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HER2 is a predictive biomarker for HER2-targeted therapeutics. For antibody–drug conjugates (ADCs; e.g., trastuzumab emtansine (T-DM1)), HER2 is utilized as a transport gate for cytotoxic agents into the cell. ADC biomarkers may therefore be more complex, also reflecting the intracellular drug transport. Here we report on a positive correlation between the early endosome marker RAB5A and T-DM1 sensitivity in five HER2-positive cell lines. Correlation between RAB5A expression and T-DM1 sensitivity is confirmed in breast cancer patients treated with trastuzumab emtansine/pertuzumab in the I-SPY2 trial (NCT01042379), but not in the trastuzumab/paclitaxel control arm. The clinical correlation is further verified in patients from the KAMILLA trial (NCT01702571). In conclusion, our results suggest RAB5A as a predictive biomarker for T-DM1 response and outline proteins involved in endocytic trafficking as predictive biomarkers for ADCs., Antibody Drug Conjugates (ADCs) are emerging in the field of precision cancer medicine. Here, the authors suggest using endocytosis as a predictive biomarker for response

HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms ‘graduate’ in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome., HER2-targeted therapy improves patient’s outcome in early breast cancer. Here, the authors present the efficacy and biomarker analysis of two HER2-targeted combinations (ado-trastuzumab emtansine plus pertuzumab and paclitaxel, trastuzumab and pertuzumab) in the context of the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence.

Background Suppression of background parenchymal enhancement (BPE) is commonly observed after neoadjuvant chemotherapy (NAC) at contrast-enhanced breast MRI. It was hypothesized that nonsuppressed BPE may be associated with inferior response to NAC. Purpose To investigate the relationship between lack of BPE suppression and pathologic response. Materials and Methods A retrospective review was performed for women with menopausal status data who were treated for breast cancer by one of 10 drug arms (standard NAC with or without experimental agents) between May 2010 and November 2016 in the Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging and Molecular Analysis 2, or I-SPY 2 TRIAL (NCT01042379). Patients underwent MRI at four points: before treatment (T0), early treatment (T1), interregimen (T2), and before surgery (T3). BPE was quantitatively measured by using automated fibroglandular tissue segmentation. To test the hypothesis effectively, a subset of examinations with BPE with high-quality segmentation was selected. BPE change from T0 was defined as suppressed or nonsuppressed for each point. The Fisher exact test and the Z tests of proportions with Yates continuity correction were used to examine the relationship between BPE suppression and pathologic complete response (pCR) in hormone receptor (HR)-positive and HR-negative cohorts. Results A total of 3528 MRI scans from 882 patients (mean age, 48 years ± 10 [standard deviation]) were reviewed and the subset of patients with high-quality BPE segmentation was determined (T1, 433 patients; T2, 396 patients; T3, 380 patients). In the HR-positive cohort, an association between lack of BPE suppression and lower pCR rate was detected at T2 (nonsuppressed vs suppressed, 11.8% [six of 51] vs 28.9% [50 of 173]; difference, 17.1% [95% CI: 4.7, 29.5]; P = .02) and T3 (nonsuppressed vs suppressed, 5.3% [two of 38] vs 27.4% [48 of 175]; difference, 22.2% [95% CI: 10.9, 33.5]; P = .003). In the HR-negative cohort, patients with nonsuppressed BPE had lower estimated pCR rate at all points, but the P values for the association were all greater than .05. Conclusions In hormone receptor-positive breast cancer, lack of background parenchymal enhancement suppression may indicate inferior treatment response. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Philpotts in this issue.

PURPOSE: Despite evidence-based guidelines recommending early palliative care, it remains unclear how to identify and refer oncology patients, particularly in settings with constrained access to palliative care. We hypothesize that patient-reported outcome (PRO) data can be used to characterize patients with palliative care needs. To determine if PRO data can identify latent phenotypes that characterize indications for specialty palliative care referral. METHODS: We conducted a retrospective study of self-reported symptoms on the Edmonton Symptom Assessment System collected from solid tumor oncology patients (n = 745) referred to outpatient palliative care. Data were collected as part of routine clinical care from October 2012 to March 2018 at eight community and academic sites. We applied latent profile analysis to identify PRO phenotypes and examined the association of phenotypes with clinical and demographic characteristics using multinomial logistic regression. RESULTS: We identified four PRO phenotypes: (1) Low Symptoms (n = 295, 39.6%), (2) Moderate Pain/Fatigue + Mood (n = 180, 24.2%), (3) Moderate Pain/Fatigue + Appetite + Dyspnea (n = 201, 27.0%), and (4) High Symptoms (n = 69, 9.3%). In a secondary analysis of 421 patients, we found that two brief items assessing social and existential needs aligned with higher severity symptom and psychological distress phenotypes. CONCLUSION: Oncology patients referred to outpatient palliative care in a real-world setting can be differentiated into clinically meaningful phenotypes using brief, routinely collected PRO measures. Latent modeling provides a mechanism to use patient-reported data on a population level to identify distinct subgroups of patients with unmet palliative needs.

PURPOSE: Obesity increases the risk of cancer recurrence and death in survivors of breast cancer. This study tested the hypothesis that exercise alone, diet alone, and the combination of exercise plus diet reduce body weight and improve body composition in survivors of breast cancer. METHODS: In this 2×2 factorial trial, 351 survivors of breast cancer with overweight or obesity were randomized to one of four treatment groups for 52 weeks: control, exercise alone, diet alone, or exercise plus diet. Endpoints included body weight and body composition measured by dual-energy x-ray absorptiometry. RESULTS: After 52 weeks, compared with control, diet alone [−5.39 kg (95% CI: −7.24, −3.55); −6.0% (95% CI: −8.0, −3.9)] and exercise plus diet [−6.68 kg (95% CI: −8.46, −4.90); −7.4% (95% CI: −9.4, −5.4)] reduced body weight; exercise alone did not change body weight. Compared with control, diet alone [−3.59 kg (95% CI: −5.00, −2.17)] and exercise plus diet [−4.28 kg (95% CI: −5.71, −2.84)] reduced fat mass; exercise alone did not change fat mass. Compared with control, diet alone [−0.82 kg (95% CI: −1.50, −0.15)] and exercise plus diet [−1.24 kg (95% CI: −1.92, −0.56)] reduced lean mass; exercise alone did not change lean mass. Compared with control, exercise alone, diet alone, and exercise plus diet did not change bone mineral density. CONCLUSION: In survivors of breast cancer with overweight or obesity, diet alone or diet plus exercise produced clinically meaningful weight loss at week 52. The majority of weight loss was fat mass.

Patients with cancer have high mortality from coronavirus disease 2019 (COVID-19), and the immune parameters that dictate clinical outcomes remain unknown. In a cohort of 100 patients with cancer who were hospitalized for COVID-19, patients with hematologic cancer had higher mortality relative to patients with solid cancer. In two additional cohorts, flow cytometric and serologic analyses demonstrated that patients with solid cancer and patients without cancer had a similar immune phenotype during acute COVID-19, whereas patients with hematologic cancer had impairment of B cells and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses. Despite the impaired humoral immunity and high mortality in patients with hematologic cancer who also have COVID-19, those with a greater number of CD8 T cells had improved survival, including those treated with anti-CD20 therapy. Furthermore, 77% of patients with hematologic cancer had detectable SARS-CoV-2-specific T cell responses. Thus, CD8 T cells might influence recovery from COVID-19 when humoral immunity is deficient. These observations suggest that CD8 T cell responses to vaccination might provide protection in patients with hematologic cancer even in the setting of limited humoral responses.

Background Given excellent survival outcomes in breast cancer, there is interest in de‐escalating the amount of chemotherapy delivered to patients. This approach may be of even greater importance in the setting of the COVID‐19 pandemic. Methods This concurrent mixed methods study included (1) interviews with patients and patient advocates and (2) a cross‐sectional survey of women with breast cancer served by a charitable nonprofit organization. Questions evaluated interest in de‐escalation trial participation, perceived barriers/facilitators to participation, and language describing de‐escalation. Results Sixteen patient advocates and 24 patients were interviewed. Key barriers to de‐escalation included fear of recurrence, worry about decision regret, lack of clinical trial interest, and dislike for focus on less treatment. Facilitators included trust in physician recommendation, toxicity avoidance, monitoring for progression, perception of good prognosis, and impact on daily life. Participants reported that the COVID‐19 pandemic made them more likely to avoid chemotherapy if possible. Of 91 survey respondents, many (43%) patients would have been unwilling to participation in a de‐escalation clinical trial. The most commonly reported barrier to participation was fear of recurrence (85%). Few patients (19%) considered clinical trials themselves as a barrier to de‐escalation trial participation. The most popular terminology describing chemotherapy de‐escalation was “lowest effective chemotherapy dose” (53%); no patients preferred the term “de‐escalation.” Conclusions Fear of recurrence is a common concern among breast cancer survivors and patient advocates, contributing to resistance to de‐escalation clinical trial participation. Additional research is needed to understand how to engage patients in de‐escalation trials., Over 40% of patients would not be interested in participating in clinical trials testing de‐escalation, with the most common barriers being fear of recurrence. Common facilitators included toxicity avoidance, trust in the physician, and use of patient‐centric language to describe the trial.

BACKGROUND We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.

