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Our objective was to assess distress levels in female breast cancer patients as a function of race, ethnicity, and preferred language. We hypothesized minority patients and non-English screen-takers would report higher distress levels compared to English screen-takers and non-Hispanic whites. We conducted a retrospective observational study of female breast cancer patients at an NCI designated cancer center from 2009 to 2016 who were administered a validated biopsychosocial distress screening questionnaire. Self-reported data on race and ethnicity was collected. A total of 3,156 patients were included in the analysis; mean age of 56.3 (SD 12.25) years. The racial/ethnic cohort distribution included 54% non-Hispanic white (NHW), 19% Hispanic, 16% Asian, 7% Black/African American, and 4% other. On multivariable analysis only Hispanic patients were significantly more likely to report overall distress compared to NHW (OR [1.39; CI [1.03-1.87; p=0.03). Asians were significantly less likely to report distress in the functional domain (OR 0.71, CI [0.58-0.88]; p=0.002), while Black patients were significantly more likely to report highest distress levels in the physical (OR 1.53, CI [1.11-2.12]; p=0.01) domain. Hispanic Spanish screen-takers reported significantly more distress compared to Hispanic English screen-takers across all four domains of distress (p

Background Genomic testing of somatic and germline DNA has transformed cancer care. However, low genetic knowledge among patients may compromise care and health outcomes. Given the rise in genomic testing, we sought to understand patients’ knowledge of their genetic test results. Materials and Methods We conducted a survey‐based study with 85 patients at a comprehensive cancer center. We compared self‐reported recall of (a) having had somatic/germline testing and (b) their specific somatic/germline results to the genomic test results documented in the medical record. Results Approximately 30% of patients did not recall having had testing. Of those who recalled having testing, 44% of patients with pathogenic/likely pathogenic germline mutations and 57% of patients with reported somatic alterations did not accurately recall their specific gene or variant‐level results. Conclusion Given significant knowledge gaps in patients’ recall of genomic testing, there is a critical need to improve patient‐directed education and return‐of‐results strategies., Considering the increase in genomic testing for cancer care, this study aimed to better understand patients’ knowledge of their genetic test results.

Trastuzumab emtansine (T-DM1) is an antibody drug conjugate used to treat HER2-positive breast cancer. We hypothesized that functional imaging with 64Cu-DOTA-trastuzumab PET/CT would predict patient response to T-DM1 therapy. Methods: Ten women with biopsy-proven HER2-positive metastatic breast cancer who were to be treated with T-DM1 underwent pretreatment 18F-FDG PET/CT. 64Cu-DOTA-trastuzumab PET/CT was performed 1 and 2 days post-injection. Treatment outcome was assessed by (a) response to T-DM1 (3.6 mg/kg every 3 wk) as evaluated by follow-up 18F-FDG PET/CT using PERCIST criteria and (b) time to treatment failure (TTF). Tumors measurable for response were evaluated for 64Cu-DOTA-trastuzumab uptake in terms of maximum voxel standardized uptake value (SUVmax, units g/mL). Results: Response was clearly related to tumor uptake of 64Cu-DOTA-trastuzumab. Comparing group means, responsive patients (n = 5) had higher day 1 minimum SUVmax (5.6 vs 2.8, P threshold (P < 0.01). Patients with day 2 minimum SUVmax above versus below threshold had median TTF = 28 months versus 2 months (P < 0.02).

Purpose of Review This review summarizes the most recent data on the management of small, node-negative Her2+ and triple-negative breast cancer. Recent Findings Both Her2+ and triple-negative breast cancers are characterized by high rates of recurrence and worse survival outcomes compared to hormone-positive cancers. De-escalation of systemic therapy in early-stage breast cancer is a recent national trend in clinical research. Recent prospective trials support the scaling back of cytotoxic agents and maximization of targeted therapy regimens. Similarly, large retrospective studies on small, node-negative triple-negative breast cancer report the omission of chemotherapy in women with T1a,N0 triple-negative cancers with favorable short term outcomes. Summary De-escalation of systemic therapy for Her2+ breast cancer is effective in the management of early-stage, node-negative disease. Future prospective studies on the omission of systemic therapy for triple-negative breast cancer are required to safely adopt into consensus guidelines.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor–positive, HER2-negative breast cancer.

Background: ZN-c5 is an orally bioavailable selective estrogen receptor degrader (SERD) that binds potently to the estrogen receptors alpha and beta. It shows improved activity over fulvestrant in human tumor xenograft models and activity in tumor models that are resistant to tamoxifen. This is a Phase 1/2, open-label, multicenter, dose-escalation and expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), and clinical activity of ZN-c5 in subjects with advanced/metastatic estrogen receptor (ER) positive/ human epidermal growth factor receptor (HER2) negative breast cancer, both as monotherapy and in combination with palbociclib. The results from the ongoing monotherapy dose escalation are reported. Methods: Single agent ZN-c5 is being evaluated at sequentially escalating doses starting at 50 mg/day, administered orally, once daily (QD). The endpoints are to determine a maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D), preliminary clinical activity and to characterize the PK profile. Subjects must be intolerant to or have breast cancer refractory to established therapies and to have received up to 2 prior lines of chemotherapy for the treatment of advanced breast cancer. Subjects must have a documented prior response to endocrine therapy for advanced/metastatic disease (SD, PR, or CR) lasting > 6 months or disease recurrence after at least 24 months of adjuvant endocrine treatment. Results: A total of 15 female subjects (median age 57 years, range 51 - 89 years) were enrolled across 5 cohorts (3 subjects/dose level). The dose levels were 50, 75, 100, 150, and 300 mg/day. The subjects had a median of 4 prior therapies for advanced/metastatic disease, with a median of 3 prior hormonal-based therapies and a median of 1 prior chemotherapy. Eleven of 15 subjects (73%) received prior fulvestrant. The cut off-date for this analysis was 30 June 2020. There was no increase in incidence or severity of TEAEs with increase in dose level. The most frequent TEAEs reported in > 1 subject were nausea (33%), arthralgia, cough, musculoskeletal pain and vomiting (20% each), alanine aminotransferase increased, anemia, back pain, blood alkaline phosphatase increased, breast pain, diarrhea, fatigue, gamma-glutamyl transferase increased, headache, hypophosphatemia, myalgia and skin mass (13% each). Grade 3 events were COVID-19, hypercalcemia, arthralgia, back pain musculoskeletal chest pain, pain in extremity and hypertension, none were deemed related to ZN-c5. Grade 4 events were not reported. No bradycardia was observed. A single subject reported a Grade 1 visual field defect, not deemed related to ZN-c5. No DLTs were reported. ZN-c5 demonstrated a best response of stable disease (SD) in 10/15 subjects (66.5%), while progression of disease (PD) was reported in 5/15 subjects (33.5%). The clinical benefit rate (CBR, SD ≥ 24 weeks) was 40%. In addition, the progression free survival (PFS) was a median of 3.8 months (95% [CI], 1.6 to 6.3). The preliminary PK was characterized by fast absorption with median Tmax values of 1 - 2 hrs. The exposures were approximately dose-proportional at the dose levels of 50 - 100 mg and less than dose-proportional between 100 - 300 mg. No ZN-c5 accumulation after 15 days of QD dosing was observed. The estimated mean elimination half-lives ranged between 11 - 18 hrs. Conclusion: This monotherapy dose escalation study demonstrates that ZN-c5 is very well-tolerated and has promising clinical activity in patients with ER+/HER2-negative advanced breast cancer who have disease that progressed on standard therapies. The trial with ZN-c5 in monotherapy and with palbociclib is ongoing and the RP2D has not been determined yet. Citation Format: Pavani Chalasani, Vandana Abramson, Joanne Mortimer, Julie R Nangia, Jose Suarez, Matt Suster, Mieke Ptaszynski, Kevin Kalinsky. A dose escalation study of the novel oral SERD-ZN-c5 in women with ER-positive, HER2-negative advanced/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 PS12-20.

Background: Neratinib is a potent small molecule tyrosine kinase inhibitor (TKI) of human epidermal growth factor receptors (HER1,2,4). One of the major side effects of neratinib is diarrhea. The human gut contains a dense microbiome ecosystem that is essential in maintaining a healthy host physiology, and its disruption may lead to increased risk of toxicities from cancer therapy. In this study, we aimed to develop a machine learning model based on analysis of gut microbiota data to predict neratinib-induced diarrhea. Methods: Patients were enrolled in a phase II trial evaluating safety and tolerability of neratinib in older adults with HER2+ breast cancer (NCT02673398). Neratinib was administered as single agent, 240 mg oral daily in a 28-day cycle. Stool samples were collected at baseline and during treatment for 16S rRNA gene sequencing. Using microbial relative abundance data, we developed gradient-boosted tree models with two nested loops of cross validations to classify whether diarrhea would occur or not after treatment onset. For the inner validation loop, we used ten-fold cross validation to determine the optimal model from hyper-parameters including regularization. For the outer validation loop, we utilized a leave-one-patient-out cross validation to test this model on the hold-out patient’s baseline data and the predictions were used for model assessment. Results: A total of 11 patients and 50 longitudinal stool samples were collected. The median age was 66 years. 73% developed grade ≥ 1 diarrhea attributed to neratinib. Shannon diversity index of gut microbiome was not associated with diarrhea. For predictive modeling, the outer validation loop Area Under the Receiver Operating Characteristic Curve (AUROC) and Area Under the Precision Recall Curve (AUPRC) were 0.92 and 0.97, respectively. The two most important taxa predictive of protection from diarrhea were Ruminiclostridium 9, and Bacteroides sp. HPS0048. We found that patients with a larger relative abundance of Ruminiclostridium 9 and Bacteroides sp. HPS0048 have reduced risk of neratinib-related diarrhea. Conclusions: The machine learning model can identify breast cancer patients at risk of diarrhea prior to neratinib use. Future studies are required to validate this finding. Citation Format: Chi Wah Wong, Susan E. Yost, Jin Sun Lee, John D. Gillece, Megan Folkerts, Lauren Reining, Sarah K. Highlander, Zahra Eftekhari, Joanne Mortimer, Yuan Yuan. Machine learning model of gut microbiota predicts neratinib induced diarrhea in patients with 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 PS5-41.

