either above or below the median values observed in all pt values using a Pearson chi-squared test. Similarly, we analyzed the qualified protein/phosphoprotein markers quantified by RPPA by median dichotomization. Univariate analysis showed that 1-yr PFS correlated with below median levels of phospho and total RB (Chi-sq = 8.71, p-value = 0.003); phospho-FoxM1 (Chi-sq = 4.44, p-value = 0.035); Cyclin D1 S286 (Chi-sq = 4.44, p-value = 0.035); total and phospho-p27 and Ki67 (Chi-sq = 4.44, p-value = 0.035). None of these biomarkers were individually significant as continuous variables on multivariate analysis by logistic regression. Conclusions: Functional CDK 4/6 drug target pathway mapping analysis is possible from the pre-treatment diagnostic FFPE material. Our results indicate that pts whose tumors had low inherent proliferative and CDK 4/6 kinase activity were more likely to respond to first line CDK4/6 inh plus ET indicating possible prognostic determinants of the biomarkers. Citation Format: Maysa M Abu-Khalaf, Christos Hatzis, K. Alex Hodge, Frances Valdes, William Sikov, Monica Mita, Neelima Denduluri, Kris Awerkamp, Rita Murphy, Daniel Zelterman, Bryant Dunetz, Emanuel Petricoin, Mariaelena Pierobon. Multiomic advanced diagnostics for CDK 4/6 drug target activation mapping of HR+/HER2- metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-28.

The human epidermal growth factor receptor 2 (HER2), is amplified and/or overexpressed in approximately 15%-20% of breast cancers. Targeting of the HER2 receptor with the humanized monoclonal antibody trastuzumab in combination with chemotherapy has become the backbone of treatment for both early stage and metastatic breast cancer for the last 2 decades. Relapsed or de novo metastatic HER2-positive breast cancer essentially remains an incurable disease. Nonetheless, with advances in therapeutics, survival rates in this group continue to increase with median survival now in excess of 57 months. First line systemic therapy for HER2-positive metastatic breast cancer using taxane chemotherapy combined with trastuzumab and pertuzumab, and second line therapy with trastuzumab emtansine, are well established. Recent studies of small molecule oral tyrosine kinase inhibitors such as tucatinib and neratinib, and antibody drug conjugates such as trastuzumab deruxtecan further improve outcomes. Major treatment challenges remain in the areas of brain metastases and development of drug resistance. This review details an up to date analysis of current and emerging treatments of metastatic HER2-positive breast cancer.

Instances of stomatitis are very painful and compromise nutrition and oral hygiene as well as induce an increased risk for local and systemic infection. Stomatitis is a well-known toxicity of radiotherapy, chemotherapy and other targeted therapies and is associated with dose interruptions, reductions, and treatment discontinuation. For upcoming Dato DXd phase III trials, the mitigation strategies included patient education delivered at the site and supported by printed material to foster continued adherence to an oral care protocol (OCP). The study team thought to leverage digital technology, namely patient-provisioned smartphones to bring the OCP right “to the patients’ fingertips”, while enabling health care providers at the site to monitor onset or worsening of stomatitis for each patient. The digital solution consists of a patient interface for data acquisition and personalized education/behavioral reinforcement, and a clinician interactive data dashboard to access, in real time, patients’ records of stomatitis-related symptoms and their impact on nutrition and hydration, respectively. For a few days post infusion, the solution surfaces personalized illustrated vignettes to provide the participant with simple recommendations for self-care and probe to contact the clinical site team when symptom(s) reach a given morbidity threshold. The clinical team can visualize data on demand or upon being prompted, to quickly assess trends towards stomatitis worsening and decide on the next course of action. This solution for remote patient monitoring of stomatitis risk is deployed in four studies and is planned for an additional three, reaching approximately a total of 7,000 patients across 49 sites in 16 countries. Early feedback from patients confirmed the engaging design, the low burden daily usage, and the perceived utility of the solution. Patients who had experienced stomatitis previously indicated that such a solution would have given them confidence to engage with their site sooner to receive care. Further structured feedback from clinical study teams and analyses of clinical trial data are planned to inform patients’ sustained compliance using the solution and its effectiveness in mitigating high grade of stomatitis and helping patients to better manage their treatment and outcomes. Citation Format: Rebecca H. Wray, Elisabeth Piault, Lucie Miller-Potucka, Jill A. Bell, Rick Fairhurst, Sabrina S. Khan, Micah J. Maxwell, Neelima Denduluri, Leora Horn. Improving treatment outcomes: a digital solution for remote patient monitoring of stomatitis for patients receiving Dato-DXd [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB143.

BACKGROUND: Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation. METHODS: In this two-part, open-label, single-group, multicenter, phase 2 study, we evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine. In the first part of the study, we evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose; in the second part, we evaluated the efficacy and safety of the recommended dose. The primary end point was the objective response, according to independent central review. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety. RESULTS: Overall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval [CI], 53.4 to 68.0). The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95% CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%). CONCLUSIONS: Trastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast01 ClinicalTrials.gov number, NCT03248492.)

BACKGROUND Little is known about longitudinal symptom burden, its consequences for well-being, and whether lifestyle moderates the burden in older survivors. METHODS The authors report on 36-month data from survivors aged ≥60 years with newly diagnosed, nonmetastatic breast cancer and noncancer controls recruited from August 2010 through June 2016. Symptom burden was measured as the sum of self-reported symptoms/diseases as follows: pain (yes or no), fatigue (on the Functional Assessment of Cancer Therapy [FACT]-Fatigue scale), cognitive (on the FACT-Cognitive scale), sleep problems (yes or no), depression (on the Center for Epidemiologic Studies Depression scale), anxiety (on the State-Trait Anxiety Inventory), and cardiac problems and neuropathy (yes or no). Well-being was measured using the FACT-General scale, with scores from 0 to 100. Lifestyle included smoking, alcohol use, body mass index, physical activity, and leisure activities. Mixed models assessed relations between treatment group (chemotherapy with or without hormone therapy, hormone therapy only, and controls) and symptom burden, lifestyle, and covariates. Separate models tested the effects of fluctuations in symptom burden and lifestyle on function. RESULTS All groups reported high baseline symptoms, and levels remained high over time; differences between survivors and controls were most notable for cognitive and sleep problems, anxiety, and neuropathy. The adjusted burden score was highest among chemotherapy-exposed survivors, followed by hormone therapy-exposed survivors versus controls (P

BACKGROUND Sleep disturbance and genetic profile are risks for cognitive decline in noncancer populations, yet their role in cancer-related cognitive problems remains understudied. This study examined whether sleep disturbance was associated with worse neurocognitive outcomes in breast cancer survivors and whether sleep effects on cognition varied by genotype. METHODS Newly diagnosed female patients (n = 319) who were 60 years old or older and had stage 0 to III breast cancer were recruited from August 2010 to December 2015. Assessments were performed before systemic therapy and 12 and 24 months later. Neuropsychological testing measured attention, processing speed, executive function, learning, and memory; self-perceived cognitive functioning was also assessed. Sleep disturbance was defined by self-report of routine poor or restless sleep. Genotyping included APOE, BDNF, and COMT polymorphisms. Random effects fluctuation models tested associations of between-person and within-person differences in sleep, genotype, and sleep-genotype interactions and cognition and controlled for age, reading level, race, site, and treatment. RESULTS One-third of the patients reported sleep disturbances at each time point. There was a sleep-APOE e4 interaction (P = .001) in which patients with the APOE e4 allele and sleep disturbances had significantly lower learning and memory scores than those who were APOE e4-negative and without sleep disturbances. There was also a sleep disturbance-COMT genotype interaction (P = .02) in which COMT Val carriers with sleep disturbances had lower perceived cognition than noncarriers. CONCLUSIONS Sleep disturbance was common and was associated with worse cognitive performance in older breast cancer survivors, especially those with a genetic risk for cognitive decline. Survivorship care should include sleep assessments and interventions to address sleep problems.