Background Findings from randomized clinical trials may have limited generalizability to patients treated in routine clinical practice. This study examined the effectiveness of first-line palbociclib plus letrozole versus letrozole alone on survival outcomes in patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor–negative (HER2−) metastatic breast cancer (MBC) treated in routine clinical practice in the USA. Patients and methods This was a retrospective observational analysis of electronic health records within the Flatiron Health Analytic Database. A total of 1430 patients with ≥ 3 months of follow-up received palbociclib plus letrozole or letrozole alone in the first-line setting between February 3, 2015, and February 28, 2019. Stabilized inverse probability treatment weighting (sIPTW) was used to balance baseline demographic and clinical characteristics. Real-world progression-free survival (rwPFS) and overall survival (OS) were analyzed. Results After sIPTW adjustment, median follow-up was 24.2 months (interquartile range [IQR], 14.2–34.9) in the palbociclib group and 23.3 months (IQR, 12.7–34.3) in those taking letrozole alone. Palbociclib combination treatment was associated with significantly longer median rwPFS compared to letrozole alone (20.0 vs 11.9 months; hazard ratio [HR], 0.58; 95% CI, 0.49–0.69; P P = 0.0002). The 2-year OS rate was 78.3% in the palbociclib group and 68.0% with letrozole alone. A propensity score matching analysis showed similar results. Conclusions In this “real-world” population of patients with HR+/HER2− MBC, palbociclib in combination with endocrine therapy was associated with improved survival outcomes compared with patients treated with letrozole alone in the first-line setting. Trial registration Clinicaltrials.gov; NCT04176354

Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk stage II/III breast cancer. The primary endpoint is pathologic complete response (pCR, ypT0/Tis ypN0). SGN-LIV1A is an investigational antibody drug conjugate consisting of an antibody to LIV1A, a zinc transporter highly prevalent in breast cancer, and a highly potent microtubule inhibitor, monomethyl auristatin E. Retrospective IHC analysis of LIV1A expression levels amongst tumor samples from 100 previous ISPY-2 patients showed 88% of breast tumor samples with moderate to high expression of LIV1A (Yau, C. et al SABCS 2018).Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment, hormone-receptor positive (HR+) patients had to have MP high molecular profile. Treatment included SGN-LIV1A 2.5 mg/kg (max dose 250 mg) every 3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2-3 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. All patients undergo serial MR imaging where response at 3 & 12 weeks combined with accumulating pCR data are used to estimate, and continuously update, predicted pCR rate for the trial arm. Analysis set was modified intention to treat with patients who switched to non-protocol therapy counted as non-pCR and not as their pCR status at time of surgery. The goal is to identify/graduate regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 neoadjuvant trial with a pCR endpoint within signatures defined by HR & HER2 status & MP result. This investigational arm was eligible for graduation in 3 of 10 pre-defined signatures: HER2-, HR+HER2- and HR-HER2-. Regimens may also leave the trial for futility (< 10% probability of success), maximum sample size accrual (10% < probability of success Results: Sixty patients were randomized and evaluable to SGN-LIV1A. The study arm was stopped due to reaching the predetermined time limit for patient accrual of 2 yrs. Final estimated pCR rates are below. The estimated pCR rates were similar between the SGN-LIV1A and control arms for any tumor subtype. Preliminary safety events for SGN-LIV1A include increased rates of transaminitis and hyperglycemia and reduced rates of peripheral neuropathy compared to control. One patient was removed from the analysis as she was determined to have angiosarcoma of the breast. Notably, this patient had a dramatic early response and subsequent pCR to SGN-LIV1A treatment. Conclusion: The value of I-SPY 2 is to give insight about the performance of an investigational agent’s likelihood of achieving pCR. SGN-LIV1A delivered every 3 weeks was comparable to paclitaxel for the primary endpoint of pCR in I-SPY2 and may have a similar side effect profile, however, with less peripheral neuropathy. Clinical trials evaluating weekly dosing of SGN-LIV1A are ongoing. A trial of SGN-LIV1A in the treatment of angiosarcoma is under consideration at this time. Final Estimated pCR Rates and Predictive ProbabilitiesEstimated pCR rate(95% prob interval)SignatureSGN-LIV1AControlProbability SGNLIV1A Superior to ControlPredictive Probability of Success in Phase 3HER2-0.16 (0.08-0.24) N= 600.20 (0.16-0.25) N= 3270.180.02HR-/HER2-0.25 (0.12-0.37) N=360.28 (0.21-0.35) N=1460.310.06HR+/HER2-0.09 (0-0.18) N=240.14 (0.09-0.19) N=1810.150.03 Citation Format: Heather Beckwith, Richard Schwab, Christina Yau, Erica Stringer-Reasor, Shi Wei, A. Jo Chien, Kathy S Albain, Kevin Kalinsky, Anne Wallace, Anthony Elias, Douglas Yee, Amy S Clark, Judy C Boughey, Heather Han, Rita Nanda, Claudine Isaacs, Zahi Mitri, Julie E Lang, Alexandra Thomas, Tara Sanft, Angela DeMichele, Jane Perlmutter, Hope S Rugo, Nola M Hylton, W. Fraser Symmans, Michelle E Melisko, Laura J van't Veer, I-SPY 2 Consortium, Amy Wilson, Smita M Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of SGN-LIV1a followed by AC in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-10.

Introduction: One of the principal limiting factors to achieving cures in patients with cancer is drug resistance. Drug repositioning is the application of FDA-approved drug compounds for novel indications beyond the scope of the drug’s original intended use. This approach offers advantages over traditional drug development by reducing development costs and providing shorter paths to approval, as drug safety has already been established during the drug’s original regulatory process. One approach for computational drug repositioning involves generating a disease gene expression signature and then identifying a drug that can reverse this disease signature. In this study, we extracted drug resistance signatures from the I-SPY 2 TRIAL by comparing gene expression profiles of responder and non-responder patients stratified by treatment and molecular subtype. We then applied our drug repositioning pipeline to predict compounds that can reverse the gene expression profiles of these drug resistance signatures. We hypothesize that reversing these drug resistance signatures will resensitize tumors to treatment and improve patient outcome. Methods: We first generated the drug resistance signatures by performing differential expression between responders (RCB 0/I) and non-responders (RCB III) within treatment arms and molecular subtypes. An optimal log fold-change cutoff was selected for each signature by identifying the cutoff that best separates the responder and non-responder samples using k-means clustering. We then applied our drug repositioning pipeline to identify compounds that significantly reverse these signatures using the drug perturbation profiles generated in a breast cancer cell line in the Connectivity Map v2 dataset. Briefly, the pipeline uses a non- parametric, rank-based pattern-matching strategy based on the Kolmogorov-Smirnov (KS) statistic to assess the enrichment of resistance genes in a ranked drug gene expression list. Significance of each prediction is estimated from a null distribution of scores generated from random gene signatures. Results: We found that few individual genes are shared among the resistance signatures across the treatment arms and molecular subtypes, with the most common genes present in only 5/17 of the treatment arm and molecular subtype groups. At the pathway-level, however, we found that immune-related pathways are generally enriched among the responders and estrogen-response pathways are generally enriched among the non-responders. Although most of our drug predictions are unique to treatment arms and molecular subtypes, our drug repositioning pipeline identified the selective estrogen receptor degrader (SERD) fulvestrant as a compound that can potentially reverse resistance across a majority of the treatment arms and molecular subtypes. Conclusion: We applied our drug repositioning pipeline to identify novel agents to sensitize drug-resistant tumors in the I-SPY 2+ clinical trial and identified a SERD, fulvestrant, as a potential candidate for multiple molecular subtypes and treatment arms. Citation Format: Katharine Yu, Amrita Basu, Christina Yau, Denise Wolf, Gillian Hirst, Laura Sit, Nicholas O’Grady, Thelma Brown, I-SPY 2 TRIAL Investigators, Angela DeMichele, Don Berry, Nola Hylton, Doug Yee, Laura Esserman, Laura van 't Veer, Marina Sirota. Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatment arms and molecular subtypes [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 PS11-04.