BackgroundIn this phase II clinical trial, we evaluated the efficacy of the nonanthracycline combination of carboplatin and nab-paclitaxel in early stage triple-negative breast cancer (TNBC).Patients and MethodsPatients with newly diagnosed stage II–III TNBC (n = 69) were treated with neoadjuvant carboplatin (area under the curve 6) every 28 days for four cycles plus nab-paclitaxel (100 mg/m2) weekly for 16 weeks. Pathological complete response (pCR) and residual cancer burden (RCB) were analyzed with germline mutation status, tumor-infiltrating lymphocytes (TILs), TNBC molecular subtype, and GeparSixto immune signature (GSIS).ResultsSixty-seven patients were evaluable for safety and response. Fifty-three (79%) patients experienced grade 3/4 adverse events, including grade 3 anemia (43%), neutropenia (39%), leukopenia (15%), thrombocytopenia (12%), fatigue (7%), peripheral neuropathy (7%), neutropenia (16%), and leukopenia (1%). Twenty-four patients (35%) had at least one dose delay, and 50 patients (72%) required dose reduction. Sixty-three (94%) patients completed scheduled treatment. The responses were as follows: 32 of 67 patients (48%) had pCR (RCB 0), 10 of 67 (15%) had RCB I, 19 of 67 (28%) had RCB II, 5 of 67 (7%) had RCB III, and 1 of 67 (2%) progressed and had no surgery. Univariate analysis showed that immune-hot GSIS and DNA repair defect (DRD) were associated with higher pCR with odds ratios of 4.62 (p = .005) and 4.76 (p = .03), respectively, and with RCB 0/I versus RCB II/III with odds ratio 4.80 (p = .01). Immune-hot GSIS was highly correlated with DRD status (p = .03), TIL level (p < .001), and TNBC molecular subtype (p < .001). After adjusting for age, race, stage, and grade, GSIS remained associated with higher pCR and RCB class 0/I versus II/III with odds ratios 7.19 (95% confidence interval [CI], 2.01–25.68; p = .002) and 8.95 (95% CI, 2.09–38.23; p = .003), respectively.ConclusionThe combination of carboplatin and nab-paclitaxel for early stage high-risk TNBC showed manageable toxicity and encouraging antitumor activity. Immune-hot GSIS is associated with higher pCR rate and RCB class 0/1. This study provides an additional rationale for using nonanthracycline platinum-based therapy for future neoadjuvant trials in early stage TNBCs. Clinical trial identification number: NCT01525966Implications for PracticePlatinum is an important neoadjuvant chemotherapy agent for treatment of early stage triple-negative breast cancer (TNBC). In this study, carboplatin and nab-paclitaxel were well tolerated and highly effective in TNBC, resulting in pathological complete response of 48%. In univariate and multivariate analyses adjusting for age, race, tumor stage and grade, “immune-hot” GeparSixto immune signature (GSIS) and DNA repair defect (DRD) were associated with higher pathological complete response (pCR) and residual cancer burden class 0/1. The association of immune-hot GSIS with higher pCR holds promise for de-escalating neoadjuvant chemotherapy for patients with early stage TNBC. Although GSIS is not routinely used in clinic, further development of this immune signature into a clinically applicable assay is indicated.

PURPOSE Evidence-based somatic and germline sequencing has transformed cancer care and improves patient outcomes. However, patients’ low genetic literacy and misunderstanding of their own genomic results poses a threat to the realization of precision oncology. To optimize patient genomic comprehension, we developed a Web-based, patient-directed, genomic sequencing education and return-of-results tool, HOPE-Genomics. METHODS The HOPE-Genomics prototype included somatic and germline sequencing results, embedded multimedia genomic education, and interactive features (eg, request for genetic counseling). Between January and April 2018, we elicited feedback on tool usability and comprehensiveness through participant surveys, 4 focus groups of patients with cancer and their family members, and 3 provider focus groups (comprising 8 patients, 5 family members, and 19 providers). RESULTS We identified themes in patient/family tool-related responses, including the desire to view a patient-friendly report, a desire to receive multiple types of genomic information (eg, prognostic and uncertain), high acceptability of report content, and interest in tool-enabled access to genetic counseling. Major themes from the clinician focus groups included believing the tool could help patients formulate questions and facilitate patients’ communication of results to family members. However, there were diverse responses from all participants in terms of tool implementation (ie, timing and nature of report release). Some participants preferred report release before meeting with the provider, and others preferred it during the appointment. Additionally, some clinicians were concerned about providing prognostic and treatment information through the tool. CONCLUSION There was high acceptability and interest from patients, family members, and providers in a patient-directed genomics report. Future work will determine whether direct-to-patient reporting of genomic results improves patient knowledge, care engagement, and compliance with genomically guided interventions.

ABBV-176 is an antibody-drug conjugate composed of the humanized antibody h16f (PR-1594804) conjugated to a highly potent, cytotoxic cross-linking pyrrolobenzodiazepine dimer (PBD; SGD-1882) targeting the prolactin receptor (PRLR), which is overexpressed in several solid tumor types. This phase 1, dose-escalation study (NCT03145909) evaluated the safety, pharmacokinetics, and preliminary activity of ABBV-176 in patients with advanced solid tumors likely to exhibit elevated levels of PRLR. Patients received ABBV-176 once every 3 weeks. Dose escalation was by an exposure-adjusted, continual reassessment method. Dose-limiting toxicities (DLTs) were assessed from the first day of dosing until the next dose of ABBV-176 to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Nineteen patients received ABBV-176 at doses from 2.7-109.35 μg/kg. Patients enrolled had colorectal cancer (n = 11), breast cancer (n = 6), or adrenocortical carcinoma (n = 2). DLTs occurred in 4 patients and included thrombocytopenia (n = 2; both at 99.9-μg/kg dose level), neutropenia (n = 2; 78.3-μg/kg and 99.9-μg/kg dose levels), and pancytopenia (n = 1; 109.35-μg/kg dose level). The most common treatment-emergent adverse events related to ABBV-176 were thrombocytopenia, neutropenia, increased aspartate aminotransferase, nausea, fatigue, and pleural effusions. Effusions and edema were common, and timing of onset suggested possible cumulative ABBV-176 toxicity. Tumor expression of PRLR varied among patients enrolled and analyzed. No patient had an objective response. MTD was not formally determined, as identification of a tolerable dose was confounded by late-onset toxicities. ABBV-176 was associated with significant toxicity in this phase 1, dose-escalation study. Although cytopenias were often dose limiting, effusions and edema were also common and had late onset that suggested cumulative toxicity. No responses were observed, although data were available from a small number of patients with variable tumor PRLR expression. This study was terminated after the dosing of 19 patients.

Anthracycline chemotherapy is commonly used to treat breast cancer yet may increase the level of matrix metalloproteinases (MMP) -2 and -9, which increase the risk of atherosclerosis. While exercise has been shown to reduce the level of MMP in patients with diabetes, high intensity interval training (HIIT) has not been utilized to improve level of MMP in women with breast cancer receiving anthracycline chemotherapy. Thirty women were randomized to either 8-week HIIT or control (CON) group. The CON group was offered the HIIT intervention after 8 weeks. MMP-1, -2 -7, -9, tissue inhibitor of MMP (TIMP) -1, and-2 were measured at baseline and post-intervention. Repeated measures ANCOVA and paired t-test were performed to assess changes in MMP and TIMP. Post-intervention, no significant between-group differences were observed for MMP and TIMP. However, within-group decrease in MMP-9 was observed in the HIIT group [104.3(51.9) to 65.2(69.1); P = 0.01]. MMP-9 in the CON group was not significantly changed [115.5(47.2) to 90.4(67.9);]. MMP-2 significantly increased in both the HIIT group [76.6(11.2) to 83.2(13.1); P = 0.007) and the CON group [69.0(8.9) to 77.6(11.1) P = 0.003). It is unclear whether an 8-week HIIT intervention influences MMP-9 in breast cancer patients undergoing anthracycline chemotherapy. Additional investigations are required to understand the exercise-induced changes in MMP-2 and -9 in women undergoing anthracycline chemotherapy.

Background: The combination of CDK4/6 inhibitor and aromatase inhibitor is the current standard of care therapy for patients with estrogen receptor positive (ER+) metastatic breast cancer (MBC). Single agent immune check point inhibitor (ICI) pembrolizumab has a response rate of 12% in selected patients (PD-L1+), and preclinical studies demonstrated immune-modulatory effect of CDK4/6 inhibitors. The combination of CDK 4/6 inhibitors and ICI might turn “immune-cold” breast cancer tumors into “immune-hot” tumors. This study was designed to evaluate the safety and efficacy of adding pembrolizumab to letrozole and palbociclib in patients with ER+ MBC. Methods: This is an open-label single arm study enrolling patients with biopsy proven ER+ MBC with measurable disease by RECIST1.1, ECOG performance status 0-1. Patient received letrozole (2.5mg po daily), palbociclib (125mg po daily 3 weeks on, 1 week off), and pembrolizumab (200mg iv q3wks). Two cohorts were included: cohort 1 for patients who were previously on letrozole and palbociclib for > 6 months and had pembrolizumab added on C1D1, and cohort 2 for patients who had all 3 drugs started on C1D1. Premenopausal patients received ovarian suppression prior to C1D1. The primary objective was to determine the safety and tolerability of the combination. The secondary objectives were RR, PFS, and OS. For both cohorts, a three-at-risk design (modified rolling design) was used for safety-lead to ensure the triplet was well-tolerated. This design permitted only 3 patients to be a risk for DLT at any one time during the “safety lead-in” and permitted continuing accrual if ≤1 DLT occurred in the first 6 patients. Secondary consideration was response (cohort 2 only), with an a priori requirement of at least 9 responses to warrant further evaluation. Baseline tumor specimen, peripheral blood plasma, and PBMCs were collected for immune correlative analysis. Results: A total of 20 patients were accrued to this trial (4 in cohort 1, 16 in cohort 2), with 19 eligible for response assessment because one patient was determined to be TNBC upon repeat of biopsy. Median age was 49 years, with 40% Hispanic, and 60% non-Hispanic. There were 2 DLTs (1 biopsy site infection and delay in treatment that was possibly related to treatment in cohort 1, and 1 pneumonitis in cohort 2). 9/20 patients (45%) had dose delay and 9/20 patients (45%) had dose reduction, with the most common cause being neutropenia. Gr 4 AEs included neutropenia (n=4), WBC (n=3), LFT (n=1), and bowel perforation (n=1). Grade 3 AEs included neutropenia (n=11), WBC (n=9), LFT (n=3), PLT (n=2), and pneumonitis, pruritus, anemia, biopsy site infection (n=1 each). Other immune-related toxicities of Grade 2 included: hypothyroidism, colitis, LFTs, and dermatitis (n≤2 each). Responses were CR 1/19 (5.3%), PR 8/19 (42.1%), SD 6/19 (31.6%) and PD 4/19 (21.1%). Median follow up was 13.7 (95% CI 6.4-16.9) months and median PFS was not reached. No association of baseline tumor PD-L1 (22C3) and clinical response were observed (data available on 13 patients). PBMC flow from the first 9 patients (5 PR, 4 SD) showed lower percentage of naïve CD8+ T cells (CD8+CD45RA+ CD27+), and higher level of non-naïve KLRG1+CD8+ T cell (CD8+CD45RA− CD27− KLRG1+) were associated with clinical response (p Conclusion: The combination of letrozole, palbociclib, and pembrolizumab is well tolerated in patients with ER+ MBC. Citation Format: Yuan Yuan, Susan E Yost, Jin Sun Lee, Colt Egelston, Paul H Frankel, Christopher Ruel, Simran Padam, Aileen Tang, Norma Martinez, Jana Portnow, Christina Yeon, Cary Presant, Swapnil Rajurkar, Mina Sedrak, Niki Patel, Peter Lee, Joanne Mortimer. A phase II study of pembrolizumab, letrozole and palbociclib in patients with metastatic estrogen receptor positive 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 P3-11-04.