Purpose The effects of chemotherapy dose intensity on survival in patients with advanced non-small-cell lung cancer (NSCLC) are poorly understood. We retrospectively analyzed dose delays/reduction, relative dose intensity (RDI), and the association between chemotherapy intensity and survival in advanced NSCLC. Methods This retrospective cohort study included adults with advanced lung cancer who received first-line myelosuppressive platinum-based chemotherapy (January 2007–December 2010) in ~ 230 US Oncology Network community practices. Dose delays ≥ 7 days, dose reductions ≥ 15%, and RDI relative to standard regimens were described. Overall survival (OS) was measured using Kaplan-Meier and Cox proportional hazard (PH) models. Results Among 3866 patients with advanced NSCLC, 32.4% experienced dose delays ≥ 7 days, 50.1% experienced dose reductions ≥ 15%, and 40.4% had RDI

Increasing enrollment into clinical trials is a top priority across the field of oncology. Because the vast majority of those afflicted with cancer receive their care in the community, creating strong clinical research programs in the community-based setting is important. This article comprehensively outlines the most important elements of creating and sustaining a successful community-based research program. Establishing a clear mission and defining the scope of the research program in collaboration with key physicians and administrative leadership are critical to success. Standard operating procedures should detail operational processes. Ensuring sound financial planning and protected physician time are crucial for a healthy program. Providing mentorship opportunities to investigators and other team members will provide necessary guidance for junior investigators and long-term program stability. Prioritizing provider and patient volunteer engagement through education and awareness will potentially improve enrollment and research ownership. Incorporating administrative and clinical research staff and health care providers, including physicians, advanced practice providers, and pharmacists, will result in a multidisciplinary and unified approach and may also promote research as a routine part of patient care. Regular safety and scientific meetings will reduce regulatory complications and, most importantly, improve patient care. Other keys to a successful program include establishing a diverse trial portfolio, collaboration between different institutions, and ensuring appropriate technological infrastructure. Serial programmatic review provides opportunities to refine suboptimal practices and recognize successful strategies. Community-based research programs are critical to improve access to optimal cancer care. Implementation of successful programs is possible with a collaborative and multidisciplinary approach.

PURPOSE The aim of this work is to update key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer. METHODS An Expert Panel conducted a targeted systematic literature review guided by a signals approach to identify new, potentially practice-changing data that might translate into revised guideline recommendations. RESULTS The Expert Panel reviewed abstracts from the literature review and identified one article for inclusion that reported results of the phase III, open-label KATHERINE trial. In the KATHERINE trial, patients with stage I to III human epidermal growth factor receptor 2 (HER2)–positive breast cancer with residual invasive disease in the breast or axilla after completing neoadjuvant chemotherapy and HER2-targeted therapy were allocated to adjuvant trastuzumab emtansine (T-DM1; n = 743) or to trastuzumab (n = 743). Invasive disease–free survival was significantly higher in the T-DM1 group than in the trastuzumab arm (hazard ratio, 0.50; 95% CI, 0.39 to 0.64; P < .001), and risk of distant recurrence was lower in patients who received T-DM1 than in patients who received trastuzumab (hazard ratio, 0.60; 95% CI, 0.45 to 0.79). Grade 3 or higher adverse events occurred in 190 patients (25.7%) who received T-DM1 and in 111 patients (15.4%) who received trastuzumab. RECOMMENDATIONS Patients with HER2-positive breast cancer with pathologic invasive residual disease at surgery after standard preoperative chemotherapy and HER2-targeted therapy should be offered 14 cycles of adjuvant T-DM1, unless there is disease recurrence or unmanageable toxicity. Clinicians may offer any of the available and approved formulations of trastuzumab, including trastuzumab, trastuzumab and hyaluronidase-oysk, and available biosimilars. Additional information can be found at www.asco.org/breast-cancer-guidelines

Bilateral salpingo-oophorectomy (BSO) is a risk management approach with strong evidence of mortality reduction for women with germline mutations in the tumor suppressor genes BRCA1 and BRCA2 (BRCA1/2). Few studies to date have evaluated uptake of BSO in women from diverse racial and ethnic backgrounds who carry BRCA1/2 mutations. The objective of the UPTAKE study was to explore rates and predictors of risk-reducing BSO among Latinas affected and unaffected with breast cancer who had a deleterious BRCA1/2 mutation. We recruited 100 Latina women with deleterious BRCA1/2 mutations from community hospitals, academic health systems, community, and advocacy organizations. Women completed interviews in Spanish or English. We obtained copies of genetic test reports for participants who provided signed medical release. After performing threefold cross-validation LASSO for variable selection, we used multiple logistic regression to identify demographic and clinical predictors of BSO. Among 100 participants, 68 had undergone BSO at the time of interview. Of these 68, 35 were US-born (61% of all US-born participants) and 33 were not (77% of the non-US-born participants). Among Latinas with BRCA1/2 mutations, older age (p = 0.004), personal history of breast cancer (p = 0.003), higher income (p = 0.002), and not having a full-time job (p = 0.027) were identified as variables significantly associated with uptake of BSO. Results suggest a high rate of uptake of risk-reducing BSO among a sample of Latinas with BRCA1/2 mutations living in the US. We document factors associated with BSO uptake in a diverse sample of women. Relevant to genetic counseling, our findings identify possible targets for supporting Latinas' decision-making about BSO following receipt of a positive BRCA1/2 test.

Background [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is an antibody-drug conjugate with a HER2 antibody, peptide-based cleavable linker, and a novel topoisomerase I inhibitor payload. In a phase 1 trial, the objective response rate (ORR) was 59.5% (66/111) and median progression-free survival (PFS) was 22.1 mo in subjects with HER2-positive metastatic breast cancer (BC) previously treated with T-DM1 (Tamura, Lancet Oncol, 2019). DESTINY-Breast01 (NCT03248492) is an open-label, international, multicenter, phase 2 registration study of T-DXd in subjects with centrally confirmed HER2-positive metastatic BC. Methods Part 1 of this 2-part study was performed in 2 stages (pharmacokinetics and dose finding; T-DXd 5.4, 6.4, 7.4 mg/kg) and served to identify the recommended Part 2 dose (RP2D). In Part 2, subjects were treated at the RP2D. Subjects in Parts 1 and 2a were required to have metastatic BC that progressed on or after T-DM1. Subjects in a small additional cohort (Part 2b) had discontinued T-DM1 for reasons other than progression. The primary endpoint was ORR (complete response [CR] + partial response [PR]) per independent central review (ICR). Additional endpoints included disease control rate (DCR; CR + PR + stable disease [SD]), duration of response (DOR), and PFS. Abstract results represent 6 mo of follow-up from the date the last subject enrolled in the study. Results As of data cutoff (March 21, 2019), 253 subjects were enrolled and 184 received the RP2D (5.4 mg/kg), 4 of which were enrolled in Part 2b. All subjects were female, 55% were white, and 38% were Asian. Median age was 55 y (range, 28-96 y; ≥ 65 y, 24%); 53% were hormone receptor (HR) positive and 45% were HR negative. Median number of prior treatment regimens was 6 (range, 2-27), including trastuzumab (100%), T-DM1 (100%), pertuzumab (66%), and other HER2-targeted regimens (54%). The reported best response to T-DM1 before enrollment was 22% CR or PR, 21% SD, and 36% progressive disease (PD); 21% were not evaluable. At data cutoff, 60% of subjects remained on T-DXd treatment; primary reasons for discontinuation were PD (21%) and treatment-related adverse events (TEAEs, 8%). The confirmed ORR by ICR in subjects treated at the RP2D in Parts 1, 2a, and 2b was 60% (111/184 [95% CI, 53%-68%]). ORRs were consistent across subgroups, including those with prior pertuzumab (64%) and those with ≥ 3 prior regimens (59%). The DCR was 97% (95% CI, 94%-99%); only 5 of 184 subjects did not have SD or better at the time of first post-baseline scan. As of the data cutoff, median DOR and PFS had not been reached; median duration of follow up was 7.2 mo (range, 0.7-17.2 mo). In the 184 subjects, the median treatment duration was 6.9 mo (range, 0.7-16 mo); 70% had > 6 mo of treatment. TEAEs occurred in 99% of subjects (grade ≥ 3, 51%); the most common any-grade TEAEs were gastrointestinal (nausea [77%], vomiting [45%], constipation [34%], decreased appetite [29%], and diarrhea [27%]), alopecia (48%), fatigue (48%), and hematologic (decreased neutrophil count [31%] and anemia [26%]). Most common grade ≥ 3 AEs were decreased neutrophil count (17%), nausea (7.6%), anemia (6.5%), decreased lymphocyte count (5.4%), and fatigue (5.4%). 15 subjects (8.2%) had interstitial lung disease (ILD) adjudicated as ILD related to T-DXd by an independent adjudication committee; ILD was primarily grade 1 or 2 (6.0%; no grade 3 or 4; 2.2% grade 5). [Additional follow up and first DOR/PFS data will be presented at the meeting.] Conclusion Overall, T-DXd treatment demonstrated clinically meaningful and durable activity in a heavily pretreated patient population with HER2-positive metastatic BC. T-DXd had a generally manageable safety profile, with ILD identified as a risk warranting proactive awareness and management. Citation Format: Ian E Krop, Cristina Saura, Toshinari Yamashita, Yeon Hee Park, Sung-Bae Kim, Kenji Tamura, Fabrice André, Hiroji Iwata, Yoshinori Ito, Junji Tsurutani, Joohyuk Sohn, Neelima Denduluri, Christophe Perrin, Kenjiro Aogi, Eriko Tokunaga, Seock-Ah Im, Keun Seok Lee, Sara Hurvitz, Javier Cortes, Caleb Lee, Shuquan Chen, Lin Zhang, Javad Shahidi, Antoine Yver, Shanu Modi. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: A phase 2, multicenter, open-label study (DESTINY-Breast01) [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 GS1-03.