I-SPY2 is a neoadjuvant trial evaluating experimental therapies in combination with cytotoxic chemotherapy compared to chemotherapy alone with the primary endpoint of pathologic complete response (pCR). Abundant preclinical evidence suggested the type I insulin-like growth factor receptor (IGF-1R) regulated breast cancer growth, although multiple clinical trials did not show benefit. We were the first to report the results of a monoclonal IGF-1R antibody ganitumab (G) in combination with chemotherapy. PGM followed by doxorubicin/cyclophosphamide (AC) did not result in substantial increases in pCR when compared to P followed by AC. In this report, we examined several potential predictive biomarkers. IGF-1R inhibitors induce hyperglycemia and we examined hemoglobin A1C (HgbA1c) as a measure of glucose control in patients before and after PGM therapy. 106 patients received PGM and 104 patients had baseline HgbA1c with a median of 5.4%. However, 27% (28/104) had levels greater than 5.7% the upper limit of normal as defined by the NIDDK. 4 of 104 had HgbA1c greater than 6.5%, a level associated with type 2 diabetes. pCR rates are similar between patients with baseline HgbA1c ≤5.7% (21%) vs. >5.7% (25%) (Fisher test p=0.79). 72 of these patients had an additional HgbA1c during the course of PGM therapy. For patients with HgbA1c ≤5.7%, 27% (14/52) had subsequent elevation above 5.7% after PGM. For patients with a baseline HgbA1C >5.7%, all 20 patients continued to have elevated levels through PGM. We also examined pre-treatment tumor gene expression profiles derived from custom Agilent 44K full-genome microarrays. We studied 11 genes associated with the IGF-1R signaling (IGF1, IGF2, IGF1R, INSR, IGFBP2, IRS1, IRS2, IGFBP3, IGFBP4, IGFBP5, CDH1), the IGFBP5/IGFBP4 ratio, and two IGFR expression signatures (Creighton, et al. J Clin Oncol 26:4078 2008 PMID: 18757322; Mu, et al. Breast Cancer Res Treat 133:321 2012 PMID: 22297468). The 2 signatures evaluated: the IGF1 ligand score and the IGF1-R signature are anti-correlated (Rp= - 0.79). In the population as a whole, lower levels of IRS1 and IGFBP5 significantly associated with response to PGM (likelihood ratio test (LR) p< 0.05), as do lower levels of the IGF1 ligand score and higher levels of the IGF-1R signature. However, levels of IRS1 and the two expression signatures also trend toward or are significantly associated with response in the control arm; and treatment interactions for all four biomarkers are non-significant (LR p>0.05). Therefore, none of these biomarkers qualify as specific predictors of response to PGM. Similarly, high MammaPrint scores (MP2) were associated with higher pCR scores in both PGM and Control arms. Previous gene expression profiles were divided into tertiles (low, intermediate, high). Similar to the continuous case, IGF1Rsig-class associates with pCR in both the PGM and control arms (Fisher test p=0.033 and 0.044, respectively), and thus also fails as a specific predictor of response to PGM. We conclude that PGM therapy results in worsening of glucose control and likely increases serum insulin levels. While IGF gene expression profiling associated with treatment response, they were not specific for PGM. Further, biomarker analysis and strategies to control glucose will be needed to optimize anti-IGF-1R therapies. Citation Format: Douglas Yee, Paul Haluska, Denise M Wolf, Christina Yau, Amy Wilson, I-SPY2 TRIAL Consortium, Angela DeMichele, Claudine Isaacs, Jane Perlmutter, Joan Venticinque, Hope S Rugo, Richard Schwab, Nola M Hylton, W Fraser Symmans, Michelle E Melisko, Teresa L Helsten, Laura J van't Veer, Donald A Berry, Laura J Esserman. Biomarker analysis of paclitaxel, ganitumab, and metformin (PGM) therapy in the I-SPY2 neoadjuvant clinical trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-08.

Background: Disseminated tumor cells (DTCs) in bone marrow detected after treatment may represent occult residual disease. We enumerated DTCs after neoadjuvant chemotherapy (NACT) in patients (pts) diagnosed with high-risk early stage breast cancer and examined the relationship of these cells with response and survival. Methods: I-SPY SURMOUNT is a sub-study of the I-SPY 2 TRIAL (NCT01042379). Pts enrolled on I-SPY 2, who signed consent for this sub-study, had bone marrow aspirates (BMA) collected after NACT at the time of surgery. DTCs were isolated and enumerated from BMA using immunomagnetic enrichment/flow cytometry (IE/FC). DTCs were defined as EPCAM-positive and CD45-negative nucleated cells. Samples were considered positive using a predetermined threshold of >4 DTCs per mL (Magbanua et al, unpublished data). Pathologic response was assessed using the residual cancer burden (RCB) method at local sites, and pts underwent standard adjuvant therapy if indicated and follow up for recurrence events and death. Relationship of DTCs with clinicopathologic variables was examined using Chi-squared test. Group means were compared using t tests. The log-rank test was used to compare survival curves. Results: A total of 73 patients were enrolled, 51 of whom had successful DTC assessment. The median DTC per mL was 4 (interquartile range 1.2-11.6). 24/51 (47%) were DTC-positive. Clinical characteristics by DTC status are shown in the table. DTC-positive pts were significantly younger (p=0.02) and had larger pretreatment tumors (longest diameter by magnetic resonance imaging) compared to DTC-negative pts (p=0.032). DTCs were not associated with receptor subtype. Thirty pts (41%) achieved a pathologic complete response (pCR). DTCs were not associated with pCR (p= 0.166); however, DTC-positive patients were significantly more likely to have residual cancer (RCB-II/III) after NACT compared to DTC-negative patients (OR 3.3, p=0.037). Median follow up of this cohort was 2.8 years (range: 0.9-4.8). Interim survival analysis showed that DTCs were not significantly correlated with EFS (p=0.6) or DRFS (p=0.41). Conclusions: Detection of DTCs at surgery after NACT is significantly more common in young patients, those with larger tumors, and those with residual disease at surgery. While these associations suggest higher risk for later recurrence, larger studies and longer follow up are necessary to determine if DTCs add prognostic value over pathologic evaluation alone for pts receiving NACT. Citation Format: Mark Jesus M Magbanua, Laura van 't Veer, Amy Clark, A. Jo Chien, Judy Boughey, Heather Han, Anne Wallace, Heather Beckwith, Minetta Liu, Christina Yau, E. Paul Wileyto, Lamorna Brown Swigart, Jane Perlmutter, Lauren Bayne, Shannon Deluca, Stephanie Yee, Erica Carpenter, Laura Esserman, John Park, Lewis Chodosh, Angela DeMichele. Outcomes associated with disseminated tumor cells at surgery after neoadjuvant chemotherapy in high-risk early stage breast cancer: The I-SPY SURMOUNT study [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 PS2-07.

Introduction: Given excellent survival outcomes in breast cancer and new methods to predict treatment response, oncologists are interested in de-escalating the amount of chemotherapy delivered to patients. This is particularly important in the setting of COVID-19, where patient perspectives of de-escalation may be altered by perception of COVID-19 risk.Methods: This concurrent mixed methods study included (1) semi-structured interview data from patients with breast cancer treated at the University of Alabama at Birmingham and patient advocates from nationally representative advocacy organizations (10/2019-5/2020) and (2) cross-sectional survey data from a nationwide sample of women with breast cancer (11/19-12/2019). Questions evaluated interest in de-escalation study participation, perceived barriers/facilitators to participation, and language describing de-escalation. Participant perspectives surrounding COVID-19 impact on de-escalation were elicited in interviews post 3/2020.Results: Quantitative and qualitative findings were synergistic. Interviews were conducted with 40 female participants (24 patients, 16 patient advocates). Participant ages ranged from 33-79 years old; 30% were minorities; 35% didn’t have a college degree. Common barriers to acceptance of de-escalation included fear of recurrence, worry about decision regret, lack of clinical trial interest, and dislike for the focus on less treatment. Fear of recurrence was the most commonly expressed barrier, with one participant stating, “I’m just afraid it wouldn’t get it all”. Common facilitators included trust in the physician, toxicity avoidance, monitoring with the option of increasing treatment intensity, perception of good prognosis, and impact on daily life. Participants interviewed during the COVID-19 pandemic (n=16) expressed substantial virus-related fear, including fear of exposure, fear of infecting their personal contacts or health care team, fear of cancer-related complications, and fear about their immunocompromised state. These fears contributed to participants perspective on de-escalation, as highlighted by participants stating, “I wouldn't worry about getting the chemo as much as I would worry about getting the virus” and “Less is more for me right now”.Of 91 survey respondents (69% response rate), median age was 58 years (interquartile range [IQR] 48-69), 86% had early stage breast cancer. Many (43%) patients were not interested in participation in a study testing lower doses of chemotherapy than standard of care. Patients not interested in participating were more often unmarried (55% vs. 32%, V=.23), disabled (56% vs. 40%, V=.17), or diagnosed with early stage cancer (45% vs. 22%, V=.14). Barriers to participation included fear of cancer recurrence (85%) and regret about the decision to receive less chemotherapy if the cancer were to recur (79%). Few patients (19%) considered clinical trials themselves as a barrier. Patients were interested in participation due to lessened physical side effects of treatment (82%), lessened long-term problems related to treatment (76%), and lessened impact on daily life (72%). The most popular terminology describing chemotherapy de-escalation was “lowest effective chemotherapy dose” (53%); no patients preferred the term “de-escalation.” Conclusion: Fear of recurrence is a common barrier to de-escalation clinical trial participation in patients with breast cancer. Fears may be altered for patients considering treatment during the COVID-19 pandemic. Trust in the physician and use of patient-generated language, such as “customized” instead of “de-escalation”, are potential areas for future interventions engaging patients in trials. Citation Format: Gabrielle Rocque, Courtney P. Williams, Courtney J. Andrews, Kathleen Gallagher, Timothy C. Childers, Kimberly D. Wiseman, Alan Balch, Stacey A. Ingram, Thelma Brown, Tara Kaufman, Nadine Tung, Mary Lou Smith, Antonio C. Wolff, Angela DeMichele, Lynn Wagner. Patient perspectives on chemotherapy de-escalation: “Don’t de-escalate! I don’t want to die!” [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-10.

Summary Background Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. Methods PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II–III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1–21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). Findings Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9–29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2–90·6) for palbociclib plus endocrine therapy and 88·5% (85·8–90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76–1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3–4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. Interpretation At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. Funding Pfizer.

Author(s): Magbanua, MJM; Swigart, LB; Wu, H-T; Hirst, GL; Yau, C; Wolf, DM; Tin, A; Salari, R; Shchegrova, S; Pawar, H; Delson, AL; DeMichele, A; Liu, MC; Chien, AJ; Tripathy, D; Asare, S; Lin, C-HJ; Billings, P; Aleshin, A; Sethi, H; Louie, M; Zimmermann, B; Esserman, LJ; van 't Veer, LJ | Abstract: BackgroundPathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence.Patients and methodsCell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years.ResultsAt T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, Pn= 0.012). After NAC, all patients who achieved pCR were ctDNA negative (nn= 17, 100%). For those who did not achieve pCR (nn= 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence [hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6]; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5).ConclusionsLack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.