Background Breast cancer survivors have approximately double the risk of mortality from cardiovascular disease than age-matched women without a cancer history. Reynolds risk score is a validated algorithm for the assessment of cardiovascular disease, which incorporates high sensitivity C-Reactive Protein (hsCRP), hemoglobin A1c (HbA1c), and parental history of myocardial infarction with traditional biomarkers including cholesterol, systolic blood pressure (SBP), and presence of diabetes. We previously demonstrated that exercise improves Framingham risk score (12.0±2.0 to 2.0±1.5), calculated by traditional risk factors of cardiovascular disease, SBP (132.9±13.0 to 120.7±9.5 mmHg), high-density lipoprotein cholesterol (HDL-C; 43.1±6.6 to 64.7±7.8 mg/dL), and total cholesterol (TC; 196.5 ± 53.4 to 157.5 ± 37.1 mg/dL), in breast cancer survivors. This secondary analysis sought to examine the effects of a 16-week aerobic and resistance exercise intervention on Reynolds risk score in breast cancer survivors. Methods One hundred overweight or obese (BMI>25kg/m2) sedentary breast cancer survivors (stage I-III) who completed cancer treatment within 6 months prior to enrollment were randomized to the Exercise group (EX; n=50) or the Control (CON; n=50). The EX underwent supervised moderate-to-vigorous intensity aerobic and resistance exercise sessions 3 times/week for 16 weeks. The CON was asked to maintain their current level of activity. Reynolds risk score was calculated for each participant by assigning values for each of the following eight categories: age, SBP, TC, HDL-C, presence of diabetes; HbA1c, smoking status, hsCRP; and parental history of myocardial infarction. Within-group and between-group differences in mean change for individual outcomes measured at 16 weeks were evaluated using general linear models repeated-measures analyses of variance and mixed model repeated-measures analysis, respectively. Results Following the 16-week study period, Reynolds risk score was significantly reduced (8.3% to 0.9%), with improvements in hsCRP (3.4±0.6 to 2.3±0.3 mg/L), presence of diabetes (40 to 20%), and HbA1c (7.5±0.9 to 2.9±0.2%) in EX compared to CON (P0.05). Conclusion A 16-week supervised aerobic and resistance exercise intervention is an effective approach to reduce the risk of developing cardiovascular disease by reducing hsCRP, cholesterol, diabetes status, and SBP in breast cancer survivors. Participation in supervised exercise training during cancer survivorship should be considered to reduce the risk for cardiovascular disease mortality in breast cancer survivors. Citation Format: Kyuwan Lee, Debu Tripathy, Wendy Demark-Wahnefried, Kerry Courneya, Joanne Mortimer, Christina Dieli-Conwright. Effect of aerobic and resistance exercise on Reynolds risk score in overweight or obese breast cancer survivors [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 P1-11-01.

Background: In postmenopausal women, use of hormone therapy is associated with a lower incidence of diabetes (DM). The association of adjuvant endocrine therapy (AET) with DM has not been well studied among women treated for early stage breast cancer. The objective of this study was to examine the association of AET with risk of developing DM among postmenopausal women who developed breast cancer. Methods: 5,013 postmenopausal women from the Women’s Health Initiative diagnosed with non-metastatic breast cancer who were diabetes-free at cancer diagnosis and who had information on use of AET were included. AET use was gathered using 2 methods: 1) review of medication inventories for use of tamoxifen or aromatase inhibitors (AI) and 2) review of the Life and Longevity after Cancer (LILAC), a supplemental questionnaire used from 2009-2010 to gather treatment information from women who developed cancer. Results from these 2 collection methods were analyzed separately due to the timing of the surveys as well as data granularity (i.e. LILAC queried use of AET, not type). The primary outcome of interest for this study was diabetes-free survival, which was calculated from the date of breast cancer diagnosis to first diagnosis of DM. Participants who did not develop DM after breast cancer were censored at their last follow-up visit or date of death. Cox proportional hazards models were used to compute hazard ratios (HR) and 95% confidence intervals (CI). Results: After 10.4 median year’s follow-up post breast cancer diagnosis, 13% (632/5,013) of participants developed DM. Of the 2,646 who had medication inventory data, 1,352 (51%) reported AI use and 1,449 (55%) reported tamoxifen use. Participants who reported use of AIs were 13% more likely to develop DM than participants who did not use AIs (HR=1.13, CI=0.91-1.39). Participants who reported use of tamoxifen were 11% less likely to develop DM than those who did not use tamoxifen (HR=0.89, CI=0.72-1.11). Of the 3,769 participants with LILAC data from the supplemental questionnaire, 2,543 (67%) reported use of AET; these participants were 25% more likely to develop DM than those who did not use AET (HR=1.25, CI=1.02-1.53). When plotted over time, the risk of diabetes in AET users versus non-users was identical at 5 years (5% v 5%, respectively), was 35% higher at 10 years (12% v 9%, respectively), and 30% higher at 15 years (18% v 14%, respectively) (log-rank p=0.029). Conclusion: DM has not been reported as an adverse event in women on AET. Our data suggest an association of AET with DM among postmenopausal women with early stage breast cancer. When looking at specific types of AETs, the risk was marginally increased for AIs but marginally decreased for tamoxifen, with risk more apparent in subsequent years. These data have significance for survivorship care. Citation Format: Joanne E Mortimer, Rebecca A Nelson, Laura Kruper, Kathy Pan, Christina M Dieli Conwright, Aladdin H Shadyab, Lewis Kuller, Barbara Howard, Rowan T Chlebowski. Association of adjuvant endocrine therapy with diabetes among women with postmenopausal breast cancer in the Women’s Health Initiative (WHI) [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 P5-12-04.

BACKGROUND AND PURPOSE: The Breast and Cervical Cancer Treatment Program (BCCTP) Act, passed by Congress in 2000, provides time-limited coverage to uninsured breast or cervical cancer patients. We examine survival differences between BCCTP cases and insured controls. METHODS: Stage I-III breast cancer patients, covered under California’s BCCTP from 2005–2009 (N=6,343), were 1:1 matched with California Cancer Registry (CCR) controls on age, race/ethnicity, and cancer stage. Overall and disease-specific (OS and DSS) survival were compared using multivariate regression. RESULTS: BCCTP cases were more often unmarried (Odds Ratio [OR]=2.47, 95% Confidence Interval [CI]=2.30–2.66), with poorly/undifferentiated tumors (OR=1.26, CI=1.13–1.40), classified as ER negative (OR=1.10, CI=1.02–1.20) and/or PR negative (OR=1.09, CI=1.01–1.17). Cases were more likely to undergo mastectomy (OR=1.13, CI=1.05–1.21) or no surgery (OR=1.64, CI=1.31–2.05) versus lumpectomy. Cases were also more likely to undergo radiation (OR=1.11, CI=1.03–1.19). Endocrine therapy rates were marginally lower in cases (OR=0.93, CI=0.86–1.00). OS and DSS were shorter in BCCTP cases on multivariate analysis (HR=1.29, CI=1.17–1.42 and HR=1.27, CI=1.14–1.42, respectively). When stratified by socioeconomic status (SES), cases had significantly shorter OS and DSS except in the lowest quintile. When stratified by stage, cases had significantly shorter OS and DSS, except for stage I. CONCLUSIONS: The BCCTP provides uninsured breast cancer patients with comprehensive and timely care. Although our results suggest that BCCTP delivers quality care, BCCTP patients have shorter survival rates, even after accounting for SES and stage differences. Further assistance to vulnerable populations is warranted, including longer duration of treatment coverage, and surveillance adhering to NCCN compliant surveillance programs.

To investigate whether enhancement on MRI could help identify HER2 overexpression in breast cancer brain metastases.We derived a cohort of 38 histologically proven breast cancer brain metastases with preoperative contrast-enhanced brain MRI and HER2 fluorescent in-situ hybridization of the resected/biopsied brain specimens from 2018 to 2021. Enhancement of the lesions was measured and compared using t-tests. Receiver operating characteristic and logistic regression analyses were performed to evaluate the performance of MRI enhancement in identifying HER2 overexpression.The study cohort was comprised of 29 women with a mean age of 55 years (range: 31-81 years) with a total of 38 distinct lesions. The HER2-positive subcohort was comprised of 17 patients, while the HER2-negative subcohort was comprised of 13 patients. The percent signal intensity change (PSIC) of HER2-positive breast cancer brain metastases was significantly greater than that of HER2-negative lesions (310 v. 153, P = 0.002). The PSIC differentiated HER2-positive lesions from HER2-negative lesions with an area under the curve of 0.88 (P 0.001). In a model controlling for lesion size, lesion location, tumor grade, patient age, scanner magnetic field strength, and contrast agent, the PSIC had an accuracy of 92% (35/38), sensitivity of 96% (23/24), and specificity of 86% (12/14) in differentiating HER2-positive lesions from HER2-negative lesions.Enhancement on MRI may assist in identifying HER2 overexpression in breast cancer brain metastases, if validated prospectively.

BACKGROUND: Breast cancer mortality is substantially higher in Black compared to White women due in part to higher rates of poor prognosis triple-negative breast cancer (TNBC) in Black women. The influence of African ancestry on this disparity has not been adequately examined. METHODS: Using the Women’s Health Initiative cohort of 161,808 postmenopausal women, we examined risk of TNBC in 6,166 Black participants with information on African ancestry, of whom 374 had incident localized breast cancers. African ancestry was based on genetic information from 656,852 single nucleotide polymorphisms with ancestry groups stratified by

Background Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC. Methods The primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5 mg daily; eribulin 1.4 mg/m2 days 1 and 8 every 3 weeks), A2 (everolimus 7.5 mg daily; eribulin 1.4 mg/m2, days 1 and 8 every 3 weeks), and B1 (everolimus 5 mg daily; eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks). Results Twenty-seven patients with median age 55 years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ≥ grade 3 toxicity, 44% had ≥ grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0–8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6 months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3 months (95% CI [5.5, undefined]). Conclusion Eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks with everolimus 5 mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle. Trial registration ClinicalTrials.gov, NCT02120469. Registered 18 April 2014

Purpose We update a patient series that reported a high incidence of infection with Gram-positive cocci in women treated with the combination of pertuzumab and trastuzumab and further characterize this clinical problem. Patients Treating physicians and advanced practice partners identified women who developed infections while on treatment with pertuzumab and trastuzumab alone or in combination with chemotherapy and enrolled them onto this registry trial. Results Between March, 2014 and May, 2017, 48 patients with HER2-positive breast cancers were reported to have 59 individual infections. The median age was 48 years. Twenty-four patients received neoadjuvant therapy, 17 were treated for metastatic disease, and 7 were treated in the adjuvant setting. Pertuzumab and trastuzumab were combined with carboplatin and docetaxel in 24 (49%) patients, docetaxel in 10 (21%), nab-paclitaxel in 12 (24%), and without other agents in 2 (4%). Granulocyte growth factors were administered in 24 (49%) patients and no patients were documented to be neutropenic. Folliculitis developed in 25 (52%) patients and was counted as a single infection. Abscesses developed at a number of sites in 24 (49%) patients, including a septic knee requiring total knee replacement. Paronychia occurred in 7 (15%) patients, and 5 (10%) developed cellulitis. When cultures were obtained, Gram-positive cocci were consistently identified. Hypogammaglobulinemia was documented in 14 (36%) of the 33 patients tested. Conclusions Our data continue to support an increased risk of infections with Gram-positive cocci as a potentially serious adverse event in women treated with pertuzumab and trastuzumab.