The effects of chemotherapy dose intensity on patient outcomes in advanced cancer are not well understood. We studied the association between chemotherapy relative dose intensity (RDI) and overall survival (OS) among patients with advanced breast or ovarian cancer.This retrospective cohort study included adults with advanced breast or ovarian cancer who received first-line myelosuppressive chemotherapy (January 2007 to December 2010) in US Oncology Network community practices. Dose delays ≥ 7 days, dose reductions ≥ 15%, and RDI relative to standard regimens were described. OS was measured by the Kaplan-Meier method and Cox proportional hazards models.Among 874 patients with advanced breast cancer, 33.2% experienced dose delays ≥ 7 days, 48.7% experienced dose reductions ≥ 15%, and 38.9% had RDI 85%. In the multivariable Cox proportional hazards model, Eastern Cooperative Oncology Group performance status 1/2 versus 0 (hazard ratio [HR] = 1.45; 95% confidence interval [CI], 1.15-1.82) and triple-negative status (HR = 3.14; 95% CI, 1.15-8.62) were significantly associated with mortality. Among 170 patients with advanced ovarian cancer, 43.5% experienced dose delays ≥ 7 days, 48.2% experienced dose reductions ≥ 15%, and 46.5% had RDI 85%. In the multivariable Cox proportional hazards model, dose reductions ≥ 15% (HR = 1.94; 95% CI, 1.09-3.46) and other tumor histology (vs. nonserous adenocarcinoma; HR = 3.55; 95% CI, 1.38-9.09) were significantly associated with mortality.Dose delays, dose reductions, and reduced RDI were common. In advanced breast cancer, health status and triple-negative disease were significantly associated with mortality. In advanced ovarian cancer, dose reductions and tumor histology were significantly associated with mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality.

Purpose To update key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer. Methods An Expert Panel conducted targeted systematic literature reviews guided by a signals approach to identify new, potentially practice-changing data that might translate to revised practice recommendations. Results The Expert Panel reviewed phase III trials that evaluated adjuvant capecitabine after completion of standard preoperative anthracycline- and taxane-based combination chemotherapy by patients with early-stage breast cancer HER2-negative breast cancer with residual invasive disease at surgery; the addition of 1 year of adjuvant pertuzumab to combination chemotherapy and trastuzumab for patients with early-stage, HER2-positive breast cancer; and the use of neratinib as extended adjuvant therapy for patients after combination chemotherapy and trastuzumab-based adjuvant therapy with early-stage, HER2-positive breast cancer. Recommendations Patients with early-stage HER2-negative breast cancer with pathologic, invasive residual disease at surgery following standard anthracycline- and taxane-based preoperative therapy may be offered up to six to eight cycles of adjuvant capecitabine. Clinicians may add 1 year of adjuvant pertuzumab to trastuzumab-based combination chemotherapy in patients with high-risk, early-stage, HER2-positive breast cancer. Clinicians may use extended adjuvant therapy with neratinib to follow trastuzumab in patients with early-stage, HER2-positive breast cancer. Neratinib causes substantial diarrhea, and diarrhea prophylaxis must be used. Additional information can be found at www.asco.org/breast-cancer-guidelines .

Advances in treatment for women with advanced breast cancer (ABC) have led to improvements in survival. Although the condition remains incurable, treatment goals focus on stabilizing disease, prolonging life, and maintaining patient quality of life. Hormone receptor-positive (HR+) subtypes constitute the majority of breast cancers, and an increasing number of effective endocrine therapies are available. Although practice guidelines provide important recommendations and principles for treatment selection, the choice of specific agents from among existing options should be customized to the individual based on patient and disease characteristics, as well as the nature and duration of response to previous treatments. This review examines endocrine and endocrine-based options, including combinations with targeted agents, for HR+ and human epidermal growth factor receptor 2-negative (HER2-) ABC. It also elaborates on the factors that enter into treatment decision-making, using patient case examples to illustrate how ABC can present and the clinical issues involved in treatment selection. Case examples are included to provide evidence for the clinical scenarios of de novo HR+/HER2- ABC and progression during adjuvant treatment for early breast cancer.