Background Palbociclib is highly active in oestrogen-receptor positive (ER+) metastatic breast cancer, but neutropenia is dose limiting. The goal of this study was to determine whether early neutropenia is associated with disease response to single-agent palbociclib. Methods Blood count and disease-response data were analysed from two Phase 2 clinical trials at different institutions using single-agent palbociclib: advanced solid tumours positive for retinoblastoma protein and advanced liposarcoma. The primary endpoint was PFS. The primary exposure variable was the nadir absolute neutrophil count (ANC) during the first two cycles of treatment. Results One hundred and ninety-six patients (61 breast, 135 non-breast) were evaluated between the two trials. Development of any grade neutropenia was significantly associated with longer median PFS in both the breast cancer (HR 0.29, 95% CI 0.11–0.74, p = 0.010) and non-breast cancer (HR 0.57, 95% CI 0.38–0.85, p = 0.006) cohorts. Grade 3–4 neutropenia was significantly associated with prolonged PFS in the non-breast cohort (HR 0.57, 95% CI 0.38–0.85, p = 0.006) but not in the breast cohort (HR 0.87, 95% CI 0.51–1.47, p = 0.596). Multivariate analysis yielded similar results. Conclusions Treatment-related neutropenia in the first two cycles was significantly and independently associated with prolonged PFS, suggesting that neutropenia may be a useful pharmacodynamic marker to guide individualised palbociclib dosing. Clinical trials registration information Basket Trial: NCT01037790; Sarcoma Trial: NCT01209598.

Background: A variety of investigational HER2-inhibitor agents/combinations have been tested in I-SPY 2, including neratinib (N), TDM1 combined with pertuzumab (P) (TDM1/P), and trastuzumab (H) combined with pertuzumab (H/P; prior to this combination becoming standard of care), all with trastuzumab as control (Ctr). All three experimental arms graduated, showing improved efficacy over control in one or more receptor subsets (HR+HER2+, HR-HER2+, or/and HER2+). Here we assess 10 biomarkers in the HER2, ER/PR, and proliferation pathways on multiple levels of resolution (expression, protein, phospho-protein) as predictors of response in these four arms, hypothesizing that highly HER2-activated, proliferative tumors may be more sensitive to HER2-inhibition than those that are more luminal and quiescent. Methods: 192 HER2+ patients were considered in this analysis: (31 Ctr, 65 N, 52 TDM1/P, and 44 H/P). 10 biomarkers relating to HER2, ER, or proliferation were evaluated from pre-treatment biopsies: HER2 IHC (n=145), 3 expression signatures (n=192), BluePrint subtype (n=192), and 5 protein/phospho-protein analytes by RPPA (n=175). Each biomarker was tested for association with pCR in the whole population and within each arm using a logistic model. This analysis was adjusted for HR status and treatment arm as covariates, and performed within receptor subtypes. This analysis does not adjust for multiplicities of other biomarkers. Results: In the population as a whole, HER2 and HER2-signaling biomarkers, evaluated at multiple levels of resolution: IHC, total-/phospho-protein by RPPA, and mRNA (HER2 amplicon module) - are highly correlated (rho=0.8 [0.65-0.92]). Higher HER2 levels and activity are associated with response: HER2 IHC 3+ status (LR p=0.00032), total quantitative ERBB2 protein by RPPA (LR p=5.4E-09), ERBB2 activation levels (LR p=6.58E-06 (pERBB2 (Y1248)) and 9.95E-06 (pEGFR Y1173)), and the ERBB2 amplicon expression signature (LR p=2.38E-08). In contrast, higher average ER/PR expression associates with non-response to HER2-targeted therapy (LR p=4.28E-08). Both HER2 and ER/PR signaling phenotypes are captured by BluePrint subtyping; and consistent with the individual pathway markers, tumors classified Luminal-type had a lower pCR rate relative to those classified as Her2-type (or Basal-type) (LR p=4.84E-11). These associations all retain significance in a model adjusting for HR status and treatment arm, and in the HR+HER2+ subset. In addition, we quantitatively assessed proliferation markers at the total protein (RPPA: Ki67), phospho-protein (pAURKA) and mRNA (proliferation signature Module11_Prolif) levels. All three proliferation biomarkers predict response overall; but this association is strongest within the HR+HER2+ subset (LR p=0.0012 (Module11_prolif), 0.0036 (pAURK), and 0.045 (Ki67)). None of the biomarkers tested were associated with response in the HR-HER2+ subset. Numbers are small within individual arms. Within the HR+HER2+ subtype, higher HER2 and lower ER/PR is observed in responders in all experimental arms; but the proliferation markers Module11_Prolif (LR p=0.0031) and Ki67 total protein (LR p=0.0029) are associated with response to TDM1/P but not H/P or N. Conclusion: High HER2 signaling at the expression, protein, and phospho-protein levels, and low ER signaling, all predict response to HER2-inhibition across treatment arms. Proliferation markers may be useful for prioritizing therapies in the HR+HER2+ subset. Citation Format: Denise M Wolf, Christina Yau, Julia Wulfkuhle, Lamorna Brown-Swigart, Smita M. Asare, Gillian L. Hirst, Laura Sit, Jane Perlmutter, I-SPY 2 TRIAL Consortium, Minetta Liu, John Park, Angela DeMichele, Douglas Yee, Don Berry, Laura Esserman, Emanuel Petricoin, Laura van t' Veer. HER2 signaling, ER, and proliferation biomarkers predict response to multiple HER2-targeted agents/combinations plus standard neoadjuvant therapy in the I-SPY 2 trial [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 P4-10-02.

Background: Palbociclib (PB), the first clinically available oral CDK4/6 inhibitor, in combination with endocrine therapy has become standard of care for HR+/HER2- advanced/metastatic breast cancer (MBC). The phase III PALOMA-2 trial demonstrated significant progression-free survival benefit of PB plus letrozole (LE) vs LE + placebo (27.6 vs 14.5 months; HR=0.56, 0 Table 1. Patient characteristics and overall survival (OS)VariablePB+LELE alone(N=766)(N=622)Median age (IQR), years66.0 (58.0—73.0)70.0 (61.0—79.0)White (%)68.368.0Median number of metastatic sites (n)2.02.0Bone-only disease (%)27.731.2Visceral disease (%)52.949.4De novo MBC (%)41.539.4Median follow-up (95%CI), months 22.0 (20.5—23.7)19.0 (16.7—21.2)Percent of events censored (%)79.970.6Estimated OS rate (%)6 months95.988.912 months91.384.624 months81.270.836 months72.060.6PB+LE= Palbociclib plus letrozole; LE= Letrozole alone; CI = Confidence interval; IQR = interquartile range Citation Format: Angela DeMichele, Massimo Cristofanilli, Adam Brufsky, Xianchen Liu, Jack Mardekian, Lynn McRoy, Rachel M Layman, Hope S Rugo, Richard S Finn. Overall survival for first-line palbociclib plus letrozole vs letrozole alone for HR+/HER2- metastatic breast cancer patients in US real-world clinical practice [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 P1-19-02.

Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. The goal is to identify (graduate) regimens with ≥ 85% Bayesian predictive probability of success (i.e., demonstrating superiority to control) in a future 300-patient phase 3 1:1 randomized neoadjuvant trial with pCR endpoint within signatures defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status. Regimens may leave the trial for futility (< 10% probability of success), maximum sample size accrual (with probability of success ≥ 10% and < 85%), or safety concerns as recommended by the independent DSMB. For HER2+ patients, the I-SPY2 control arm was 12 weekly cycles of paclitaxel+trastuzumab (TH, control) followed by doxorubicin/cyclophosphamide (AC) q2-3 weeks x4 and surgery. Patritumab is a fully human monoclonal antibody that inhibits HER3. In this experimental arm for HER2+ patients, patritumab was given q3w x 4 cycles (18mg/kg loading dose followed by 9mg/kg/dose) concurrent with paclitaxel and trastuzumab q1w x 12 weeks (PTH, treatment), followed by AC q2-3w. Methods: Women with tumors ≥ 2.5cm were eligible for screening. MP low/HR+ tumors were ineligible. MRI scans (baseline, 3 weeks after start of therapy, prior to AC, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients. Analysis was intention to treat. Patients who switched to non-protocol therapy count as non-pCR. Patients on treatment arm therapy at the time of arm closure are non-evaluable. Graduation potential was in 3 of 10 pre-defined signatures: all HER2+, HR-/HER2+, and HR+/HER2+. Results: The PTH regimen was stopped at the recommendation of the Safety Working Group and DSMB based on a safety event (bilateral sensorineural hearing loss, Gr 3) observed in one patient. At the time of arm closure, N=31 patients had received PTH treatment; 4 patients receiving PTH were changed to non-protocol therapy and removed from the analysis. The final estimated pCR report will consider 27 PTH and 31 TH as evaluable patients. Accrual was insufficient to assess graduation, however, there appears to be good signal in the HER2+HR- but not HER2+HR+ signatures. I-SPY 2 TRIAL Est. pCR at time of arm closureSignaturesPTH (Treatment)N= 31TH (Control)N = 31All (HER2+)0.40 (0.22 - 0.59), n=310.23 (0.09 - 0.37), n=31HR-/HER2+0.64 (0.36 - 0.91), n=110.30 (0.12 - 0.47), n=12HR+/HER2+0.28 (0.08 - 0.48), n=200.20 (0.06 - 0.34), n=19 HR+/HER2+0.28 (0.08 - 0.48), n=200.20 (0.06 - 0.34), n=19The patient who developed Gr3 sensorineural hearing loss 6 days after the 2nd patritumab (and 4th paclitaxel/trastuzumab) treatment, did not recover her hearing after patritumab was stopped, and also reported Gr3 vulvovaginal pain, vulvitis, and vaginal inflammation. Other gynecological symptoms in the PTH arm include: 1 pt with Gr1 vaginal hemorrhage, and 1 pt with Gr2 dyspareunia. There was a higher frequency of Gr3 hypokalaemia (12.5% vs. 3.2%). One pt in the PTH arm reported Gr3 small intestinal obstruction which resolved with conservative management. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial; PTH was stopped due to safety concerns, although there was activity in the HER2+ HR- signature. This is the first report of Gr3 hearing loss associated with patritumab/paclitaxel/trastuzumab, and thus attribution is uncertain. Citation Format: Teresa L Helsten, Shelly S Lo, Christina Yau, Kevin Kalinsky, Anthony D Elias, Anne M Wallace, A. Jo Chien, Janice Lu, Julie E Lang, Kathy S Albain, Erica Stringer-Reasor, Amy S Clark, Judy C Boughey, Erin D Ellis, Douglas Yee, Angela DeMichele, Claudine Isaacs, Jane Perlmutter, Hope S Rugo, Richard Schwab, Nola M. Hylton, W. Fraser Symmans, Michelle E Melisko, Laura J van't Veer, Amy Wilson, Ruby Singhrao, Smita M Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of patritumab/paclitaxel/trastuzumab over standard paclitaxel/trastuzumab in early stage, high-risk HER2 positive breast cancer: Results from the neoadjuvant I-SPY 2 trial [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 P3-11-02.