Abtract Background Adverse upper limb musculoskeletal effects occur after surgical procedures and radiotherapy for breast cancer and can interfere with activities of daily living. Objective The objective of this study was to examine the effects of a 16-week exercise intervention on shoulder function in women who are overweight or obese and have breast cancer. Design This study was a randomized controlled trial. Setting The study was performed at the Division of Biokinesiology and Physical Therapy at the University of Southern California. Participants One hundred women with breast cancer were randomly allocated to exercise or usual-care groups. The mean (SD) age of the women was 53.5 (10.4) years, 55% were Hispanic white, and their mean (SD) body mass index was 33.5 (5.5) kg/m2. Intervention The 16-week exercise intervention consisted of supervised, progressive, moderate to vigorous aerobic and resistance exercise 3 times per week. Measurements Shoulder active range of motion, isometric muscular strength, and patient-reported outcome measures (including Disabilities of the Arm, Shoulder, and Hand and the Penn Shoulder Scale) were assessed at baseline, after the intervention, and at the 3-month follow-up (exercise group only). Differences in mean changes for outcomes were evaluated using mixed-model repeated-measures analysis. Results Compared with the usual-care group, the exercise group experienced significant increases in shoulder active range of motion (the mean between-group differences and 95% confidence intervals (CIs) were as follows: shoulder flexion = 36.6° [95% CI = 55.2–20.7°], external rotation at 0° = 23.4° [95% CI = 31.1–12.5°], and external rotation at 90° = 34.3° [95% CI = 45.9–26.2°]), improved upper extremity isometric strength, and improved Disabilities of the Arm, Shoulder, and Hand and Penn Shoulder Scale scores. Limitations Limitations include a lack of masking of assessors after the intervention, an attention control group, and statistical robustness (shoulder function was a secondary end point). Conclusions A 16-week exercise intervention effectively improved shoulder function following breast cancer treatment in women who were overweight or obese, who were ethnically diverse, and who had breast cancer.

The purpose of this study was to determine the effects of an 8-week high-intensity interval training (HIIT) intervention on vascular endothelial function, measured as brachial artery flow-mediated dilation (baFMD), and vascular wall thickness measured by carotid intima media thickness (cIMT) in breast cancer patients undergoing anthracycline-based chemotherapy. Thirty women were randomized to either HIIT or non-exercise control groups (CON). The HIIT group participated in an 8-week HIIT intervention occurring three times per week on a cycle ergometer. The CON group was offered the HIIT intervention after 8 weeks. baFMD was measured from the brachial artery diameter at baseline (D0) and 1 min after cuff deflation (D1); percent change was calculated by measuring brachial artery diameter after cuff deflation relative to the baseline [baFMD = (D1 − D0)/D0 × 100]. The cIMT was obtained from the posterior wall of common carotid artery 10 mm below the carotid bulb. Paired t test and repeated measures ANCOVA were performed to assess changes in baFMD and cIMT. At baseline, the HIIT (n = 15) and CON (n = 15) groups did not differ by age (46.9 ± 9.8 years), BMI (31.0 ± 7.5 kg/m2), and blood pressure (123.4 ± 16.8/72.3.9 ± 5.6 mmHg). Post-exercise, baFMD significantly increased [4.3; 95% confidence interval (CI): (1.5, 7.0), p = 0.005] in HIIT versus CON group. cIMT did not significantly change [0.003, 95% CI − 0.004, 0.009), p = 0.40] in HIIT group, while IMT significantly increased from baseline to post-intervention (0.009, 95% CI 0.004, 0.010, p = 0.003) in CON group. This study may suggest that HIIT improved vascular endothelial function and maintained wall thickness in breast cancer patients undergoing anthracycline-based chemotherapy. Trial registration: ClinicalTrials.gov: NCT02454777.

Introduction Phase II clinical trials including geriatric assessment (GA) measures are critical for improving the evidence base for older adults with cancer. We assessed the efficacy and tolerability of nab-paclitaxel in older adults with metastatic breast cancer (MBC). Patients and Methods Patients aged ≥ 65 years with MBC and ≤ 1 previous line of chemotherapy received 100 mg of nab-paclitaxel on days 1, 8, and 15 of a 28-day cycle. A GA was completed pre-chemotherapy, and the validated Cancer and Aging Research Group (CARG) chemotherapy toxicity risk score was calculated. Relationships between tolerability (number of courses, hospitalizations, dose reductions, and toxicity) and risk score were assessed using general linear models, Student t tests, and the Fisher test. Response rate and progression-free survival were evaluated using the Kaplan-Meier method. Results Forty patients (mean age, 73 years; range, 65-87 years) were included. The median number of cycles was 6, 75% (n = 30) of patients had ≥ 1 dose hold, and 50% (n = 20) had ≥ 1 dose reduction. Fifty-eight percent (n = 23) had treatment-related ≥ grade 3 toxicities, and 30% (n = 12) were hospitalized owing to toxicity. Thirty-five percent (n = 14) responded, and the median progression-free survival was 6.5 months (95% confidence interval, 5.5 months to undefined). Patients with intermediate/high toxicity risk scores had higher risk of grade ≥ 3 toxicity than those with low risk scores (odds ratio, 5.8; 95% confidence interval, 1.3-33.1; P = .01). A higher mean risk score was associated with higher likelihood of dose reductions and hospitalizations. Conclusions Among older adults with MBC receiving weekly nab-paclitaxel, more than one-half experienced ≥ grade 3 chemotherapy toxicity. However, a GA-based risk score could predict treatment tolerability.

Background: We have demonstrated that 64Cu-DOTA trastuzumab is an effective PET imaging agent for HER2 positive breast cancer and are now seeking to evaluate the methodology for prediction of response and benefit to ado-trastuzumab emtansine (TDM1) in women with metastatic disease. Methods: Patients with metastatic breast cancer were eligible if they had biopsy confirmed HER2 + disease, at least 1 site of metastasis 2.0 cm or larger outside the biopsy site, and were to receive TDM1 as therapy. Pretreatment staging included 18F-FDG/PET. Prior to injection of 64Cu-DOTA-trastuzumab, patients received 45 mg of cold trastuzumab to reduce liver uptake. PET-CT scans were obtained at 21-25 h and 47-48 h over fields of view chosen in reference to 18F-FDG scans. TDM1 was administered at a dose of 3.6 mg/kg every 3 weeks. Restaging 18F-FDG/PET was performed every 2 cycles, and response to therapy was determined by PERCIST criteria. The radiolabel uptake was measured in terms of maximum voxel standardized uptake value (SUVmax). Results: Ten women enrolled on study and are evaluable for response; three continue on TDM1 for 22-40 months and four patients remained on treatment for at least 1 year. The median age was 54.5 years (48-83 years); seven received prior trastuzumab-containing chemotherapy 3 wks to 55 months prior to study entry. HER2 was positive by IHC in 5 and by FISH in 5 (3 were 2+ by IHC; 1 was 1+ and 1 indeterminate). Complete or partial metabolic response was observed in 5 patients. Patients had their average SUVmax on 64Cu-DOTA trastuzumab PET (aSUVmax) assessed in addition to individual assessments on up to 8 lesions on both Day1 and Day2. The mean aSUVmax was (6.3, 8.8) for responding patients and (4.4, 5.2) for non-responder (day1, day2). The difference between responders and non-responders on Day1 aSUVmax was marginally significant (p=0.06), but significant on Day2 (p=0.04). The three highest aSUVmax on both day1 and day2 were three of the four patients with PFS>1 year. Data on the relationship of 64Cu-DOTA trastuzumab PET to IHC and FISH, and individual lesion SUVmax including evidence suggesting a potential threshold effect will be presented. Conclusions: In women with biopsy confirmed HER2 positive metastatic disease, 64Cu-DOTA-trastuzumab PET imaging is predictive for response to TDM1. Citation Format: Mortimer JE, Bading JR, Frankel P, Tumyan L, Tran TT, Rockne RC, Shively JE, Gidwaney N, Park J, Colcher DM. Use of 64Cu-DOTA-trastuzumab positron emission tomography (PET) to predict response to ado-trastuzumab emtansine (TDM1) [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 PD4-12.

Background: Response to neoadjuvant therapy is a predictor of progression-free and overall survival in HER2+. To decrease treatment associated toxicities in patients with HER2+ breast cancers we utilized a non-anthracycline regimen with pertuzumab (pert), trastuzumab (trast), and nab-paclitaxel (nab). Pre- neoadjuvant therapy biopsies were procured to evaluated possible biological predictors of pathologic complete response (pCR). Methods: Women with locally advanced HER2 positive breast cancers were recruited from our breast cancer clinics. After obtaining informed consent for this IRB-approved trial, patients were treated with 6 cycles of pertuzumab (day 1 every 21 days [d]), and weekly trastuzumab 2 mg/kg with and nab-paclitaxel 100 mg/m2. Formalin fixed paraffin embedded (FFPE) or frozen biopsies pre-NT and post-NT were collected, along with blood samples at pre-treatment, and at the end of study for correlative analysis. Results: Accrual is complete, with 42 of the 45 HER2+ patients assessed for pCR rate (3 too early to evaluate). The median age was 54 yrs (range 31-77 years). 12 patients were stage 3, 26 stage 2, and 1 stage 1 patient. The pCR rate was 64.2% (27/42), with 73.7% (14/19) in ER/PR negative patients and 56.5% (13/23) in ER/PR positive patients. The initial primary tumor size was similar for in those who achieved pCR and non-pCR patients (mean 4.1 cm vs 3.2 cm, respectively). Most patients required dose modifications. Grade 3 AEs reported included 6 patients with hypertension, 3 patients with hematological AEs, 3 patients with elevated LFTs, and 2 patients with diarrhea. Conclusions: This anthracycline-free regimen in HER2+ BC can achieve promising pCR response rates, with toxicities well-managed with dose modifications. Results of correlative analysis will be presented. Citation Format: Somlo G, Waisman J, Yuan Y, Kruper L, Frankel P, Jones V, Lusi T, Schmolze D, Yim J, Hurria A, Mortimer J. Pathologic complete response (pCR) in locally advanced HER2+ (HER2+) breast cancer (BC) treated with anthracycline-free neoadjuvant 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 P6-17-18.

Background: Almost a quarter of older adults in the United States will identify themselves as Hispanic/Latino by 2060. Our group has previously developed and validated a self-administered geriatric assessment tool which can be used to identify functional, psychological, social and cognitive impairments among older patients with various types of cancer. Among English-speaking older adults, completing this tool using paper/pencil or a tablet takes a median of 15-21 minutes (min), with < 10% needing assistance to answer it (Hurria, JOP 2016). However, the utilization of this tool among Spanish-speaking older adults has not been tested. We assessed the feasibility of administering a translated and validated Spanish version of our geriatric assessment tool for older Hispanic women with breast cancer, and identified their preferred format (tablet or paper/pencil). Methods: Spanish-speaking women aged ≥ 65 years with a diagnosis of breast cancer completed the geriatric assessment twice on the same day. Patients were randomized into 3 groups: paper/pencil twice; tablet and paper/pencil in random order; and tablet twice. We assessed the proportion of patients requiring assistance to complete the geriatric assessment, the time needed to complete it, and the proportion of patients who thought the geriatric assessment was difficult/very difficult. Results: 140 older women with breast cancer completed the geriatric assessment twice and were evaluable. Mean age was 71.6 years (SD 5.8), 53% had ≤ 8th grade education, 43% were married, 45% were retired, 32% were homemakers, and 6% were employed. The participants came from 13 different Spanish-speaking countries, although 70% were born in Mexico. For 90%, Spanish was their primary language, and 75% spoke only in Spanish at home. Regarding computer skills, 64% of the patients said they had none. 39% (n = 54) were unable to complete the geriatric assessment on their own; mean time to complete the geriatric assessment was 29 min (range 8-90); and 28% (n = 39) thought the geriatric assessment was difficult/very difficult. The most common reasons for needing assistance were difficulty understanding questions (39%) and visual problems (31%). Patients with ≤ 8th grade education took longer to complete the geriatric assessment (mean 37.2 vs 29.4 min, p < 0.01), and more often needed help completing the assessment (51% vs 19%, p < 0.01) than those with ≥9th grade education. 53% of the participants preferred using a tablet to answer the geriatric assessment, while 47% preferred paper/pencil. Conclusions: A substantial proportion of Spanish-speaking older women with breast cancer required assistance to complete our self-administered geriatric assessment tool. This may be a consequence of the low educational level we found among this patient population. Tailoring assessments for diverse populations with particular attention to educational level is needed in multicultural settings. Citation Format: Soto-Perez-de-Celis E, Vazquez J, Kim H, Sun C-L, Somlo G, Yuan Y, Waisman JR, Mortimer JE, Kruper L, Taylor L, Patel NH, Moreno J, Charles K, Roberts E, Uranga C, Levi A, Katheria V, Paredero-Perez I, Mitani D, Hurria A. A self-administered geriatric assessment tool for Spanish-speaking older women with breast cancer [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 P6-16-04.