Background: Poor clinical outcomes are noted in pts with TNBC who do not achieve a pathologic complete response (pCR). We characterized peripheral immune subsets and the role of minimal residual disease (MRD) detection via ctDNA in pts who participated in the OXEL study. Methods: OXEL (Opdivo® -XELoda ®) is a recently completed phase II open-label 3-arm randomized study of nivolumab (nivo), capecitabine (cape) or the combination as adjuvant therapy (tx) for pts with residual TNBC after appropriate neoadjuvant chemo. Residual disease was defined as ≥ 1.0 cm of primary tumor and/or nodal involvement. Eligible pts had completed definitive local tx. Pts were randomly assigned to nivo 360 mg iv q3wks x 6 (arm A); cape 1250mg/m2 po bid D1-D14 q3 wks x 6 (arm B); nivo 360mg iv q3wks + cape 1250mg/m2 po bid D1-D14 q3 wks x 6 (arm C). Peripheral blood mononuclear cells (PBMCs) and ctDNA were assessed at baseline (D1 of cycle 1), 6, and 12 wks and at time of recurrence, if applicable. PBMCs were stained with 30 markers and analyzed by flow cytometry to identify changes in 158 immune cell subsets at 6 wks, as a percent of total PBMCs. RaDaRTM, a deep sequencing based, tumor-informed personalized assay was utilized to detect the presence of ctDNA in plasma. Distant disease-free survival (DDFS) and overall survival (OS) were analyzed by the Kaplan-Meier method and Log-Rank test was used to compare DDFS and OS according to baseline MRD results. All pts will be followed for distant recurrence and survival for 3 yrs. Here we report the translational endpoints of the OXEL study. Clinical endpoints according to treatment received will be reported in a future analysis. Results: 45 pts were enrolled between 8/2018 and 6/2021. 29 (64%) were Caucasian and 14 (31%) were African American. Mean age at enrollment was 51 [+/- 12]. 93% of pts received a taxane-anthracycline containing neoadjuvant tx. 15 pts were randomized to each arm. DDFS probability at 1-yr and 2-yrs was 0.71 (+/- 0.07) and 0.66 (+/- 0.08) respectively. At 12 mos of median follow up, 13/45 pts (29%) experienced distant recurrence, none had local recurrence. 43 pts were evaluated for PBMC subsets. Changes in PBMC subsets at 6 wks were different amongst the arms; in arm A, reductions in NK subsets, including a 33% reduction in CD56dimCD16- cells, were observed, while in arm B, increases in naïve CD4+ T cells (+45%) and CD73+CD8+ T cells (+12%) and reductions in ki67+CD8+ T cells (-48%) were noted. In arm C, increases were observed in conventional dendritic cells (+36%), effector memory ki67+CD4+ T cells (+46%), and CD56dimCD16- NK cells (+29%). 33 pts underwent successful MRD analysis. 12/33 (36%) pts were MRD+ at baseline. 2/12 pts MRD+ at baseline subsequently cleared MRD, with undetectable ctDNA on future time points; neither patient has had recurrence to date. The remaining 10/12 MRD+ pts (83%) have experienced distance recurrence. 21/33 (64%) pts were ctDNA negative at baseline; 20/33 remained negative for all follow up timepoints. 10/11 pts experiencing distant recurrence were MRD+ at baseline, compared to 1/11 pt who became MRD+ at wk 6 post initiation of tx. At 12 mos of median follow-up, baseline MRD+ testing was significantly associated with an inferior DDFS ( p Citation Format: Filipa Lynce, Candace Mainor, Xue Geng, Greg Jones, Ilana Schlam, Hongkun Wang, Ute Feger, Renee Donahue, Nicole Toney, Caroline Jochems, Jeffrey Schlom, Christopher Gallagher, Rita Nanda, Deena Graham, Erica M Stringer-Reasor, Neelima Denduluri, Julie Collins, Asma A Dilawari, Ami Chitalia, Shruti Tiwari, Raquel Nunes, Rebecca Kaltman, Katia Khoury, Margaret Gatti-Mays, Sandra M Swain, Heather A. Parsons, Paula Pohlmann, Claudine Isaacs. Peripheral immune subsets and circulating tumor DNA (ctDNA) in patients (pts) with residual triple negative breast cancer (TNBC) treated with adjuvant immunotherapy and/or chemotherapy (chemo): The OXEL study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD9-02.

Background: Neratinib is a pan-HER tyrosine kinase inhibitor that blocks the PI3K/Akt and MAPK signaling pathways downstream from HER2. The international, randomized, placebo-controlled phase III ExteNET trial showed that a 1-year course of neratinib after trastuzumab-based adjuvant therapy significantly improved 2-year invasive disease-free survival (iDFS) in early-stage HER2+ breast cancer (HR 0.67; 95% CI 0.50–0.91; p=0.0091) [Chan et al. Lancet Oncol 2016]. Furthermore, the effects of neratinib on iDFS were shown to be durable at 5 years' follow-up (HR 0.73; 95% CI 0.57–0.92; p=0.008) [Martin et al. ESMO 2017]. PIK3CA alterations are common in HER2+ breast cancers, and in general are associated with a worse prognosis. We sought to assess the prognostic and predictive significance of PIK3CA alterations in an exploratory substudy of the ExteNET trial. Methods: ExteNET is an international, multi-center, randomized, double-blind, placebo-controlled phase III trial (Clinicaltrials.gov: NCT00878709). Patients received oral neratinib 240 mg/day or placebo for 1 year. Of the intent-to-treat (ITT) population (n=2840), primary formalin-fixed paraffin-embedded (FFPE) tumor specimens were available from 991 patients for PIK3CA mutation testing by RT-PCR for two hot-spot mutations in exon 9 (E542K, E545K/D) and one hot-spot mutation in exon 20 (H1047R). 702 FFPE tumor slides underwent FISH analysis for PIK3CA amplification with a ratio of ≥2.2 considered as amplified. Primary endpoint: iDFS. iDFS events were tested by 2-sided log-rank tests, and HR (95% CI) were estimated using Cox proportional-hazards models. Data cut-off: March 2017. Results: Baseline demographics and disease characteristics between treatment arms of the correlative cohort (n=1201) were balanced. Overall, 21.2% (n=210) of primary tumors harbored one of the specified PIK3CA mutations, and 8.7% (n=61) were PIK3CA FISH-amplified. Patients with PIK3CA-altered tumors (i.e. PIK3CA mutations or FISH-amplified) had fewer iDFS events with neratinib compared with placebo (HR 0.41; 95% CI 0.17-0.90, p=0.028). The interaction test was not significant (p=0.1842). Results of the various correlative analyses within treatment arms are shown in the table. NeratinibPlacebo iDFS iDFS 2-sidedPopulationnevents, nnevents, nHR (95% CI)P valueaITT142011614201630.73 (0.57–0.92)b0.008bCorrelative cohort59345608700.67 (0.45–0.96)0.0317PIK3CA-mutation positive1047106170.43 (0.17–1.01)0.056PIK3CA-mutation negative38527396420.66 (0.40-1.06)0.089PIK3CA-amplified3312840.20 (0.01-1.33)0.106PIK3CA-non-amplified31629325360.85 (0.52-1.39)0.521PIK3CA-altered1308132200.41 (0.17-0.90)0.028a. Log-rank test; b. Stratified analysis Conclusions: One year of neratinib treatment after trastuzumab-based adjuvant therapy significantly improves iDFS after 5 years in patients with early-stage HER2+ breast cancer. From this modest-sized exploratory cohort, it appears that PIK3CA may be a biomarker for differential sensitivity to neratinib after 1 year of trastuzumab in the adjuvant setting.These exploratory results should be validated in a larger subset. Citation Format: Chia SKL, Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, von Minckwitz G, Mansi J, Barrios CH, Gnant M, Tomašević Z, Denduluri N, Šeparović R, Kim S-B, Hugger Jakobsen E, Harvey V, Robert N, Smith II J, Harker G, Lalani AS, Zhang B, Eli LD, Buyse M, Chan A. PIK3CA alterations and benefit with neratinib after trastuzumab-based adjuvant therapy in early-stage HER2+ breast cancer: Correlative analyses of the phase III ExteNET trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-12.

Background Oncotype DX Recurrence Score (RS) is used to stratify breast tumors into those likely to respond to cytotoxic chemotherapy. Women and men with hereditary cancers tend to have tumors that are chemosensitive. We hypothesize that a high RS may harbor a signal of potential hereditary risk. This analysis aims to identify whether breast cancer patients with hereditary cancer syndromes have a disproportionate amount of high RS compared to sporadic cases. Methods Individuals with a personal history of breast cancer who received treatment at participating research facilities and had hormone receptor positive breast cancer, Oncotype DX testing and hereditary cancer mutation testing were included. Oncotype DX RS was recorded along with the type of genetic testing and the genetic testing results. RS was categorized as low (0-17), intermediate (18-30), and high (31+). Those with deleterious mutations in any known hereditary cancer gene were considered positive. Individuals with a variant of uncertain significance (VUS) or negative genetic testing result were considered negative. Difference in distribution of tumors with low, intermediate, and high Oncotype DX results in those with hereditary breast cancers compared to those with sporadic breast cancers was determined with Chi-square. Results 419 patients with Oncotype DX testing from two clinical sites were collected from 2013. Of those, 123 underwent genetic risk assessment. Mutations identified included the following genes: BRCA1 (1), BRCA2 (5); CHEK2 (3); BRIP1 (3); NBN (2); MSH6 (1). Of those testing positive for a deleterious mutation, the number of patients with RS results in each category were 5, 4 and 6 for low, intermediate and high, respectively. For those considered negative on hereditary cancer panel testing, the RS results were 76, 52 and 8, respectively. Of those with high RS, 43% had deleterious mutations. Chi square test was statistically significant for a difference between the RS of those with deleterious hereditary mutations versus those with sporadic cancers (p = 0.000086). Conclusions High RS may indicate a higher likelihood of harboring a hereditary cancer syndrome. Further investigation with larger numbers and multivariate analysis is needed to validate if a high RS serves as an independent predictor of benefit from genetic counseling and testing. Citation Format: Toltzis S, Casasanta N, Lipinski S, Marino A, McHenry A, Denduluri N, Rodriguez P, Kaltman R. Relationship between hereditary cancer syndromes and oncotype DX recurrence score [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-21.