Background: I-SPY2 is a multicenter, response-adaptive randomization phase 2 trial to evaluate novel agents when added to standard neoadjuvant therapy for women with high-risk stage II/III breast cancer - weekly paclitaxel + investigational treatment x 12 wks followed by doxorubicin & cyclophosphamide(AC) q3 wks x 4 vs. weekly paclitaxel/AC (control). The primary endpoint is pathologic complete response (pCR). The goal for all investigational arms is to identify/graduate regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 1:1 randomized neoadjuvant trial with a pCR endpoint within signatures defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP). Findings from the graduated, previously reported Pembro4 arm (Nanda et al, ASCO 2017) supported investigation of de-escalating therapy, and determining if pembrolizumab (an anti-PD-1 antibody) alone q3 wks x 4 after weekly paclitaxel x 12 wks + pembrolizumab q3 wks x 4 was sufficient to sustain response without AC. Methods: Women with tumors ≥2.5cm were eligible for screening. MP low/HR+ were ineligible. MRI scans (at baseline, 3 wks, 12 wks, and prior to surgery) were used in a longitudinal statistical model to predict pCR for individual patients (pts). Pts who receive non-protocol therapy (e.g., carboplatin or AC for the Pembro8-noAC arm) count as non-pCR. Pembro8-noAC was open to HER2- pts for evaluation in 3 of 10 pre-defined signatures: HER2-, HR+/HER2-, and HR-/HER2-. Regimens exit the trial for futility ( Results: Pembro8-noAC was randomized to 73 pts, 3 of whom progressed while receiving pembrolizumab alone on study. Randomization to this arm continued after the first report because the rate of progression during AC over the course of the trial was estimated to be 6.5% based on serial MRI studies. However, notification of the third case prompted the study team to ask the DSMB for the summary response for this arm. Although it did not meet formal stopping rules for either graduation or futility, Pembro8-noAC was not near the target threshold pCR rates of 60% for HR-/HER2- and 30% for HR+/HER2+. As a result of this information, combined with the on-treatment progressions, assignment to Pembro8-noAC was discontinued. Treatment with pembrolizumab alone was no longer allowed due to the potential concern for progression, and investigators were given the option to administer AC with pembrolizumab or proceed with definitive surgery following the 12 weeks of paclitaxel + pembrolizumab. 34 pts had surgery results at the time the study was closed. Of the remaining 39 pts, 34 pts have on-therapy MRI assessments. Estimated pCR rates were based on all pts with information at the time (see table). Immune-related adverse events included grade 3 colitis (n=2), grade 3 pneumonitis (n=1), grade 3 transaminitis (n=1), grade 3 hypothyroidism (n=1), and grade 1-2 adrenal insufficiency (n=5). Conclusion: Although Pembro8-noAC is performing at least as well as standard paclitaxel/AC, the likelihood is very low that the regimen would be successful in a phase 3 trial. Pembrolizumab alone following 12 weeks of paclitaxel + pembrolizumab was not sufficient to sustain a response. This was quickly assessed with a small number of patients. Estimated pCR rateSignature(95% prob interval)Pembro8-noACControlHER2-0.210.2(0.09-0.32)(0.15-0.25)HR-/HER2-0.270.27(0.09-0.45)(0.19-0.35)HR+/HER2-0.150.15(0.01-0.29)(0.09-0.20) Citation Format: Minetta C. Liu, Patricia A Robinson, Christina Yau, Anne M Wallace, A. Jo Chien, Erica Stringer-Reasor, Rita Nanda, Douglas Yee, Kathy S Albain, Judy C Boughey, Heather S Han, Anthony D Elias, Kevin Kalinsky, Amy S Clark, Kathleen Kemmer, Claudine Isaacs, Julie E Lang, Janice Lu, Tara Sanft, Angela DeMichele, Nola M Hylton, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, Richard Schwab, W. Fraser Symmans, Laura J van't Veer, Patricia K Haugen, Amy Wilson, Ruby Singhrao, Smita Asare, Ashish Sanil, Donald A Berry, Laura J Esserman. Evaluation of a novel agent plus standard neoadjuvant therapy in early stage, high-risk HER2 negative breast cancer: Results from the I-SPY 2 TRIAL [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 P3-09-02.

Importance: It is essential to refine the populations most likely to benefit from targeted chemotherapy combinations. Background: MINDACT showed that molecularly low risk patients, as assessed by the Amsterdam 70-gene profile MammaPrint® (Agendia) (MP), did not benefit from chemotherapy. In the I-SPY2 trial, MP low risk Hormone Receptor (HR) positive/HER2 negative patients are not eligible; however, HR negative or HER2 positive patients were considered high risk and included for treatment with chemotherapy plus novel agents. The neoadjuvant setting provides an opportunity to evaluate whether molecularly low risk HER2 positive patients are good candidates for neoadjuvant chemo/anti-HER2 therapy, where pathologic complete response (pCR) and 3-year outcomes are measured. Objective: To evaluate and further characterize the fraction of and outcomes for patients molecular low-risk disease in the I-SPY2 trial. Methods: The I-SPY2 platform trial is an ongoing multicenter phase 2 multi-arm study utilizing adaptive design and evaluating efficacy and tolerability of investigational agents in combination with standard-of-care chemotherapy for patients with high-risk anatomic stage II/III breast cancer. Patients with HR+HER2- MP low-risk tumors are not eligible. All enrolled patients undergo pretreatment biopsy for genomic evaluation of early recurrence risk with MP for risk stratification and with the 80-gene BluePrint® (Agendia) test for intrinsic subtype classification. Primary endpoint of the study is pCR in breast and lymph nodes (ypT0/is, ypN0). Secondary outcomes included event-free survival (EFS) and distant-recurrence free survival (DRFS). Following standard neoadjuvant treatment with or without a concomitant investigational agent, patients are followed for long-term outcomes. EFS and DRFS at 3 and 5 years in the pCR vs non-pCR groups within histologic and molecular subtypes are determined using the Kaplan Meier method. Results: Of the 1038 enrolled patients by November 2016, 24 patients (3.2%) had molecular low-risk disease as determined by MP. Of these, 21 (87.5%) had HR+HER2+, 1 (4.2%) had HR-HER2+, and 2 (8.4%) had HR-HER2-. BluePrint expression subtyping classified 17 as luminal-type, 6 HER2 enriched-type and 1 basal type. One patient withdrew consent for follow-up. Of the 23 remaining, none achieved pCR and only one (HR+/HER2+) had an EFS event (with median follow-up of 4.3 years). Overall, EFS and DRFS data were available for 950 of the 1038 patients (as of February 2019), with median follow-up of 3.8 years. Of the 173 HR+HER2+ in this cohort, 20 (11.6%) had molecular low-risk tumors. The EFS and DRFS for the 173 HER2+HR+ pCR group is 97% and 98% (non-pCR group 89% and 94%), respectively at 3 years. Removing the molecular low-risk HER2+ patients from the denominator reveals the worse outcome for patients with non pCR: EFS 86% and DRFS 92% at 3 years. The difference is more apparent at 5 years, changing from 74% to 66% for EFS and from 81% to 75% for DRFS. Intrinsic subtypes vary and do not predict early risk. Conclusions: I-SPY2 focuses on women with high clinical risk with only 3.2% of enrolled patients having low molecular risk tumors. However, 12% of HER+ breast cancer enrolled patients had molecular low risk tumors of which 95% were also HR+. In this group, early recurrence is very low despite absence of pCR and irrespective of intrinsic subtype. Refining the population using molecular high-risk classification of patients reveals a greater difference between the pCR and non-pCR groups within the HR+HER2+ subtype in the EFS and DRFS analysis. Clinical trial designs could address the opportunity to find more targeted and less toxic treatments for the HER2+ low molecular risk patient population. Citation Format: Paula R Pohlmann, Christina Yau, Angela DeMichele, Claudine Isaacs, Judy C Boughey, Nola Hylton, Michelle E Melisko, Jane Perlmutter, Hope S Rugo, W. Fraser Symmans, I-SPY 2 TRIAL Consortium, Donald A Berry, Laura Esserman. Amsterdam 70-gene profile (MammaPrint) low risk, even in the HER2 positive subset, identifies a population of women with lower early risk for recurrence despite low response rates to chemotherapy and to HER2 targeted therapy [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 P6-10-06.