Background: Alteration of PI3K/Akt/mTOR pathway is the most common genomic abnormality detected in triple negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in inducing apoptosis in TNBC cell lines and xenografts in our preclinical study. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients (pts) with metastatic TNBC. Methods: The overall objective of this study was to describe the safety and toxicities of the combination. The secondary objective was to assess activity based on response rate (RR) and progression free survival (PFS). Eligibility criteria included pts with metastatic TNBC, ECOG 0-2, 0-3 lines of prior chemotherapy in metastatic setting, and prior treatment with anthracycline and/or taxane therapy. The study utilized the toxicity equivalence range (TEQR) design with a target equivalence range for dose-limiting toxicities (DLTs) of 0.20-0.35. The recommended phase 2 dose (RP2D) will be the dose closest to the target of 0.25 below 0.51 based on isotonic regression.Three dosing levels of the combinations were tested: level A1 (everolimus 5mg daily; eribulin 1.4 mg/m2 days 1, 8 every 3 weeks), level A2 (everolimus 7.5mg daily; eribulin 1.4 mg/m2, days 1, 8 every 3 weeks), level B1(everolimus 5mg daily; eribulin 1.1 mg/m2 days 1, 8 every 3 weeks). Nanostring RNA analysis and genomic mutation analysis were conducted in 16 pts with available tumor tissue. Results: A total of 27 pts were enrolled. Median age was 55 years (range 36-76). Two pts were ineligible due to HER2+ on repeat biopsy and were only included in the toxicity analysis. Dose level B1 (everolimus 5mg daily and eribulin 1.1 mg/m2 days 1, 8 every 3 weeks) was determined to be the RP2D doses. The DLTs were neutropenia, stomatitis and hyperglycemia. Across all cycles, 59% (16/27) had a ≥ Gr3 toxicity attributed to treatment at the possible or above level. 44% (12/27) had Gr3 heme-toxicities. The most common toxicities were ≥ Gr3 neutropenia (10 pts), Gr3 lymphopenia (6 pts) and ≥ Gr3 leukopenia (7 pts). 33% (9/27) had Gr3 non-heme toxicities. The most common were Gr3 stomatitis (3 pts), Gr3 hyperglycemia (3 pts) and Gr3 fatigue (5 pts). The median number of cycles completed was 4 (0-8). 68% (17/25) had a dose modification or hold, 14 of 25 (56%) were for eribulin and 15 of 25 (60%) were for everolimus. Of 25 eligible pts, 8 (32%) achieved a best response as partial response, 11 (44%) had stable disease and 6 (24%) had progression. 80% (20/25) experienced progression by RECIST or showed clinical progression, and the median time to progression was 2.7 mo (95% CI (2.2, 4.6)). At the time of this analysis, 16 participants had died, median OS was 6.3 mo (95% CI (5.3, undefined)). Two pts are still being followed on treatment. PI3K-Akt-mTOR pathway genes and mutations profiles were studied. Conclusion: Eribulin 1.1 mg/m2 days 1, 8 and everolimus 5mg daily was defined as the RP2D. Genomic analysis is currently underway to understand the molecular mechanisms of resistance. Citation Format: Yuan Y, Yost S, Blanchard S, Yin H, Li M, Robinson K, Tang A, Martinez N, Leong L, Somlo G, Tank Patel N, Waisman J, Portnow J, Hurria A, Luu T-H, Mortimer J. Phase I trial of eribulin and everolimus in patients with metastatic triple negative breast cancer [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 P6-18-18.

Background: Response to neoadjuvant therapy (NT) predicts progression-free and overall survival in triple negative breast cancer (TNBC). Carboplatin has shown efficacy in patients with TNBC. The current phase II prospective neoadjuvant trial was designed to decrease toxicities and improve efficacy. Methods: Patients with TNBC received carboplatin (carb) and nab-paclitaxel (nab). Pre-NT biopsies were procured to evaluate for biological predictors of pathological complete response (pCR). Newly diagnosed stage II-III patients with TNBC were treated with 4 cycles of carb (AUC 6, day 1 of 28 day cycle) and weekly nab 100 mg/m2 x 16. Targeted accrual goal is 70. RNA extracted from formalin fixed paraffin embedded (FFPE) biopsies pre-NT was tested for MammaPrint/BluePrint and custom Agilent full genome microarrays for gene expression (GE, by Agendia Inc). The raw gMeanSignal was log2 transformed and normalized to the 75thpercentile for GE analysis. Association between MammaPrint/ BluePrint results and pCR was tested by Fisher exact test. The linear model from R limma package was applied. Ingenuity Pathway Analysis (IPA) was applied to assess functional pathways associated with pCR. Cellular distribution by CIBERSORT analysis was carried out to estimate the abundance of 22 different cell types in each patient sample, and test whether the distribution of cell types is different between pCR and non-responders. Results: A total of 64 patients were enrolled. Two patients were deemed ineligible (Her2+), and three were too early, resulting in 59 patients evaluable for pathological response. The pCR rate was 47% (RCB0, 28/59). Eight patients had RCB I. RCB0 plus RCBI reached 61%. Sufficient quality RNA and DNA were available from the first 43 of 55 pts with TNBC. 44/59 (75%) required dose modifications (mostly hematologic), 5 patients had grade 3 peripheral neuropathy (PN), 3 had grade 2 PN, and 3 patients had grade 2 LFTs. In the 53 pts with GE assessment, pCR was inversely associated with luminal BluePrint type (p=0.04). With fold change >1.5 and p-value < 0.05, 36 genes were differentially expressed (DE) in TNBC. CIBERSORT analysis suggested that T-cell regulatory cells (TREGS) were associated with pCR in TNBC, and 5 cell types (plasma cells, TREGS, macrophage, dendritic cells and neutrophils) presented differently between all pCR and non-pCRs with P-value Conclusions: The combination of carboplatin and nab-paclitaxel given in the neoadjuvant setting reached a promising pCR rate of 47%. The MammaPrint non-luminal BluePrint subtype was predictive of pCR in TNBC. Preliminary analysis suggested that a 36-gene signature for TNBC was associated with pCR. CIBERSORT analysis revealed 5 cell types with different abundance between the pCR and non-responders, suggesting the need to target the tumor microenvironment. Citation Format: Yuan Y, Frankel P, Li M, Kruper L, Jones V, Treece T, Waisman J, Yim J, Tumyan L, Schmolze D, Hurria A, Yeon C, Mortimer J, Somlo G. Phase II trial of neoadjuvant carboplatin and nab-paclitaxel in patients with locally advanced triple negative breast cancer [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 P1-15-07.

Purpose: Age-related biopsychosocial distress in breast cancer patients has been poorly studied and understood. The breast cancer experience may be different based on chronological age, which may be a surrogate marker of biologic, psychological, social, and functional age. This study reports patient-reported biopsychosocial problem-related distress in breast cancer patients. Methods: All new patients seen at the City of Hope breast cancer clinic undergo a validated comprehensive biopsychosocial screening prior to their first visit with a medical/surgical oncologist. This touchscreen driven technology queries patients on their physical symptoms, psychosocial concerns, informational and resource needs, interests in clinical trials, and other breast cancer specific concerns. This IRB approved study was conducted in 3,352 patients evaluated from 2009 to 2017. Screening occurred immediately prior to meeting with the physician so that the information could be integrated into the clinical encounter. Results: The age-related groups included 268 Adolescent and young adult (AYA) patients ages 18-39, 2,244 middle aged adults 40-64 years, and 840 older adults ages 65+ years. Regardless of age, four of the top seven highly distressing problems were the same: worry about the future, side effects of treatment, sleep and fatigue. AYA patients and middle aged adults, but not older adults, identified finances and being anxious or fearful among their top five causes of distress. Middle aged adults and older adults, but not AYA patients, identified physical pain among their top seven causes of distress. Interestingly, both AYA and older adults, but not middle aged adults, identified getting information about complementary and alternative practices as a top source of distress. Although a serious problem across all age categories, thoughts of ending one's life and seriously considering taking one's life were the least common problems identified. Conclusions: In this series with 3,352 patients, biopsychosocial concerns raised with a diagnosis of breast cancer were similar regardless of age. However, patients under the age of 65 may worry more about finances and patients over the age of 40 may worry more about physical symptoms such as pain. Both AYA patients and older adults cited distress learning about complementary and alternative practices, suggesting a need for providers to address this, especially in these patient populations. Thoughts of ending one's own life were uncommon, which is relevant in a state with the End of Life Option Act. Citation Format: Hill A, Obenchain R, Clark K, Loscalzo M, Mortimer J. Age-related distress in 3352 breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-12-02.

Background:Obese postmenopausal women are at higher breast cancer risk potentially driven by hyperinsulinemia. However, reports of insulin level associations with breast cancer incidence and survival are inconsistent. Therefore, we examined associations among insulin resistance by homeostasis model assessment-insulin resistance (HOMA-IR) index and incident breast cancer, deaths from breast cancer, and deaths after breast cancer in postmenopausal women participating in the Women's Health Initiative (WHI). Patients and Methods:From the 161,808 postmenopausal women, aged 50-79 years, enrolled at 40 US clinical centers from 1993 through1998 in WHI clinical trials or the observational study, 22,837 with available fasting serum insulin and glucose by the same methodology and no prior breast cancer represent the current study population. The exposure was insulin resistance (HOMA-IR index) as [fasting insulin (qIU/ml) times fasting glucose (mg/dL) / 22.5. Survival by cause was determined by central medical record or death certificate review, enhanced by National Death Index queries. Breast cancers, initially ascertained by serial survey, were confirmed by medical record review. Associations between HOMA-IR quartiles and breast cancer outcomes were examined using Cox multi- variate proportional hazards models with results reported as hazard ratios (HR) and 95% confidence intervals. Results: At entry, women in the highest HOMA-IR quartile were more likely to be Black, have lower education level, have higher body mass index (BMI), higher waist circumference ≥ 88 cm and lower physical activity levels, but have lower calculated five-year breast cancer risk. After 18.1 years median follow-up from randomization with 1,148 incident breast cancers, breast cancer incidence was higher in women in the highest, compared to the lowest, HOMA-IR index quartile (HR 1.39 95% CI 1.14 -1.69, P = 0.0012). Of the women with incident breast cancer, 353 (31%) have died, with cause of death available on 334 (95% of cases) where breast cancer was the most common cause of death (33%); followed by cardiovascular disease (24%); and other cancers (13%). With median post-breast cancer diagnosis follow-up of 10.5 years, breast cancer mortality was examined from breast cancer diagnosis. No association was found between death from breast cancer and HOMA-IR. However, women with breast cancer in the highest HOMA-IR quartile, compared to women in the lowest, were significantly more likely to experience death after breast cancer from any cause (HR 1.45 95% CI 1.00 - 2.09, P = 0.0488) and were at somewhat higher risk of death from cardiovascular disease (HR 1.51 95% CI 0.67 - 3.41) and other causes (HR 1.93 95% CI 0.87-4.27). Conclusion:In postmenopausal women, higher insulin resistance is associated with higher breast cancer incidence and more deaths after breast cancer, likely due to insulin influence on several causes of death. However, deaths from breast cancer, even in this older postmenopausal population, remains a major factor limiting survival which needs to be addressed. The findings suggest insulin resistance represented a potential intervention target for postmenopausal women with early stage breast cancer. Citation Format: Chlebowski RT, Pan K, Mortimer J, Cespedes Feliciano EM, Gunter MJ, Hurria A, Rohan T, Vitolins MZ, Adams-Campbell L, Ho G, Cheng T-YD, Nelson R. Insulin resistance and breast cancer incidence and mortality in postmenopausal women [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 P1-08-10.