PurposeCardiac dysfunction is a serious adverse effect of certain cancer-directed therapies that can interfere with the efficacy of treatment, decrease quality of life, or impact the actual survival of the patient with cancer. The purpose of this effort was to develop recommendations for prevention and monitoring of cardiac dysfunction in survivors of adult-onset cancers.MethodsRecommendations were developed by an expert panel with multidisciplinary representation using a systematic review (1996 to 2016) of meta-analyses, randomized clinical trials, observational studies, and clinical experience. Study quality was assessed using established methods, per study design. The guideline recommendations were crafted in part using the Guidelines Into Decision Support methodology.ResultsA total of 104 studies met eligibility criteria and compose the evidentiary basis for the recommendations. The strength of the recommendations in these guidelines is based on the quality, amount, and consistency of the evidence and the balance between benefits and harms.RecommendationsIt is important for health care providers to initiate the discussion regarding the potential for cardiac dysfunction in individuals in whom the risk is sufficiently high before beginning therapy. Certain higher risk populations of survivors of cancer may benefit from prevention and screening strategies implemented during cancer-directed therapies. Clinical suspicion for cardiac disease should be high and threshold for cardiac evaluation should be low in any survivor who has received potentially cardiotoxic therapy. For certain higher risk survivors of cancer, routine surveillance with cardiac imaging may be warranted after completion of cancer-directed therapy, so that appropriate interventions can be initiated to halt or even reverse the progression of cardiac dysfunction.

One year of trastuzumab dramatically improves outcomes in early HER2 positive breast cancer, irrespective of anatomic stage, receptor status and chemotherapy backbone. However, up to 25% of breast cancers treated with trastuzumab and chemotherapy recur. Here, we review the current role for additional HER2 blockade to adjuvant trastuzumab. Adjuvant pertuzumab and neratinib modestly improve disease-free survival in early breast cancer, particularly for those at highest risk of recurrence. Lack of complete pathologic response to preoperative chemotherapy and HER2 targeted therapies is associated with worse outcomes. In those with lack of pCR, adjuvant trastuzumab emtansine improves outcome in early breast cancer, irrespective of chemotherapy and HER2 targeted therapy backbone. Preoperative chemotherapy and HER2 targeted therapy should be discussed in early breast cancer, especially in tumors over 2 cm. Future trials must focus on de-escalation of chemotherapy and biomarkers for further tailored therapy in early HER2 positive breast cancer.

Since the beginning of its guidelines program in 1993, ASCO has continually sought ways to produce a greater number of guidelines while maintaining its commitment to using the rigorous development methods that minimize the biases that threaten the validity of practice recommendations. ASCO is implementing a range of guideline development and implementation innovations. In this article, we describe innovations that are designed to (1) integrate consideration of multiple chronic conditions into practice guidelines; (2) keep more of its guidelines current by applying evolving signals or (more) rapid, for-cause updating approaches; (3) increase the number of high-quality guidelines available to its membership through endorsement and adaptation of other groups’ products; (4) improve coverage of its members’ guideline needs through a new topic nomination process; and (5) enhance dissemination and promote implementation of ASCO guidelines in the oncology practice community through a network of volunteer ambassadors. We close with a summary of ASCO’s plans to facilitate the integration of data from its rapid learning system, CancerLinQ, into ASCO guidelines and to develop tactics through which guideline recommendations can be embedded in clinicians’ workflow in digital form. We highlight the challenges inherent in reconciling the need to provide clinicians with more interactive, point-of-care guidance with ASCO’s abiding commitment to methodologic rigor in guideline development.

Background: The benefits of immune check point inhibition (ICI) are primarily seen in immunogenic cancer types. Unfortunately, most breast cancers are non-immunogenic, and therefore new approaches that target tumor immunogenicity are key to increasing the efficacy of ICI. Even within a single breast cancer subtype, patients with liver metastases are less responsive to ICI as compared to other metastatic sites. Therefore, the objective of this analysis is to investigate differences in prognostic and predictive ICI related biomarkers such as PD-L1 expression, tumor mutation burden (TMB), and immune-cell populations between primary tumors, liver metastases (LM) and non-liver metastatic (NLM) sites from breast cancer patients. Our goal is to provide an in-depth analysis of current and potential markers of immunogenicity within LM and NLM. Methods: Unpaired samples taken from primary and recurrent breast (BT), liver metastases (LM) and non-liver metastases (NLM) (all identified as breast cancer) were compared using Fisher-exact or Chi2 and corrected for multiple comparison. Tumors were classified as hormone receptor positive (HR+), HER2+ or triple negative breast cancer (TNBC). Breast cancer samples were tested using NextGen DNA sequencing (NextSeq, 592 gene panel) and whole transcriptome RNA sequencing (NovaSeq). PDL1 was scored on immune cells using VENTANA PD-L1 (SP142) assay. TMB was measured by counting somatic non- synonymous missense mutations on the 592 gene panel and ≥ 10 mutations/Megabase (mut/Mb) was considered high. MCP counter was used to evaluate relative cell abundance (in arbitrary units) in TME using transcriptome data. Results: Biopsies from 3166 tumors were queried, 1268 of which were from BT, 495 from LM, and 1403 from NLM, all are unpaired. All histologic subtypes are represented. HR+ breast cancer was the most prevalent among LM. Both metastatic groups (LM and NLM) were significantly more likely to have a high TMB as compared to BT (24.8 & 24.8 vs. 16.6%, p 12.9%), were observed in LM vs. BT. Conclusions: In this patient cohort, immune cells within the TME of LM were less abundant and suggest the liver is a less immunogenic niche. However, LM had increased TMB as compared to breast tumors, suggesting that immunosuppressive cells (i.e. Tregs and MDSCs) or cytokines, may be preventing cytotoxic immune cell infiltration into the TME. Moreover, immune cell populations within LM had decreased PD-L1 expression when compared to breast tumors, suggesting another mechanism that could explain the lack of response to ICI in such patients. Further characterization of the genetic and molecular alterations of breast cancer LM and NLM will help identify additional biomarkers of response and determine their role in defining tumor immune response to ICI. Citation Format: Sofi Castanon, Daniel Flores, Joanne Xiu, Paula R. Pohlmann, Foluso Ademuyiwa, Elia Obeid, Jasgit Sachdev, Michael Simon, Elisa Krill Jackson, Lee Schwartzberg, Antoinette R Tan, Neelima Denduluri, W. Michael Korn, Evanthia T Roussos Torres. The immune microenvironment of liver metastasis as a guide for immunotherapeutic potential in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-02.