Background Arthralgia is a common and debilitating toxicity of aromatase inhibitors (AI) that leads to premature drug discontinuation. We sought to evaluate the clinical and genetic risk factors associated with AI-associated arthralgia (AIAA). Methods We performed a cross-sectional study among postmenopausal women with stage 0-III breast cancer who were prescribed a third-generation AI for adjuvant therapy. The primary outcome was patient-reported AIAA occurrence. We extracted and assayed germline DNA for single nucleotide polymorphisms (SNPs) of genes implicated in estrogen and inflammation pathways. Multivariable logistic regression models examined the association between demographic, clinical, and genetic factors and AIAA. Analyses were restricted to White participants. Results Among 1049 White participants, 543 (52%) reported AIAA. In multivariable analyses, women who had a college education [Adjusted Odds Ratio (AOR) 1.49, 95% Confidence Interval (CI) 1.00–2.20], had a more recent transition into menopause (, Highlights • One in two postmenopausal women experience aromatase inhibitor-associated arthralgia. • Shorter time since starting menopause and aromatase inhibitors are clinical risk factors for AIAA. • SNP rs11648233 (HSD17B2) in the estrogen pathway may contribute to AIAA.

I-SPY2 is an adaptively randomized phase 2 clinical trial evaluating novel agents in combination with standard-of-care paclitaxel followed by doxorubicin and cyclophosphamide in the neoadjuvant treatment of breast cancer. Ganitumab is a monoclonal antibody designed to bind and inhibit function of the type I insulin-like growth factor receptor (IGF-1R). Ganitumab was tested in combination with metformin and paclitaxel (PGM) followed by AC compared to standard-of-care alone. While pathologic complete response (pCR) rates were numerically higher in the PGM treatment arm for hormone receptor-negative, HER2-negative breast cancer (32% versus 21%), this small increase did not meet I-SPY’s prespecified threshold for graduation. PGM was associated with increased hyperglycemia and elevated hemoglobin A1c (HbA1c), despite the use of metformin in combination with ganitumab. We evaluated several putative predictive biomarkers of ganitumab response (e.g., IGF-1 ligand score, IGF-1R signature, IGFBP5 expression, baseline HbA1c). None were specific predictors of response to PGM, although several signatures were associated with pCR in both arms. Any further development of anti-IGF-1R therapy will require better control of anti-IGF-1R drug-induced hyperglycemia and the development of more predictive biomarkers.

Sin financiación 32.976 JCR (2020) Q1, 7/242 Oncology 8.590 SJR (2021) Q1, 2/133 Hematology No data IDR 2020 UEM

Background: Patients (pts) treated for early stage breast cancer have a 30% lifetime risk of developing incurable, distant metastatic disease. Current models suggest that this occurs through escape of cells from the primary tumor into the circulation and subsequent sequestration of “disseminated tumor cells” (DTCs), in the bone marrow and other sequestration sites, where they enter dormancy. DTCs identified by immunohistochemistry (IHC) are associated with poor prognosis in longitudinal studies and meta-analyses, increasing odds of recurrence by approximately 2 to 5-fold. However, little is known about the test characteristics of the DTC-IHC assay, clinical DTC detection rates over time, and patient and disease risk factors that can identify pts harboring these cells. Methods: The PENN-SURMOUNT Screening Study (NCT 02732171) is a prospective, longitudinal study examining bone marrow and blood biomarkers of recurrence among pts within 5 years of diagnosis who have completed therapy for primary breast cancer (with the exception of endocrine therapy). Pts with positive lymph nodes, triple negative receptors, ER-positivity with RS ≥ 25 and/or high-risk MammaPrint (MP), or residual disease after neoadjuvant chemotherapy were screened with bone marrow aspirate (BMA) for presence of DTCs. A positive DTC-IHC result is defined by the presence of at least one pancytokeratin-DAB positive cell utilizing the methods of Naume et al. Cytospin slides prepared from the BMA are independently reviewed by two pathologists with adjudication for the presence of DTCs; Pts who screen negative for DTCs are offered repeat screening annually. Pts who screen positive are referred to an interventional clinical trial (CLEVER, NCT 03032406). Results: A total of 194 pts screened eligible for enrollment on PENN-SURMOUNT between 6/2016 and 3/2020. Of these, 158 consented and 151 underwent BMA with successful IHC analysis on 100%. Pts came from 22 U.S. states; ≥ 1/3 traveled over 50 miles to the study center. At baseline BMA, 36/151 (24%) had at least 1 measurable DTC by IHC. Patient characteristics and DTC distribution among subpopulations are shown in Table 1. Of the 78/115 who were initially DTC negative and continued to be eligible for repeat screening, as of 3/2020, 46 (59%) returned for at least one repeat BMA. 13/46 (28%) had at least 1 detectable DTC on 1 of up to 3 subsequent follow up assessments for a total DTC positivity rate of 32.5% (49/151). 48 (98%) DTC+ pts have subsequently enrolled on the CLEVER trial. Conclusions: BMA assessment for DTCs is feasible in pts with high risk, early stage breast cancer. DTCs are detected in up to a third of breast cancer survivors with repeat assessment during the surveilance period. DTC positivity rates are relatively similar across all receptor subtypes, and after both neoadjuvant and adjuvant chemotherapy. Pts harboring DTCs are highly likely to enroll on interventional trials designed to reduce recurrence risk. Table 1. Patient characteristics and distribution of % DTC positivity among subpopulationsDTC+ (N=49)DTC- (N=102)Total (N=151)DTC+ Rate (Overall: 32.5%)DEMOGRAPHICSMedian Age at BMA (yrs)51.9 (43.9-60.6*)50.5 (42.9-58.1)50.5 (43.8-58.8)N/ARaceCaucasian44 (89.8%)91 (89.2%)135 (89.4%)32.6%African American5 (10.2%)9 (8.8%)14 (9.3%)35.7%Other0 (0%)2 (2.0%)2 (1.3%)0%Menopausal StatusPre-15 (30.6%)34 (33.3%)49 (32.5%)30.6%Post-34 (69.4%)68 (66.7%)102 (67.5%)33.3%BMI at BMA (kg/m2)24.2 (21.9-28.9*)26.9 (23.4-31.4)26.1 (22.8-30.4)N/ARECEPTOR STATUSER/PR+ HER2neg (by ASCO/CAP)24 (49.0%)51 (50.0%)75 (49.7%)32.0%HER2+ (any ER/PR)9 (18.4%)12 (11.8%)21 (13.9%)42.9%ER/PRneg HER2neg23 (46.9%)48 (47.1%)71 (47.0%)32.4%RISK CRITERIALymph Node Positive24 (49.0%)65 (63.7%)89 (58.9%)27.0%Triple Negative (ER/PR Citation Format: Lauren Bayne, Isoris Nivar, Brooke Goodspeed, Shannon Deluca, E. Paul Wileyto, Natalie Shih, Anupma Nayak, Michael D Feldman, Joshua Edwards, Kevin Fox, Jennifer M. Matro, Susan Domchek, Hayley Knollman, Rachel Jankowitz, Angela Bradbury, Payal D. Shah, Jewell Graves, George Woodfield, Elizabeth Chislock, Jianping Wang, George Belka, Lewis A. Chodosh, Amy S. Clark, Angela DeMichele. Identifying breast cancer survivors with dormant disseminated tumor cells: The PENN-SURMOUNT screening study [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 PD9-11.

This study reports the MTD, recommended phase 2 dose (RP2D), and preliminary efficacy of alpelisib or buparlisib used in combination with tamoxifen plus goserelin in premenopausal patients with hormone receptor-positive (HRThis study enrolled premenopausal women with HRThe criteria for MTD were not met for both alpelisib and buparlisib. The RP2D of alpelisib and buparlisib in combination with tamoxifen and goserelin were 350 mg and 100 mg, respectively. Both combinations met protocol-specified criteria for tolerability. The most common grade 3/4 treatment-emergent adverse events (TEAE) were hypokalemia (12.5%), hyperglycemia (6.3%), and rash (6.3%) for alpelisib and alanine aminotransferase increase (30.8%), aspartate aminotransferase increase (23.1%), and anxiety (15.4%) for buparlisib. TEAEs led to treatment discontinuation in 18.8% and 53.8% of alpelisib- and buparlisib-treated patients, respectively. Progression-free survival was 25.2 months in the alpelisib group and 20.6 months in the buparlisib group.The RP2Ds of alpelisib and buparlisib were 350 mg and 100 mg, respectively. No unexpected safety findings were reported. Although an early-phase study, data suggest that alpelisib plus endocrine therapy may be a potentially efficacious treatment that warrants further evaluation for premenopausal patients with HR

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD+P). AD+P affects ∼50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD-P). Although the estimated heritability of AD+P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5,445 AD+P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p=1.26×10−8) and one spanning the 3’-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p=3.24×10−8), had genome-wide significant associations with AD+P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD+P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD+P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.