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor–positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.

Molecular subtypes of triple negative breast cancer (TNBC) are associated with variation in survival and may assist in treatment selection. However, the association of patient race or ethnicity with subtypes of TNBC and clinical outcome has not been addressed. Using nCounter Gene Expression Codesets, we classified TNBCs into subtypes: basal-like immune-activated (BLIA), basal-like immunosuppressed (BLIS), luminal androgen receptor (LAR), and mesenchymal (MES) in 48 Hispanic, 12 African-American, 21 Asian, and 34 White patients. Mean age at diagnosis was significantly associated with subtype, with the youngest mean age (50 years) in MES and the oldest mean age (64 years) in LAR (p < 0.0005). Subtype was significantly associated with tumor grade (p = 0.0012) and positive lymph nodes (p = 0.021), with a marginally significant association of tumor stage (p = 0.076). In multivariate Cox-proportional hazards modeling, BLIS was associated with worst survival and LAR with best survival. Hispanics had a significantly higher proportion of BLIS (53%, p = 0.03), whereas Asians had a lower proportion of BLIS (19%, p = 0.05) and a higher proportion of LAR (38%, p = 0.06) compared to the average proportion across all groups. These differences in proportions of subtype across racial and ethnic groups may explain differences in their outcomes. Determining subtypes of TNBC facilitates understanding of the heterogeneity of the TNBCs and provides a foundation for developing subtype-specific therapies and better predictors of TNBC prognosis for all races and ethnicities.

Background CDK4/6 inhibitors modulate immune response in breast cancer. This phase I/II trial was designed to test the safety and efficacy of palbociclib, pembrolizumab and letrozole in women with hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2−) metastatic breast cancer (MBC). Patients and methods Women with stage IV HR+ HER2− MBC were enrolled and treated with palbociclib, pembrolizumab and letrozole. Primary end-points were safety, tolerability and efficacy. Results Between November 2016 and July 2020, 23 patients were enrolled with 20 evaluable for response, including 4 patients in cohort 1 and 16 patients in cohort 2. Cohort 1 median age was 48 years (33–70) and cohort 2 median age was 55 (37–75). Cohort 1 closed early due to limited accrual. Grade III–IV adverse events were neutropenia (83%), leucopaenia (65%), thrombocytopenia (17%) and elevated liver enzymes (17%). In cohort 1, 50% achieved a partial response (PR) and 50% had stable disease (SD). In cohort 2, 31% achieved complete response (CR), 25% had PR and 31% had SD by Response Evaluation Criteria in Solid Tumours version 1.1. Median progression-free survival was 25.2 months (95% confidence interval [CI] 5.3, not reached) and median overall survival was 36.9 months (95% CI 36.9, not reached) in cohort 2 with a median follow-up of 24.8 months (95% CI 17.1, not reached). A correlative immune biomarker analysis was published separately. Conclusion The combination of palbociclib, pembrolizumab and letrozole is well tolerated, and a complete response rate of 31% was identified in HR+ MBC patients who received this combination as front-line therapy. Confirmatory trials are required to better understand the immune-priming effects of CDK4/6 inhibitors.

Background Triple-negative breast cancer (TNBC) has a high recurrence risk and poor clinical outcomes. Associations between metabolic syndrome (MetS) risk components and mortality in postmenopausal women with TNBC were examined in the Women's Health Initiative. Methods Five hundred forty-four postmenopausal women were diagnosed with nonmetastatic TNBC. Baseline risk components included a high waist circumference (≥88 cm), high blood pressure, hypercholesterolemia, and diabetes. Groups were categorized by the number of MetS risk components: none, 1 or 2, or 3 or 4. Hazard ratios (HRs) and 95% confidence intervals (CIs) across groups were computed with multivariable adjusted Cox models. Outcomes included breast cancer-specific mortality and breast cancer overall mortality (breast cancer followed by death from any cause). Variables in the multivariable model included age at TNBC diagnosis; race/ethnicity; income; education; clinical/observational trial status; history of oral contraceptive, hormone, and/or statin use; cancer stage; and chemotherapy and/or radiation treatment status. Results Of the 544 participants with TNBC, 33% had no MetS risk components (n = 178), 59% had 1 or 2 risk components (n = 323), and 8% had 3 or 4 risk components (n = 43). After a median follow-up from diagnosis of 8.3 years, multivariable results showed that women with 3 or 4 risk components had a nonsignificantly higher risk of breast cancer mortality (HR, 2.05; 95% CI, 0.94-4.47 trend P = .114) and a significantly higher risk of overall mortality (HR, 2.13; 95% CI, 1.22-3.71; trend P = .006) versus women with 0 risk components. Conclusions Postmenopausal women with TNBC and 3 or 4 MetS risk components have a nonsignificantly higher breast cancer mortality risk and a significantly higher overall mortality risk, likely because of negative influences of metabolic risk factors on several causes of death.

BackgroundPrior studies of dietary protein intake and breast cancer have been mixed and were limited by dietary self-report measurement error.MethodsBiomarker-calibrated total protein intake and estimated vegetable protein and animal protein intake were determined from baseline food frequency questionnaires in 100 024 Women’s Health Initiative participants. Associations between total, animal, and vegetable protein intake and breast cancer incidence, deaths from breast cancer, and deaths after breast cancer were estimated using Cox proportional hazards regression. Breast cancers were verified by medical record review and survival outcomes enhanced by National Death Index queries. All statistical tests were 2-sided.ResultsAfter 14 years of follow-up, there were 6340 incident breast cancers, 764 deaths from breast cancer, and 2059 deaths after breast cancer. In multivariable analyses, higher calibrated total protein intake was not associated with breast cancer incidence or deaths from or after breast cancer. Vegetable protein intake was associated with statistically significantly lower breast cancer incidence (hazard ratio [HR] = 0.98, 95% confidence interval [CI] = 0.96 to 0.99, Ptrend = .006) and statistically significantly lower risk of death after breast cancer (HR = 0.93, 95% CI = 0.91 to 0.97, Ptrend < .001) but not with deaths from breast cancer. In contrast, higher animal protein intake was associated with statistically significantly higher breast cancer incidence (HR = 1.03, 95% CI = 1.01 to 1.06, Ptrend = .02) but not with deaths from or after breast cancer.ConclusionsCalibrated total protein intake was not associated with breast cancer incidence or mortality. Higher vegetable protein intake was associated with lower breast cancer incidence and lower risk of death after breast cancer. Higher animal protein intake was associated with higher breast cancer incidence.

Neratinib has great efficacy in treating HER2+ breast cancer but is associated with significant gastrointestinal toxicity. The objective of this pilot study was to understand the association of gut microbiome and neratinib-induced diarrhea. Twenty-five patients (age ≥ 60) were enrolled in a phase II trial evaluating safety and tolerability of neratinib in older adults with HER2+ breast cancer (NCT02673398). Fifty stool samples were collected from 11 patients at baseline and during treatment. 16S rRNA analysis was performed and relative abundance data were generated. Shannon’s diversity was calculated to examine gut microbiome dysbiosis. An explainable tree-based approach was utilized to classify patients who might experience neratinib-related diarrhea (grade ≥ 1) based on pre-treatment baseline microbial relative abundance data. The hold-out Area Under Receiver Operating Characteristic and Area Under Precision-Recall Curves of the model were 0.88 and 0.95, respectively. Model explanations showed that patients with a larger relative abundance of Ruminiclostridium 9 and Bacteroides sp. HPS0048 may have reduced risk of neratinib-related diarrhea and was confirmed by Kruskal-Wallis test (p ≤ 0.05, uncorrected). Our machine learning model identified microbiota associated with reduced risk of neratinib-induced diarrhea and the result from this pilot study will be further verified in a larger study.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT02673398.

Background In the Women's Health Initiative (WHI) dietary modification (DM) randomised trial, the low-fat dietary intervention reduced deaths from breast cancer (P = 0.02). Extending these findings, secondary analysis examined dietary intervention influence on breast cancer mortality by metabolic syndrome (MS) components. Methods In total, 48,835 postmenopausal women with no prior breast cancer were randomised to a low-fat dietary intervention or comparison groups. Four MS components were determined at entry in 45,833 participants: (1) high waist circumference, (2) high blood pressure, (3) high cholesterol and (4) diabetes history. Forest plots of hazard ratios (HRs) were generated with P-values for interaction between randomisation groups and MS component score. Primary outcome was death from breast cancer by metabolic syndrome score. Results HRs and 95% confidence intervals (CI) for dietary intervention influence on death from breast cancer were with no MS components (n = 10,639), HR 1.09, 95% CI 0.63-1.87; with 1-2 MS components (n = 30,948), HR 0.80, 95% CI 0.62-1.02; with 3-4 MS components (n = 4,246), HR 0.31, 95% CI 0.14-0.69 (interaction P = 0.01). Conclusions While postmenopausal women with 3-4 MS components were at higher risk of death from breast cancer, those randomised to a low-fat dietary intervention more likely had reduction in this risk. Registry ClinicalTrials.gov (NCT00000611).

The development of new HER2-directed therapies has resulted in a significant prolongation of survival for women with metastatic HER2-positive breast cancer. Discoveries in the laboratory inform clinical trials which are the basis for improving the standard of care and are also the backbone for quality improvement. Clinical trials can be completed more rapidly by expanding trial enrollment to community sites. In this article we review some of the challenges in treating metastatic breast cancer with HER2-directed therapies and our strategies for incorporating our community partners into the research network.

While targeted therapies exist for human epidermal growth factor receptor 2 positive (HER2+) breast cancer, HER2+ patients do not always respond to therapy. We present the results of utilizing a biophysical mathematical model to predict tumor response for two HER2+ breast cancer patients treated with the same therapeutic regimen but who achieved different treatment outcomes. Quantitative data from magnetic resonance imaging (MRI) and 64Cu-DOTA-Trastuzumab positron emission tomography (PET) are used to estimate tumor density, perfusion, and distribution of HER2-targeted antibodies for each individual patient. MRI and PET data are collected prior to therapy, and follow-up MRI scans are acquired at a midpoint in therapy. Given these data types, we align the data sets to a common image space to enable model calibration. Once the model is parameterized with these data, we forecast treatment response with and without HER2-targeted therapy. By incorporating targeted therapy into the model, the resulting predictions are able to distinguish between the two different patient responses, increasing the difference in tumor volume change between the two patients by >40%. This work provides a proof-of-concept strategy for processing and integrating PET and MRI modalities into a predictive, clinical-mathematical framework to provide patient-specific predictions of HER2+ treatment response.