Background: Neratinib (NERLYNX®) is an irreversible pan-HER inhibitor that significantly improves invasive disease-free survival (iDFS) compared with placebo when given as extended adjuvant therapy in patients with HER2-positive (HER2+) early breast cancer after trastuzumab-based adjuvant therapy. In the phase 3 ExteNET trial, an absolute iDFS benefit of 2.5% and distant disease-free survival (DDFS) benefit of 1.7% were observed with neratinib after 5 years’ follow-up. As reflected in the approved indication by the European Medicines Agency (EMA), patients with hormone receptor-positive (HR+) disease who initiated neratinib treatment within 1 year of completing trastuzumab (HR+/≤1 year) experienced an absolute iDFS benefit of 5.1% and DDFS benefit of 4.7% at 5 years. In HR+/≤1 year patients with residual disease after neoadjuvant therapy, absolute 5-year iDFS and DDFS benefits of 7.4% and 7.0%, respectively, were observed. Here we report the final protocol-defined, event-driven analysis of overall survival (OS) from ExteNET, and provide descriptive analyses of subgroups of primary interest according to the EU label and current clinical practice in early-stage HER2+ disease. Methods: ExteNET was a multicenter, randomized, double-blind, placebo-controlled phase 3 trial of women with early-stage HER2+ breast cancer who had completed neoadjuvant or adjuvant trastuzumab plus chemotherapy (NCT00878709). Patients were randomly assigned to oral neratinib 240 mg/day or placebo for 1 year. Hazard ratios (HR) for OS were estimated from Cox proportional hazards models, and survival rates by the Kaplan-Meier method. The OS analysis was event-driven and powered for the intention-to-treat (ITT) population with a target of 248 events. Descriptive analyses were performed in the HR+/≤1 year subgroup per the approved indication in the EU, and in higher-risk patients, i.e. HR+/≤1 year who have residual disease after neoadjuvant therapy [i.e. those who did not achieve a pathologic complete response (pCR)]. Cut-off date: July 2019. Results: 2840 patients were randomized to study treatment (1420 per group). After a median follow-up of 8.1 years, 127 (8.9%) and 137 (9.6%) patients in the neratinib and placebo ITT groups had died, respectively. The 8-year OS rates were 90.1% (95% CI, 88.3–91.6) in the neratinib group and 90.2% (95% CI, 88.4–91.7) in the placebo group (absolute difference at 8 years -0.1%; stratified HR=0.95; 95% CI, 0.75–1.21; p=0.6914). A positive trend was seen in the prespecified HR+ subgroup (n=1631; absolute difference at 8 years 1.5%; HR=0.80; 95% CI, 0.58–1.12), and within this population, descriptive analyses suggested greater benefits with neratinib in the HR+/≤1 year subgroup (n=1334; absolute difference at 8 years 2.1%; HR=0.79; 95% CI, 0.55–1.13) and in the HR+/≤1 year subset with no pCR after neoadjuvant therapy (n=295; absolute difference at 8 years 9.1%; HR=0.47; 95% CI, 0.23–0.92). No new safety signals were reported with this long-term follow-up to 8 years. Conclusions: In this final OS analysis of ExteNET, there were fewer deaths with neratinib than placebo in the ITT population, but the results did not reach statistical significance. Analyses showed greater OS improvements with neratinib in subgroups including HR+/≤1 year, and HR+/≤1 year with residual disease after neoadjuvant therapy. These findings are consistent with the results based on the primary endpoint of iDFS, and support the use of neratinib in clinical practice in these patients. Citation Format: Frankie Ann Holmes, Beverly Moy, Suzette Delaloge, Stephen Chia, Bent Ejlertsen, Janine Mansi, Hiroji Iwata, Michael Gnant, Mark Buyse, Carlos Barrios, Tajana Silovski, Robert Separovic, Anna Bashford, Angel Guerrero-Zotano, Neelima Denduluri, Debra Patt, Erhan Gokmen, Ira Gore, John Smith, Richard Bryce, Feng Xu, Alvin Wong, Miguel Martin, Arlene Chan. Continued efficacy of neratinib in patients with HER2-positive early-stage breast cancer: Final overall survival analysis from the randomized phase 3 ExteNET trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-03.

Oncotype DX (ODX) is a genomic assay of tumor tissue that is utilized to predict the likelihood of recurrence and benefit of chemotherapy in breast cancer patients. Five to 10% of breast cancers are hereditary, and hereditary syndromes may not be uncovered through family history alone. We hypothesized that high ODX recurrence score (RS) may signal a potential hereditary cancer risk.We performed a retrospective analysis of data from hormone receptor-positive breast cancer patients who had undergone ODX and germline genetic testing. The chi-square test and Fisher exact test were used to examine univariable association between RS and germline mutation status. Multivariable logistic regression was utilized to examine if there was an association of RS with germline mutation status.In univariable analysis, the association of RS with germline mutation status was significant (P .0001). In the multivariable logistic regression model predicting germline mutation status, RS level remained significantly associated with germline mutation, in particular BRCA1 or BRCA2. The mean RS for those with non-BRCA1/2 germline mutations versus those without germline mutations was not significant (P = .38).High RS is associated with germline mutation status. Breast cancer patients with high RS are more likely to harbor a mutation in the BRCA1 or BRCA2 genes. If confirmed prospectively, oncologists may consider referring patients with high RS for genetic risk assessment and counseling to inform management plans, as well as counseling of family members.

e19165 Background: Cancer care is complex and requires synthesis of increasing amounts of clinical and financial data to optimize treatment decisions. The heightened differentiation of individual cancers, therapy sequencing, and increasing number of treatment options make it more challenging for oncologists to stay current. A survey showed that 82% of Network providers validated the utility of clinical evidence and decision-making assistance at the point-of-care. Providing education on efficacy, toxicity, and cost in the form of evidence tables (ET) as CDST may assist in value-based decision-making. Methods: We retrospectively reviewed utilization of ET developed to provide clinical and financial data about regimens included within the Value Pathways powered by NCCN. Thirty ET were embedded in the electronic health record (EHR) and posted on our intranet between June-December 2019, covering over 90% of cancers. Utilization was queried from roll out through January 2020. ET include a summary of primary literature (primary/secondary endpoints, adverse events) and monthly Medicare allowable reimbursement rates. ET are updated with each change to pathways and quarterly for cost updates. We also conducted a survey to understand provider ET utilization patterns. Results: Utilization was evaluated for 1,200 physicians across 470 sites that have access to ET. ET have been accessed 1178 times by 586 providers within the EHR and accessed 1363 times by 260 providers via intranet. Our rate of repeat users of the ET is 35% in the EHR and 97% on the intranet. A survey of 200 physicians after ET release showed that 19% of physicians use ET with every new chemotherapy start and an additional 50% refer to ET only if they are uncertain about the best option. Conclusions: Utilization patterns underscore the importance of ET as a CDST within the EHR and on the intranet. While early ET use is high, continued tracking of utilization and addition of content to assist in complex clinical decisions is a priority. Providers surveyed found that clinical informatics tools like ET are useful to enhance decision-making in complex cancer care. [Table: see text]

Context Symptoms affect quality of life (QOL), functional status, and cognitive function in cancer survivors, but older survivors are understudied. Objectives The objectives of this study were to identify prototypical presystemic therapy psychoneurological symptom clusters among older breast cancer survivors and determine whether these symptom clusters predicted cognition and QOL over time. Methods Women with newly diagnosed nonmetastatic breast cancer (n = 319) and matched noncancer controls (n = 347) aged 60+ years completed questionnaires and neuropsychological tests before systemic therapy and 12 and 24 months later. Latent class analysis identified clusters of survivors based on their pretherapy depression, anxiety, fatigue, sleep disturbance, and pain. Linear mixed-effects models examined changes in objective cognition, perceived cognition, and functional status (Instrumental Activities of Daily Living disability, functional well-being, and breast cancer–specific QOL) by group, controlling for covariates. Results Nearly one-fifth of older survivors were classified as having high pretherapy symptoms (n = 51; 16%); the remainder had low symptoms (n = 268; 84%); both groups improved over time on all outcomes. However, compared to the low symptom group and controls, survivors with high symptoms had lower baseline objective cognition and lower perceived cognition at baseline and 24 months, lower functional well-being at baseline and 12 months, greater Instrumental Activities of Daily Living disability at baseline, and lower breast cancer–specific QOL at all time points (all P Conclusion Nearly one-fifth of older breast cancer survivors had high psychoneurological symptoms at diagnosis, which predicted clinically meaningful decrements in perceived cognition and function in the first 24 months after diagnosis. Pretreatment psychoneurological symptom clusters could identify survivors for monitoring or intervention.