Importance Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials. Objective To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival. Design, Setting, and Participants The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 200 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) andERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate. Interventions Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery. Main Outcomes and Measures Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS). Results A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) andERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis. Conclusions and Relevance In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy. Trial Registration ClinicalTrials.gov Identifier:NCT01042379

Purpose: Standard-of-care treatment for metastatic hormone receptor–positive (HR+), HER2-negative (HER2−) breast cancer includes endocrine therapy (ET) combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Optimal treatment after progression on CDK4/6i is unknown. The TRINITI-1 trial investigated ribociclib, a CDK4/6i that has recently demonstrated significant overall survival benefit in two phase III trials, in combination with everolimus and exemestane in patients with HR+, HER2− advanced breast cancer (ABC) after progression on a CDK4/6i. Patients and Methods: This multicenter, open-label, single-arm, phase I/II study included patients with locally advanced/metastatic HR+/HER2− breast cancer. The primary endpoint was clinical benefit rate (CBR) at week 24 among patients with ET-refractory disease with progression on a CDK4/6i. Other endpoints included safety and biomarker analysis. Results: Of 104 patients enrolled (phases I and II), 96 had prior CDK4/6i. Recommended phase II doses (all once daily days 1–28 of 28-day cycle) were ribociclib 300 mg, everolimus 2.5 mg, and exemestane 25 mg (group 1) and ribociclib 200 mg, everolimus 5 mg, and exemestane 25 mg (group 2). CBR among 95 efficacy-evaluable patients (phases I and II) at week 24 was 41.1% (95% confidence interval, 31.1–51.6), which met the primary endpoint (predetermined threshold: 10%). Common adverse events included neutropenia (69.2%) and stomatitis (40.4%). No new safety signals were observed; no grade 3/4 QTc prolongation was reported. Conclusions: Preliminary TRINITI-1 safety and efficacy results support further investigation of CDK4/6 blockade and targeting of the PI3K/AKT/mTOR signaling pathway in patients with ET-refractory HR+/HER2− ABC after progression on a CDK4/6i.

Background This analysis investigated whether baseline characteristics affect the survival benefit derived from palbociclib‐fulvestrant and the optimal timing of cyclin‐dependent kinase 4/6 inhibitor therapy for advanced breast cancer (ABC) in patients from PALOMA‐3. Patients and Methods In total, 521 patients were randomized 2:1 to receive palbociclib (125 mg/day, 3/1 schedule)–fulvestrant (500 mg, intramuscular injection, on days 1 and 15 of cycle 1, and then day 1 of each subsequent cycle) or matching placebo‐fulvestrant. Median overall survival (OS) and progression‐free survival were estimated using the Kaplan‐Meier method. Results Multivariable analysis identified endocrine sensitivity, nonvisceral disease, no prior chemotherapy for ABC, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 as significant prognostic factors for OS. Patients without chemotherapy for ABC had fewer prior lines of treatment in any setting and in the ABC setting versus patients with prior chemotherapy for ABC (two or fewer prior systemic therapies: 69% vs. 42%; no more than one prior line for ABC: 82% vs. 33%, respectively). Median OS was prolonged with palbociclib‐fulvestrant in patients without prior chemotherapy for ABC (39.7 vs. 29.5 months; hazard ratio, 0.75; 95% confidence interval [CI]: 0.56–1.01) and was similar in patients with prior chemotherapy for ABC (25.6 vs. 26.2 months; hazard ratio, 0.91 [95% CI: 0.63–1.32]) versus placebo‐fulvestrant. Conclusion Prognostic factors for OS included endocrine sensitivity, nonvisceral disease, ECOG PS of 0, and no prior chemotherapy for ABC. Exploratory analyses suggest improved OS with palbociclib‐fulvestrant versus placebo‐fulvestrant in patients with no prior chemotherapy for ABC, prior endocrine sensitivity, and fewer prior regimens of systemic therapy. (Clinical trial identification number: NCT01942135). Implications for Practice Prognostic factors for overall survival in HR+/HER2− advanced breast cancer (ABC) include the absence of prior chemotherapy in the advanced setting, endocrine sensitivity, nonvisceral disease, and an ECOG performance status of 0. Improved overall survival benefit was observed with palbociclib‐fulvestrant versus placebo‐fulvestrant in patients (regardless of menopausal status or visceral involvement) with no prior chemotherapy for ABC, with prior endocrine sensitivity, and fewer prior regimens of systemic therapy. Progression‐free survival was prolonged with palbociclib across subgroups (regardless of chemotherapy exposure in ABC). These exploratory findings suggest that patients may receive greater clinical benefit from palbociclib‐fulvestrant if they receive the combination before chemotherapy in the advanced setting., This article focuses on whether baseline characteristics affect the survival benefit derived from palbociclib‐fulvestrant and the optimal timing of cyclin‐dependent kinase 4/6 inhibitor therapy for advanced breast cancer in patients from the PALOMA‐3 clinical trial.

PURPOSETargeted therapeutics strongly depends on validated biomarkers in order to select patients most likely to benefit from the treatment. HER2 serves as a predictive biomarker for HER2-targeted tyrosine kinase inhibitors and monoclonal antibodies. HER2 may, however, also be utilized as a transport gate for delivery of cytotoxic agents into the cell, such as for HER2-targeted antibody drug conjugates (ADCs; e.g. trastuzumab emtansine (T-DM1)). The predictive biomarkers for such ADCs may be more complex, also reflecting the intracellular transport.METHODSFive HER2-positive breast and ovarian cancer cell lines were evaluated with respect to T-DM1 sensitivity and correlated to the expression levels of proteins involved in endocytic trafficking including RAB4A, RAB5A and RAB11A, with possible impact on ADC pharmacology. The results were confirmed in a clinical cohort consisting of patients from the adaptive breast cancer clinical trial I-SPY2 where pathological complete response (pCR) was correlated to the RNA expression level of RAB4A, RAB5A and RAB11A. A subset of the clinical KAMILLA trial including 19 patients was used as a verification cohort where semi-quantitative IHC of RAB5A was correlated to progression free survival (PFS).RESULTSThe early endosome marker RAB5A, was found to correlate positively to T-DM1 sensitivity in the cell line panel. Correlation between RAB5A expression and T-DM1 sensitivity (pCR) was confirmed in patients treated with trastuzumab emtansine/pertuzumab in the I-SPY2 trial, but not in the trastuzumab/paclitaxel control arm. The clinical correlation was verified in the patients from the KAMILLA trial where semi-quantitative RAB5A IHC staining correlated significantly positive to PFS.CONCLUSIONThe present results indicate that RAB5A is a predictive biomarker for T-DM1 and outline, for the first time, proteins involved in endocytic trafficking as predictive biomarkers for ADCs.

ObjectiveCancer drug stockouts occur at high frequencies globally, however, their effects on treatment are understudied in sub-Saharan Africa (SSA). We aimed to determine whether causes of suboptimal cancer treatment prescriptions differed between periods of stockout and full treatment supply.DesignA retrospective cohort study of systemic therapy prescriptions for patients diagnosed with the twelve most common solid tumour cancers treated in 2016.SettingPrincess Marina Hospital in Gaborone, Botswana.ParticipantsPatients in the retrospective cohort who experienced any suboptimal treatment events, defined as ≥7 days delay or switch from guideline-concordant initiated therapy.Primary and secondary outcome measuresFrequency of delays and patterns of prescription changes for specific regimens and cancer types.Results167/378 patients contributed to 320 suboptimal events (115 therapy switches, 167 delays and 38 events with both), over 1452 total chemotherapy cycles received. Events during stockout were 43% delays, 43% switches and 14% both during stockout periods and 67.2% delays, 24.4% switches and 8.4% both during non-stockout periods (pConclusionsThe aetiology of suboptimal events differed during stockout and non-stockout periods. Prescription patterns that involved de-escalation of initiated therapy and substitution of paclitaxel with docetaxel occurred frequently during periods of drug stockout. Further research needs to be conducted to understand the impact of stockout on survival and barriers to maintaining essential cancer medicines supplies in SSA, and the factors driving frequent delays in therapy delivery.

The σ2 receptor is a potential in vivo target for measuring proliferative status in cancer. The feasibility of using N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-18F-fluoroethoxy)-5-methylbenzamide (18F-ISO-1) to image solid tumors in lymphoma, breast cancer, and head and neck cancer has been previously established. Here, we report the results of the first dedicated clinical trial of 18F-ISO-1 in women with primary breast cancer. Our study objective was to determine whether 18F-ISO-1 PET could provide an in vivo measure of tumor proliferative status, and we hypothesized that uptake would correlate with a tissue-based assay of proliferation, namely Ki-67 expression. Methods: Twenty-eight women with 29 primary invasive breast cancers were prospectively enrolled in a clinical trial (NCT 02284919) between March 2015 and January 2017. Each received an injection of 278–527 MBq of 18F-ISO-1 and then underwent PET/CT imaging of the breasts 50–55 min later. In vivo uptake of 18F-ISO-1 was quantitated by SUVmax and distribution volume ratios and was compared with ex vivo immunohistochemistry for Ki-67. Wilcoxon rank-sum tests assessed uptake differences across Ki-67 thresholds, and Spearman correlation tested associations between uptake and Ki-67. Results: Tumor SUVmax (median, 2.0 g/mL; range, 1.3–3.3 g/mL), partial-volume–corrected SUVmax, and SUV ratios were tested against Ki-67. Tumors stratified into the high–Ki-67 (≥20%) group had SUVmax greater than the low–Ki-67 ( 0.05). Conclusion:18F-ISO-1 uptake in breast cancer modestly correlates with an in vitro assay of proliferation.