Objective The tolerability and efficacy of targeted therapy in older adults with cancer has not been adequately studied. Neratinib is a novel HER1, HER2, HER4 tyrosine kinase inhibitor that has recently been granted FDA approval for treatment of breast cancer. The major toxicity of neratinib is diarrhea, which affects up to 90% of patients. This phase II trial evaluates the safety and tolerability of neratinib in adults ≥60. Methods Patients aged 60 or older with histologically proven metastatic breast cancer and HER2 amplification (defined by ASCO/CAP guideline) or HER2/HER3 activating mutation were enrolled to receive neratinib at 240 mg daily in 28-day cycles. The association between tolerability, defined as dose reduction and number of completed courses, and log2 Cancer and Aging Research Group (CARG) toxicity risk score was assessed using a Student's t-test and linear regression, respectively. Response rate, progression free survival, and overall survival were also evaluated. Results 25 patients were enrolled with median age of 66 (range 60–79). Seventy-six percent of patients were white, 16% Asian, and 8% African-American. Seventy-six percent were patients with hormone receptor (HR) positive metastatic breast cancer (MBC) and 24% were patients with HR negative MBC. Median number of prior lines of metastatic therapy were 3 (range 0–11). 20/25 (80%) had worst grade toxicities ≥2. A total of 9/25 (36%) had grade 3 toxicities including 5/20 (20%) diarrhea, 2/20 (8%) vomiting, and 2/20 (8%) abdominal pain. There were no grade 4 or 5 toxicities. A total of 9/25 (36%) had dose reduction, and 2/25 (8%) discontinued therapy due to toxicity. The association between dose reductions and CARG toxicity score reached borderline statistical significance suggesting a trend with participants with higher CARG toxicity risk scores being more likely to require a dose modification (p = 0.054). 1/25 (4%) had a partial response, 11/25 (44%) had stable disease, 12/25 (48%) had progression of disease, and 1/25 (4%) was not assessed. Median progression free survival (PFS) was 2.6 months (95% CI [2.56–5.26]), and median overall survival (OS) was 17.4 months (95% CI [10.3, NA]). Conclusions Neratinib was safe in this population of older adults with HER2 amplified or HER2/3 mutated metastatic breast cancer (BC). Higher CARG toxicity risk score may be associated with greater need for dose adjustments. Future studies are needed to confirm this finding.

Cancer is a disease associated with aging. As the US population ages, the number of older adults with cancer is projected to dramatically increase. Despite this, older adults remain vastly underrepresented in research that sets the standards for cancer treatments and, consequently, clinicians struggle with how to interpret data from clinical trials and apply them to older adults in practice. A combination of system, clinician, and patient barriers bar opportunities for trial participation for many older patients, and strategies are needed to address these barriers at multiple fronts, five of which are offered here. This review highlights the need to (1) broaden eligibility criteria, (2) measure relevant end points, (3) expand standard trial designs, (4) increase resources (e.g., institutional support, interdisciplinary care, and telehealth), and (5) develop targeted interventions (e.g., behavioral interventions to promote patient enrollment). Implementing these solutions requires a substantial investment in engaging and collaborating with community-based practices, where the majority of older patients with cancer receive their care. Multifaceted strategies are needed to ensure that older patients with cancer, across diverse healthcare settings, receive the highest-quality, evidence-based care.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on the clinical presentation and workup of suspected bladder cancer, treatment of non-muscle-invasive urothelial bladder cancer, and treatment of metastatic urothelial bladder cancer because important updates have recently been made to these sections. Some important updates include recommendations for optimal treatment of non-muscle-invasive bladder cancer in the event of a bacillus Calmette-Guerin (BCG) shortage and details about biomarker testing for advanced or metastatic disease. The systemic therapy recommendations for second-line or subsequent therapies have also been revised. Treatment and management of muscle-invasive, nonmetastatic disease is covered in the complete version of the NCCN Guidelines for Bladder Cancer available at NCCN.org. Additional topics covered in the complete version include treatment of nonurothelial histologies and recommendations for nonbladder urinary tract cancers such as upper tract urothelial carcinoma, urothelial carcinoma of the prostate, and primary carcinoma of the urethra.

The evolutionary changes in immune profiles of triple negative breast cancer (TNBC) are not well understood, although it is known that immune checkpoint inhibitors have diminished activity in heavily pre-treated TNBC patients. This study was designed to characterize immune profile changes of longitudinal tumor specimens by studying immune subsets of tumor infiltrating lymphocytes (TILs) in paired primary and metastatic TNBC in a cohort of “poor outcome” (relapsed within 5 years) patients. Immune profiles of TNBCs in a cohort of “good outcome” (no relapse within 5 years) patients were also analyzed. Immune subsets were characterized for CD4, CD8, FOXP3, CD20, CD33, and PD1 using immuno-fluorescence staining in stroma, tumor, and combined stroma and tumor tissue. TIL subsets in “good outcome” versus “poor outcome” patients were also analyzed. Compared with primary, metastatic TNBCs had significantly lower TILs by hematoxylin and eosin (H&E) staining. Stromal TILs (sTILs), but not tumoral TILs (tTILs) had significantly reduced cytotoxic CD8+ T cells (CTLs), PD1+ CTLs, and total PD1+ TILs in metastatic compared with matched primary TNBCs. Higher PD1+ CTLs, PD1+CD4+ helper T cells (PD1+TCONV) and all PD1+ T cells in sTILs, tTILs and total stromal and tumor TILS (s+tTIL) were all associated with better prognosis. In summary, TIL subsets decrease significantly in metastatic TNBCs compared with matched primary. Higher PD1+ TILs are associated with better prognosis in early stage TNBCs. This finding supports the application of immune checkpoint inhibitors early in the treatment of TNBCs.

While targeted therapies exist for human epidermal growth factor receptor 2 positive (HER2 +) breast cancer, HER2 + patients do not always respond to therapy. We present the results of utilizing a biophysical mathematical model to predict tumor response for two HER2 + breast cancer patients treated with the same therapeutic regimen but who achieved different treatment outcomes. Quantitative data from magnetic resonance imaging (MRI) and 64Cu-DOTA-trastuzumab positron emission tomography (PET) are used to estimate tumor density, perfusion, and distribution of HER2-targeted antibodies for each individual patient. MRI and PET data are collected prior to therapy, and follow-up MRI scans are acquired at a midpoint in therapy. Given these data types, we align the data sets to a common image space to enable model calibration. Once the model is parameterized with these data, we forecast treatment response with and without HER2-targeted therapy. By incorporating targeted therapy into the model, the resulting predictions are able to distinguish between the two different patient responses, increasing the difference in tumor volume change between the two patients by > 40%. This work provides a proof-of-concept strategy for processing and integrating PET and MRI modalities into a predictive, clinical-mathematical framework to provide patient-specific predictions of HER2 + treatment response.

BACKGROUND: Metabolic syndrome (MSY) is associated with an increased risk of cardiovascular disease, type 2 diabetes, and recurrence in breast cancer survivors (BCS). MSY is 1.5 times more common in Hispanic women compared with non-Hispanic women. Although exercise mitigates MSY in BCS, to the best of the authors’ knowledge, few studies to date have focused on minorities. This secondary analysis examined ethnicity as a moderator of the effects of a 16-week aerobic and resistance exercise intervention on MSY, sarcopenic obesity, and serum biomarkers in BCS. METHODS: A total of 100 eligible BCS were randomized to exercise (50 BCS) or usual care (50 BCS). The exercise intervention promoted moderate to vigorous aerobic and resistance exercise 3 times a week for 16 weeks. MSY z scores, sarcopenic obesity, and serum biomarkers were measured at baseline, after the intervention, and at the 28-week follow-up (exercise group only). Linear mixed models adjusted for baseline values of the outcome, age, disease stage, adjuvant treatment, and recent physical activity were used to evaluate effect modification by ethnicity. RESULTS: The study sample was 57% Hispanic BCS (HBCS) and 43% non-Hispanic BCS (NHBCS). HBCS were younger, of greater adiposity, and had been diagnosed with more advanced cancers compared with NHBCS (P

Purpose The purpose of this study was to evaluate longitudinal changes in brain gray matter density (GMD) before and after adjuvant chemotherapy in older women with breast cancer. Methods We recruited 16 women aged ≥ 60 years with stage I–III breast cancers receiving adjuvant chemotherapy (CT) and 15 age- and sex-matched healthy controls (HC). The CT group underwent brain MRI and the NIH Toolbox for Cognition testing prior to adjuvant chemotherapy (time point 1, TP1) and within 1 month after chemotherapy (time point 2, TP2). The HC group underwent the same assessments at matched intervals. GMD was evaluated with the voxel-based morphometry. Results The mean age was 67 years in the CT group and 68.5 years in the HC group. There was significant GMD reduction within the chemotherapy group from TP1 to TP2. Compared to the HC group, the CT group displayed statistically significantly greater GMD reductions from TP1 to TP2 in the brain regions involving the left anterior cingulate gyrus, right insula, and left middle temporal gyrus (pFWE(family-wise error)-corrected pFWE-corrected pFWE-corrected Conclusions Our findings indicate that GMD reductions were associated with adjuvant chemotherapy in older women with breast cancer. Future studies are needed to understand the clinical significance of the neuroimaging findings. This study is registered on ClinicalTrials.gov (NCT01992432).

Tumor invasion into draining lymph nodes, especially sentinel lymph nodes (SLNs), is a key determinant of prognosis and treatment in breast cancer as part of the TNM staging system. Using multicolor histology and quantitative image analysis, we quantified immune cells within SLNs from a discovery cohort of 76 breast cancer patients. We found statistically more in situ CD3+ T cells in tumor negative vs. tumor positive nodes (mean of 8878 vs. 6704, respectively, p = 0.006), but no statistical difference in CD20+ B cells or CD1a+ dendritic cells. In univariate analysis, a reduced hazard was seen with a unit increase in log CD3 with HR 0.49 (95% CI 0.30–0.80) and log CD20 with HR 0.37 (95% CI 0.22–0.62). In multivariate analysis, log CD20 remained significant with HR 0.42 (95% CI 0.25–0.69). When restricted to SLN tumor negative patients, increased log CD20 was still associated with improved DFS (HR = 0.26, 95% CI 0.08–0.90). The CD20 results were validated in a separate cohort of 21 patients (n = 11 good outcome, n = 10 poor outcome) with SLN negative triple-negative breast cancer (TNBC) (“good” mean of 7011 vs. “poor” mean of 4656, p = 0.002). Our study demonstrates that analysis of immune cells within SLNs, regardless of tumor invasion status, may provide additional prognostic information, and highlights B cells within SLNs as important in preventing future recurrence., Immunology: Lymph nodes full of B cells linked to better outcomes B cells within the tumor-draining lymph nodes may have an important biological role in preventing relapse of breast cancer. A team led by Peter Lee from City of Hope in Duarte, California, USA, quantified the levels of three populations of immune cells—T cells, B cells and dendritic cells—within sentinel lymph nodes biopsied from a cohort of 76 patients. They found that larger numbers of T cells and B cells were both linked to longer progression-free survival in the women. However, after statistically accounting for correlations between the two immune cell types, the researchers concluded that B cells had the dominant beneficial effect on survival times. They validated the finding that high B-cell counts are a prognostic indicator of better outcomes in a separate cohort of 21 women with triple-negative breast cancer.