Purpose To determine treatment and aging-related effects on longitudinal cognitive function in older breast cancer survivors. Methods Newly diagnosed nonmetastatic breast cancer survivors (n = 344) and matched controls without cancer (n = 347) 60 years of age and older without dementia or neurologic disease were recruited between August 2010 and December 2015. Data collection occurred during presystemic treatment/control enrollment and at 12 and 24 months through biospecimens; surveys; self-reported Functional Assessment of Cancer Therapy-Cognitive Function; and neuropsychological tests that measured attention, processing speed, and executive function (APE) and learning and memory (LM). Linear mixed-effects models tested two-way interactions of treatment group (control, chemotherapy with or without hormonal therapy, and hormonal therapy) and time and explored three-way interactions of ApoE (ε4+ v not) by group by time; covariates included baseline age, frailty, race, and cognitive reserve. Results Survivors and controls were 60 to 98 years of age, were well educated, and had similar baseline cognitive scores. Treatment was related to longitudinal cognition scores, with survivors who received chemotherapy having increasingly worse APE scores ( P = .05) and those initiating hormonal therapy having lower LM scores at 12 months ( P = .03) than other groups. These group-by-time differences varied by ApoE genotype, where only ε4+ survivors receiving hormone therapy had short-term decreases in adjusted LM scores (three-way interaction P = .03). For APE, the three-way interaction was not significant ( P = .14), but scores were significantly lower for ε4+ survivors exposed to chemotherapy (−0.40; 95% CI, −0.79 to −0.01) at 24 months than ε4+ controls (0.01; 95% CI, 0.16 to 0.18; P < .05). Increasing age was associated with lower baseline scores on all cognitive measures ( P < .001); frailty was associated with baseline APE and self-reported decline ( P < .001). Conclusion Breast cancer systemic treatment and aging-related phenotypes and genotypes are associated with longitudinal decreases in cognitive function scores in older survivors. These data could inform treatment decision making and survivorship care planning.

Preoperative systemic therapy, though primarily used to downstage breast cancers, can offer, using pathologic complete response (pCR) as an endpoint, a rapid assessment of efficacy of a given therapeutic approach, particularly in triple-negative (TNBC) and HER2-positive breast cancers. Recently, this approach resulted in the approval of pertuzumab for HER2-positive cancers, in a considerably quicker timeline than would have been possible with its assessment in the adjuvant setting. However, the use of preoperative systemic therapy remains controversial, as the higher response rates noted with newer approaches have not routinely translated into improved longer-term outcomes, nor have they been confirmed in larger adjuvant trials. Almost all trials have demonstrated that pCR is a robust prognostic marker in patients with TNBC and HER2-positive cancers, so part of this discrepancy may be due to inadequate power in the preoperative trials and/or due to the heterogeneous nature of breast cancers. PCR following preoperative chemotherapy is not prognostic in many hormone receptor (HR)-positive breast cancers, especially those with a luminal A phenotype, which typically has minimal response to chemotherapy. Given this lack of response to chemotherapy, there is considerable interest in the use of neoadjuvant endocrine therapy (NET). The rate of pCR to NET in HR-positive cancers is low, leading to the use of surrogate markers, including changes in Ki-67 and the preoperative endocrine prognostic index (PEPI) score, as biomarkers of efficacy. Overall, the use of neoadjuvant approaches offers a rapid assessment of efficacy of novel therapies and remains a useful research tool for drug evaluation.

Background: Gene expression profiling assays estimate prognosis & predict benefit from adjuvant chemotherapy in patients (pts) with estrogen receptor positive (ER+) early stage breast cancer (ESBC). The 21-gene recurrence score (RS) and 70-gene signature (MP) are widely used assays. Pts may have both tests performed to adjudicate discordant results. We compared RS and MP in pts with both tests and evaluated their impact on adjuvant treatment decisions. Methods: This was a retrospective clinical cohort study from 5 centers from 2007-2014. Eligibility included ER+ ESBC with RS and MP results from the same tissue sample; exclusions included carcinoma in situ, primary metastatic disease, & bilateral breast cancer. Two definitions of RS risk were evaluated (Genomic Health [GH] or TAILORx [TRx]): low risk (GH:0-17) or (TRx:0-10); intermediate risk (GH:18-30) or (TRx:11-25); and high risk (GH:>31) or (TRx:>26). Demographic, clinicopathologic (CP) data, and treatment decisions were extracted from medical records. Agreement was assessed between RS and MP using weighted kappa scores. CP factors were assessed with the t-test and chi-square test. Results: 123 pts were identified from UCSF or 4 US Oncology Network practices. 60 pts had low risk RS (GH); 27 were low risk by MP (45% agreement). 15 cases had a low risk RS (TRx); 9 were low risk by MP (60%). 10 pts had high risk RS (GH); 8 were high risk by MP (80.0%). Similarly, 18 cases had high risk (TRx) RS;16 were high risk by MP (88%). Using the RS GH risk definition, there was poor agreement for low risk RS/MP and high risk RS/MP (kappa=0.169). However, using the TRx RS risk definition, there was good agreement for low risk RS/ MP and high risk RS/MP (kappa=0.509). 53 pts had intermediate risk RS by (GH); by MP 16 were low risk (30%), and 37 were high risk (70%). 90 pts had an intermediate risk RS by TRx; by MP 34 were low risk (37.8%), and 56 were high risk by MP (62.2%). Using TRx RS increased the number of pts classified as intermediate risk compared to GH RS (73.2 vs 43.1%). Complete adjuvant treatment data were available for 90 patients. Of 40 pts with low risk RS (GH), 25% received chemotherapy associated with node status but not tumor size, grade, or MP. Of 10 pts with high risk RS (GH), 70% received chemotherapy without association with CP features or MP. For the 45 pts with intermediate risk RS (GH), 53% received chemotherapy, without correlation with CP features. Receipt of chemotherapy was positively associated with MP high risk, but this was not significant (odds ratio 2.08, 95% CI 0.54-8.01); p-0.29. Conclusion: Concordance in risk prediction between RS and MP was greater using RS defined by TRx compared to GH, and RS using TRx increases those categorized as intermediate risk. There appeared to be no correlation between CP features and decisions to use chemotherapy across risk groups. Interestingly, in those with intermediate risk RS (GH or TRx), there was a non-significant trend toward use of chemotherapy in those with high risk by MP. Although gene expression tests are used frequently to aid in treatment decisions in ESBC, considerable variation exists in their application in clinical practice. Citation Format: Jiang H, Denduluri N, Majure M, Favret A, Rugo HS. Comparison of risk prediction with the 21-gene recurrence score (oncotype DX) and the 70-gene signature (MammaPrint) in patients with estrogen receptor-positive early stage breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-06.

As patients are living longer after a cancer diagnosis, survivorship is becoming increasingly important in cancer care. The sequelae of multimodality therapies include weight gain and decreased cardiorespiratory fitness, which increase cardiovascular risk. Evidence suggests that physical activity reduces the risk of breast cancer recurrence and death. Avoidance of weight gain after therapy also improves outcomes after a diagnosis of breast cancer. Prospective randomized trials must be performed to determine the benefits of specific physical activity and dietary habits for survivors of breast cancer. This review outlines the important physiologic changes that occur with antineoplastic therapy and the important role of exercise and diet.