Background: Androgen receptor (AR) targeted therapy and immunotherapy represent one of the most promising strategies for metastatic triple negative breast cancer (mTNBC), which accounts for 15-20% of all breast cancers. As a nonsteroidal selective androgen receptor modulator (SARM), GTx-024 demonstrated preclinical activity in AR+ TNBC PDX model. Pembrolizumab is a highly selective humanized monoclonal antibody of the programmed cell death 1 receptor (PD-1). The complementary modes of action and low potential for overlapping toxicity make the combination promising in patients with AR+ mTNBC. Trial Design: This is an open-label Phase 2 study for AR+ mTNBC. Eligible participants receive pembrolizumab 200mg IV every 3 weeks in combination with GTx-024 18mg po daily. Eligibility Criteria: Eligible patients must have AR+ (>10%, 1+ by IHC) TNBC; failed up to 2 lines of therapy in metastatic setting; and have measurable disease per RECIST1.1. Patients are excluded if they have had prior checkpoint inhibitors or AR targeted agents. Patients with current or prior use of testosterone, testosterone-like agents, androgenic compounds, or anti-androgens (including systemic steroids and immunosuppressive medications)are excluded, as well as current or prior history of noninfectious pneumonitis requiring systemic steroid therapy. Specific Aims: The primary objective is to evaluate the safety/tolerability of GTx-024 and pembrolizumab and determine the response rate (CR or PR via RECIST 1.1) in patients with advanced AR+ TNBC. We will use clinical benefit rate (CBR), duration of response (DOR), PFS, and OS to test the efficacy of this novel drug combination. Statistical Design: A Simon's MiniMax two-stage Phase 2 design will be utilized. Based on the previously reported response rate associated with single agent pembrolizumab (19%), we consider a response rate of 19% for the combination as discouraging, and a 39% response rate as encouraging. As a result, we will initially accrue 15 patients (including 6 patients from safety lead-in treated at the tolerable dose). If 2 or fewer patients respond, we will stop accrual for futility. Otherwise, the study will accrue an additional 14 patients for a total of 29 patients. With 29 patients, if only 8 or fewer respond (≤27.6%), the study will be considered discouraging unless secondary evidence of clinical benefit is substantial. With more than 8 patients responding out of the 29 patients, the combination would be considered promising. This design has 85% power to declare a true response rate of 39% as promising (power), and a 10% probability of declaring a true 19% response rate as encouraging (type I error). The probability of early termination if the true response rate is 19% is 44%. Target Accrual: 29 Study Contact: Yuan Yuan MD PhD, City of Hope Comprehensive Cancer Center; Duarte, CA 91030; Email: yuyuan@coh.org Citation Format: Yuan Y, Frankel P, Synold T, Lee P, Yost S, Martinez N, Tang A, Mendez B, Schmolze D, Apple S, Hurria A, Waisman J, Somlo G, Tank N, Sedrak M, Mortimer J. A phase II clinical trial of the combination of pembrolizumab and selective androgen receptor modulator GTx-024 in patients with advanced androgen receptor positive triple negative breast cancer [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 OT1-05-02.

BACKGROUND: Breast cancer survivors have a high prevalence of metabolic dysfunction—characterized by high glucose and weight gain. Regardless of menopausal status, overweight and obese women are at increased risk for developing breast cancer and those who are diagnosed with breast cancer experience adverse cancer-related outcomes. The underlying principle of the Pancreatic Nutrition Program (PNP) is that bio-individualized healthy food choices—eating the correct foods and food combinations for an individual's body—can minimize fluctuations in insulin by keeping blood glucose regulated (70-100 mg/dL) and this will promote sustained weight loss, improved health, and quality of life. METHODS: The primary endpoint was change in body weight at 24 weeks post-PNP. The study was powered to detect a 10% loss of weight from baseline. Secondary endpoints included change in: glucose levels, insulin resistance, body composition, body chemistry, physical fitness, biological markers, quality of life, and compliance. Postmenopausal, non-diabetic breast cancer survivors (stages I-III) within 5 years of completion of treatment who had a body mass index of 25-33 kg/m2 were recruited. For the first 12 weeks, patients wore a glucometer (Abbott), which recorded glucose every 15 minutes continuously, and kept a food journal. During weekly meetings, glucometer data was reviewed with journal entries to identify food choices and combinations that would kept the subject's glucose levels between 70-100 mg/dL. At the end of the 12-weeks, the weekly meetings and glucometer were discontinued and patients were expected to maintain the PNP for an additional 12 weeks. Study endpoints were measured at baseline, 12-week and 24-week visits. RESULTS: Of the 21 patients enrolled in the study, 12 were non-Hispanic Caucasian, 5 were Hispanic, 2 were African-American, and 2 were Asian. The median age was 56 years (43-76 years). Twenty were estrogen-receptor positive, 18 progesterone-receptor positive, and 8 were HER2/neu positive. The mean body weight at baseline was 170.9 lbs (±20.4 lbs). Two patients dropped out prior to 12-weeks and 1 developed recurrent disease. Among the 18 eligible women who completed the first 12 weeks, the median weight loss at 12-weeks was 10.1 lbs (1.5-19.6 lbs). The median waist circumference lost was 2.5 inches (gain of 0.4 inches-loss of 5.5 inches). Among the women whose total cholesterol was above 200 mg/dL, 71% reduced their cholesterol below 200 mg/dL by 12-weeks. All women who had triglyceride levels above 150 mg/dL reduced their levels below 150 mg/dL by 12-weeks. Likewise, among women who were identified as being pre-diabetic based on fasting glucose or hemoglobin A1c levels, all were within normal range at 12-weeks. 6-month testing will be completed in August. Among the 15 women eligible for 6-month testing, 8 (53%) completed the testing. Of those, 7 (88%) maintained their positive results. CONCLUSIONS: Bio-individualized food choices based on glucose response combined with culturally-sensitive nutrition counseling may provide a feasible mechanism for sustainable weight loss in a population at high-risk of metabolic dysfunction. However, to increase adherence, a tapering strategy should be developed after the first 12-weeks of health counseling. Citation Format: Clague DeHart J, Rosen C, Wong L, Moore S, Flores S, Salehian B, Mortimer J. Pancreatic nutrition program (PNP): A novel weight reduction program for breast cancer survivors [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 P2-13-06.

Background: Older adults are less likely to be included in clinical trials leading to the approval of novel cancer treatments. The Institute of Medicine and ASCO have identified therapeutic phase II trials as a key research priority to increase the evidence base for older adults with cancer. While targeted therapies may represent a less toxic option for older patients, few trials have studied their tolerability and efficacy in older adults. Here, we present a phase II study (NCT01273610) of the combination of trastuzumab and lapatinib in older patients with HER2+ metastatic breast cancer (MBC), incorporating geriatric oncology principles in the study design. Methods: Patients age ≥ 60 years with MBC and any number of prior chemotherapy (CT) lines received trastuzumab (either 4mg/kg loading dose followed by 2mg/kg weekly or 8mg/kg followed by 6mg/kg q/3 weeks) plus lapatinib 1000 mg/m2 daily in 21-day cycles. Patients completed a pre-treatment geriatric assessment including measures of function, comorbidity, cognition, nutrition, and psychosocial status. A toxicity risk score developed for older adults receiving cytotoxic CT was calculated for each patient (Hurria et al. JCO 2011 & 2016). Relationships between tolerability (dose reductions and grade (G) ≥ 3 toxicity attributed to treatment) and risk score analyzed using a log2 transformation were assessed using generalized linear models, Student's t tests, and Fisher's exact test. Response rate (RR) and progression free survival (PFS) were evaluated. Results: 40 patients (mean age 72 [60-92]) were accrued from 04/11 to 05/15. 25% (n = 10) were ≥ 75 years of age. 65% of patients (n = 26) had HR+ tumors and 35% (n = 14) were receiving ≥ 3rd line treatment. Median number of cycles was 4 (0-28). RR was 23% (n = 9, 95% CI 11-38%; 1 complete, 8 partial). 23% (n = 9) achieved stable disease. PFS was 2.7 months (95% CI 2.5-12). Based on the toxicity risk score, 21% (n = 8), 54% (n = 21), and 26% (n = 10) were at low, intermediate, and high risk. 70% (n = 28) of patients had G ≥ 2 toxicities and 20% (n = 8) G ≥ 3 toxicities. G 2 and 3 diarrhea occurred in 28% (n = 11) and 5% (n = 2) respectively. 5% (n = 2) were hospitalized due to treatment-related toxicity. No G ≥ 3 cardiac toxicities were observed. 23% of patients (n = 9) had treatment delays, and 43% (n = 17) required a lapatinib dose reduction. The mean toxicity risk score was higher in patients who required dose reductions (Student's t: p = 0.02). No statistically significant relationship was found between toxicity risk scores and the presence of G ≥ 3 treatment toxicity (logistic regression: OR = 3.08, 95% CI [0.54, 21.2], p = 0.22). Conclusions: Among older patients with MBC (79% at intermediate or high risk of G ≥ 3 cytotoxic CT toxicity), trastuzumab and lapatinib were well tolerated, with only 20% experiencing G3 toxicities. The toxicity risk score was not found to be significantly related with treatment toxicity, which may be explained by the very low incidence of G3 events. Patients with a low toxicity risk score were not likely to require a lapatinib dose reduction. Citation Format: O'Connor T, Soto-Perez-de-Celis E, Blanchard S, Chapman A, Kimmick G, Muss H, Luu T, Waisman JR, Li D, Mortimer J, Yuan Y, Somlo G, Stewart D, Katheria V, Levi A, Hurria A. Tolerability of the combination of lapatinib and trastuzumab in older patients with HER2 positive metastatic breast cancer [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 P5-21-08.

Purpose: Therapeutic strategies against hormonal receptor–positive (HR+)/HER2+ breast cancers with poor response to trastuzumab need to be optimized. Experimental Design: Two HR+/HER2+ patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2+ breast cancers. RNA sequencing and RPPA (reverse phase protein array) analyses were conducted to decipher molecular features of the two PDXs and define the therapeutic strategy of interest, validated by in vivo drug efficacy examination and in vitro cell proliferation analysis. Results: Estrogen acted as a growth driver of trastuzumab-resistant COH-SC31 tumors but an accelerator in the trastuzumab-sensitive COH-SC1 model. In vivo trastuzumab efficacy examination further confirmed the consistent responses between PDXs and the corresponding tumors. Integrative omics analysis revealed that mammalian target of rapamycin (mTOR) and ERα signaling predominantly regulate tumor growth of the two HR+/HER2+ PDXs. Combination of the dual mTOR complex inhibitor MLN0128 and anti-HER2 trastuzumab strongly suppressed tumor growth of COH-SC1 PDX accompanied by increasing ER-positive cell population in vivo. Instead, MLN0128 in combination with antiestrogen fulvestrant significantly halted the growth of HR+/HER2+ cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivo. Conclusions: Compared with the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR+/HER2+ tumors through establishment of two PDXs coupled with integrative omics analyses and in vivo drug efficacy examination. This work presents a prototype of future “co-clinical” trials to tailor personalized medicine in clinical practice. Clin Cancer Res; 24(2); 395–406. ©2017 AACR.