ASCO is committed to addressing the needs of sexual and gender minority (SGM) populations as a diverse group at risk for receiving disparate care and having suboptimal experiences, including discrimination, throughout the cancer care continuum. This position statement outlines five areas of recommendations to address the needs of both SGM populations affected by cancer and members of the oncology workforce who identify as SGM: (1) patient education and support; (2) workforce development and diversity; (3) quality improvement strategies; (4) policy solutions; and (5) research strategies. In making these recommendations, the Society calls for increased outreach and educational support for SGM patients; increased SGM cultural competency training for providers; improvement of quality-of-care metrics that include sexual orientation and gender information variables; and increased data collection to inform future work addressing the needs of SGM communities.

Purpose To determine if older patients with breast cancer have cognitive impairment before systemic therapy. Patients and Methods Participants were patients with newly diagnosed nonmetastatic breast cancer and matched friend or community controls age > 60 years without prior systemic treatment, dementia, or neurologic disease. Participants completed surveys and a 55-minute battery of 17 neuropsychological tests. Biospecimens were obtained for APOE genotyping, and clinical data were abstracted. Neuropsychological test scores were standardized using control means and standard deviations (SDs) and grouped into five domain z scores. Cognitive impairment was defined as any domain z score two SDs below or ≥ two z scores 1.5 SDs below the control mean. Multivariable analyses evaluated pretreatment differences considering age, race, education, and site; comparisons between patient cases also controlled for surgery. Results The 164 patient cases and 182 controls had similar neuropsychological domain scores. However, among patient cases, those with stage II to III cancers had lower executive function compared with those with stage 0 to I disease, after adjustment (P = .05). The odds of impairment were significantly higher among older, nonwhite, less educated women and those with greater comorbidity, after adjustment. Patient case or control status, anxiety, depression, fatigue, and surgery were not associated with impairment. However, there was an interaction between comorbidity and patient case or control status; comorbidity was strongly associated with impairment among patient cases (adjusted odds ratio, 8.77; 95% CI, 2.06 to 37.4; P = .003) but not among controls (P = .97). Only diabetes and cardiovascular disease were associated with impairment among patient cases. Conclusion There were no overall differences between patients with breast cancer and controls before systemic treatment, but there may be pretreatment cognitive impairment within subgroups of patient cases with greater tumor or comorbidity burden.

Background: Maintaining high relative dose intensity (RDI) has been associated with improved disease-free survival, progression-free survival, and overall survival of patients with breast cancer treated in the adjuvant setting. Neutropenia and related complications, such as febrile neutropenia, are common side effects of myelosuppressive chemotherapy that can lead to dose delays, dose reductions, and reduced RDI. Primary prophylaxis with colony-stimulating factors (CSFs) can reduce the duration and severity of neutropenia and the incidence of febrile neutropenia, thereby supporting high RDI. For patients with stage IV breast cancer, dose delays and dose reductions are frequently used to manage toxicity associated with myelosuppressive chemotherapy. However, the prevalence and impact of reduced RDI in the metastatic disease setting is poorly understood. Objective: To estimate mean chemotherapy RDI and incidences of dose delays, dose reductions, RDI Methods: Using the McKesson Specialty Health/US Oncology iKnowMed™ electronic health record (HER) database, we retrospectively identified adult women with stage IV breast cancer who initiated first-line, intravenous, myelosuppressive chemotherapy from January 2007 to December 2010 in community oncology practices in the US. Patients were assigned to chemotherapy cohorts based on myelosuppressive agents received in cycle 1 and planned regimen information in the database. Standard chemotherapy regimens were defined based on NCCN breast cancer guidelines and clinical studies. Mean RDI and incidences of dose delays ≥7 days, dose reductions ≥15%, and RDI Results: This study included 1471 patients with stage IV breast cancer who received myelotoxic chemotherapy. The most common chemotherapy regimens in the metastatic setting were taxane-based, and endpoints for the three most common chemotherapy regimens (n = 307) are shown in the Table. Paclitaxel/ BevacizumabaAlbumin-bound PaclitaxelbPaclitaxelcN1767556Age, mean (SD) years58.2 (11.9)63.6 (12.4)61.8 (13.8)RDI, mean (SE)89.0% (1.9)89.1% (3.1)89.0% (3.2)RDI Conclusions: Chemotherapy dose delays, dose reductions, and reduced RDI were common in patients with stage IV breast cancer. The impact of RDI on progression-free and overall survival is being evaluated and will be presented. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-13-09.

Background: Neutropenic complications, such as febrile neutropenia (FN), often necessitate delays or reductions in doses of myelosuppressive chemotherapy. The resulting reduced relative dose intensity (RDI) may lead to poorer disease-free survival and overall survival among patients with early stage (stage I-IIIA) breast cancer (ESBC) (Chirivella, 2009; Wildiers, 2011). Methods: Using the McKesson Specialty Health/US Oncology iKnowMed™ HER database, we retrospectively identified the first course of (neo)adjuvant chemotherapy received by female adult patients with ESBC who initiated treatment from 1/1/2007-3/31/2011. We then assigned patients to chemotherapy cohorts (standard regimens described in the NCCN breast cancer guidelines or in published phase 3 trials) based on chemotherapy agents received in cycle 1 and planned regimen information in the database. Only standard regimen cohorts containing ≥100 patients were included in this study. For each standard regimen cohort, we estimated the following statistics: the proportion of patients receiving colony-stimulating factor (CSF) prophylaxis in the first 5 days of cycle 1; mean RDI; and the incidences of reduced RDI ( Results: Study results by standard regimen cohortStandard regimen cohortNAge, mean (SD)CSF prophylaxis in cycle 1,%Mean RDI,% (SE)RDI Discussion: Chemotherapy dose delays, dose reductions, and reduced RDI were common in patients with ESBC treated in community oncology practices and their frequencies were higher in older patients and in patients with BSA >2 m2. Further research should evaluate the impact of these factors on patient outcomes. Study results by patient subgroupSubgroupNMean RDI,% (SE)RDI 2 m21,84384.5 (0.4)33.237.639.8 Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-12-07.

There is a fairly consistent, albeit non-universal body of research documenting cognitive declines after cancer and its treatments. While few of these studies have included subjects aged 65 years and older, it is logical to expect that older patients are at risk of cognitive decline. Here, we use breast cancer as an exemplar disease for inquiry into the intersection of aging and cognitive effects of cancer and its therapies. There are a striking number of common underlying potential biological risks and pathways for the development of cancer, cancer-related cognitive declines, and aging processes, including the development of a frail phenotype. Candidate shared pathways include changes in hormonal milieu, inflammation, oxidative stress, DNA damage and compromised DNA repair, genetic susceptibility, decreased brain blood flow or disruption of the blood-brain barrier, direct neurotoxicity, decreased telomere length, and cell senescence. There also are similar structure and functional changes seen in brain imaging studies of cancer patients and those seen with "normal" aging and Alzheimer's disease. Disentangling the role of these overlapping processes is difficult since they require aged animal models and large samples of older human subjects. From what we do know, frailty and its low cognitive reserve seem to be a clinically useful marker of risk for cognitive decline after cancer and its treatments. This and other results from this review suggest the value of geriatric assessments to identify older patients at the highest risk of cognitive decline. Further research is needed to understand the interactions between aging, genetic predisposition, lifestyle factors, and frailty phenotypes to best identify the subgroups of older patients at greatest risk for decline and to develop behavioral and pharmacological interventions targeting this group. We recommend that basic science and population trials be developed specifically for older hosts with intermediate endpoints of relevance to this group, including cognitive function and trajectories of frailty. Clinicians and their older patients can advance the field by active encouragement of and participation in research designed to improve the care and outcomes of the growing population of older cancer patients.