BACKGROUND: Preterm delivery and current nutritional strategies result in deficiencies of critical long chain fatty acids and lipophilic nutrients increasing the risk of preterm morbidities. We sought to determine the efficacy of preventing postnatal deficits in fatty acids and lipophilic nutrients using an enteral concentrated lipid supplement in preterm piglets. METHODS: Preterm piglets were fed a baseline diet devoid of arachidonic acid (AA) and docosahexaenoic acid (DHA) and randomized to enteral supplementation as follows: (1) Intralipid®; (2) complex lipid supplement 1 (CLS1) with an AA:DHA ratio of 0.25; or (3) complex lipid supplement 2 (CLS2) with an AA:DHA ratio of 1.2. On day 8, plasma and tissue levels of fatty acids and lipophilic nutrients were measured and ileum histology performed. RESULTS: Plasma DHA levels decreased in the Intralipid® group by day 2. In contrast, DHA increased by day 2 compared to birth levels in both CLS1 and CLS2 groups. The Intralipid® and CLS1 groups demonstrated a continued decline in AA levels during the 8-day protocol, while AA levels in the CLS2 group on day 8 were comparable to birth levels. Preserving AA levels in the CLS2 group was associated with greater ileal villus height and muscular layer thickness. Lipophilic nutrients were effectively absorbed in plasma and tissues. CONCLUSIONS: Enteral administration of CLS1 and CLS2 demonstrated similar increases in DHA levels compared to birth levels. Only CLS2 maintained AA birth levels. Providing a concentrated complex lipid emulsion with an AA:DHA ratio greater than 1 is important in preventing postnatal AA deficits.

PURPOSE A large-panel gene expression analysis was conducted to identify biomarkers associated with the effectiveness of adding palbociclib to fulvestrant. METHODS The PALOMA-3 (ClinicalTrials.gov identifier: NCT01942135 ) trial randomly assigned 521 endocrine-pretreated patients with metastatic breast cancer to receive palbociclib plus fulvestrant or placebo plus fulvestrant. Primary analysis was first conducted on 10 genes on the basis of pathway biology and evidence from previous studies followed by a systematic panel-wide search among 2,534 cancer-related genes. The association of gene expression with the effect of palbociclib on progression-free survival (PFS) was evaluated using Cox proportional hazards regression analysis, with gene expression as a continuous variable or dichotomized by median. An independent breast cancer cohort from the Preoperative Palbociclib (POP) Clinical Trial (ClinicalTrials.gov identifier: NCT02008734 ) was used for validation, in 61 patients with primary breast cancer treated with 2 weeks of palbociclib. RESULTS In the PALOMA-3 trial, 302 patients had tumor tissue analyzed (palbociclib arm, 194 patients; placebo arm, 108 patients). Palbociclib efficacy was lower in patients with high versus low cyclin E1 ( CCNE1) mRNA expression (median PFS: palbociclib arm, 7.6 v 14.1 months; placebo arm, 4.0 v 4.8 months, respectively; interaction P unadjusted = .00238; false discovery rate–adjusted P = .0238). CCNE1 mRNA was more predictive in metastatic than in archival primary biopsy tissue samples. No significant interaction was found between treatment and expression levels of CDK4, CDK6, cyclin D1, and RB1. Palbociclib was efficacious in both luminal A and luminal B tumors. High CCNE1 mRNA expression was associated with poor antiproliferative activity of palbociclib in the POP trial ( P = .005). CONCLUSION Addition of palbociclib to fulvestrant demonstrated efficacy in all biomarker groups, although high CCNE1 mRNA expression was associated with relative resistance to palbociclib.

Background: Patients achieving a pathologic complete response (pCR) following neoadjuvant therapy have significantly improved event-free survival relative to those who do not; and pCR is an FDA-accepted endpoint to support accelerated approval of novel agents/combinations in the neoadjuvant treatment of high risk early stage breast cancer. Previous studies have shown that recurrence risk increased with increasing burden of residual disease (as assessed by the RCB index). As well, these studies suggest that patients with minimum residual disease (RCB-I class) also have favorable outcomes (comparable to those achieving a pCR) within high risk tumor subtypes. In this study, we assess whether integrating RCB with MRI functional tumor volume (FTV), which in itself is prognostic, can improve prediction of distant recurrence free survival (DRFS); and identify a subset of patients with minimal residual disease with comparable DRFS as those who achieved a pCR. Imaging tools can then be used to identify the subset that will do well early and guide the timing of surgical therapy. Method: We performed a pooled analysis of 596 patients from the I-SPY2 TRIAL with RCB, pre-surgical MRI FTV data and known follow-up (median 2.5 years). We first assessed whether FTV predicts residual disease (pCR or pCR/RCB-I) using ROC analysis. We applied a power transformation to normalize the pre-surgical FTV distribution; and assessed its association with DRFS using a bi-variate Cox proportional hazard model adjusting for HR/HER2 subtype. We also fitted a bivariate Cox model of RCB index adjusting for subtype; and assessed whether adding pre-surgical FTV to this model further improves association with DRFS using a likelihood ratio (LR) test. For the Cox modeling, penalized splines approximation of the transformed FTV and RCB index with 2 degrees of freedom was used to allow for non-linear effects of FTV and RCB on DRFS. Result: Pre-surgical MRI FTV is significantly associated with DRFS (Wald p Conclusion: Pre-surgical MRI FTV is effective at predicting minimal residual disease (RCB0/I) in the I-SPY 2 TRIAL. Despite the association between FTV and RCB, FTV appears to provide independent added prognostic value (to RCB and subtype), suggesting that integrating MRI volume measures and RCB into a composite predictor may improve DRFS prediction. Citation Format: Hylton NM, Symmans WF, Yau C, Li W, Hatzis C, Isaacs C, Albain KS, Chen Y-Y, Krings G, Wei S, Harada S, Datnow B, Fadare O, Klein M, Pambuccian S, Chen B, Adamson K, Sams S, Mhawech-Fauceglia P, Magliocco A, Feldman M, Rendi M, Sattar H, Zeck J, Ocal I, Tawfik O, Grasso LeBeau L, Sahoo S, Vinh T, Yang S, Adams A, Chien AJ, Ferero-Torres A, Stringer-Reasor E, Wallace A, Boughey JC, Ellis ED, Elias AD, Lang JE, Lu J, Han HS, Clark AS, Korde L, Nanda R, Northfelt DW, Khan QJ, Viscusi RK, Euhus DM, Edmiston KK, Chui SY, Kemmer K, Wood WC, Park JW, Liu MC, Olopade O, Tripathy D, Moulder SL, Rugo HS, Schwab R, Lo S, Helsten T, Beckwith H, Haugen PK, van't Veer LJ, Perlmutter J, Melisko ME, Wilson A, Peterson G, Asare AL, Buxton MB, Paoloni M, Clennell JL, Hirst GL, Singhrao R, Steeg K, Matthews JB, Sanil A, Berry SM, Abe H, Wolverton D, Crane EP, Ward KA, Nelson M, Niell BL, Oh K, Brandt KR, Bang DH, Ojeda-Fournier H, Eghtedari M, Sheth PA, Bernreuter WK, Umphrey H, Rosen MA, Dogan B, Yang W, Joe B, I-SPY 2 TRIAL Consortium, Yee D, Pusztai L, DeMichele A, Asare SM, Berry DA, Esserman LJ. Refining neoadjuvant predictors of three year distant metastasis free survival: Integrating volume change as measured by MRI with residual cancer burden [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-07-03.

18F-FluorThanatrace ([18F]-FTT) is a novel radiotracer shown to quantify Poly [ADP-ribose] polymerase 1 (PARP-1) expression in vitro and in vivo through a receptor-ligand interaction. A recent study at the University of Pennsylvania in women with ovarian cancer demonstrated in vivo visualization of PARP-1 expression in tumors using this radiotracer that closely correlated with an in vitro assay of PARP-1 in tumor tissue (Makvandi, M. J. Clin. Invest. 128:2116, 2018). A radioligand with PARP-1 specificity, [125I]-KX1, was also developed as a companion tool for ex vivo evaluation of PARP-1 expression and PARP inhibitor (PARPi) drug occupancy by radioligand binding assay (Makvandi, M. Cancer Res. 76:4516, 2016). As the first step in validating this biomarker in breast cancer, we performed a prospective clinical trial comparing in vivo [18F]-FTTuptake and ex vivo PARP-1 expression in women with primary breast cancer. Methods: 24 patients with Stage I-IV primary breast cancer were imaged with [18F]-FTT prior to any therapy including surgery. We correlated in vivo uptake with ex vivo immunohistochemistry (IHC) for PARP-1 and [125I]-KX1 autoradiography in untreated surgical specimens. Tumors were analyzed for alterations in DNA repair genes, copy number-based as well as mutational signatures indicative of homologous recombination deficiency (HRD) and mutational burden, using our established protocol (Maxwell, KN, Nature Commun. 8:319, 2017). Results: [18F]-FTT uptake was visualized above background in all primary breast tumors and known metastases. Two areas of unexpected uptake revealed an unknown contralateral breast cancer and an ovarian carcinoid, respectively. We expected that uptake might be highest in triple negative breast cancer (TNBC), where PARPi have been most heavily studied. However, a range of tracer uptake was observed in tumors independent of breast cancer subtype (hormone receptor positive/HER2 negative, TNBC, HER2+) and BRCA status. Uptake ratios (SUVmax tumor/SUV max opposite breast) ranged from 1.2-10.5 with a median 4.0. Ex vivo[125I]-KX1 autoradiography was performed on a subset of untreated primary tumors (n=5) and compared with IHC staining for PARP-1 on sequential sections. This revealed a close spatial correspondence between elevated PARP-1 expression by IHC and regions of elevated [125I]-KX1 binding radiographically. There was also a strong positive correlation between in vivo [18F]-FTT uptake and ex vivo quantitative [125I]-KX1 autoradiography (r=0.78). Genomic analysis of HRD in all tumors is pending and will be reported. Conclusion: Initial analyses support the ability of [18F]-FTT to visualize and measure PARP-1 expression in breast cancer. This is the first step toward developing an imaging companion diagnostic to help guide PARP inhibitor treatment in breast cancer. Ongoing studies are expanding upon these results, testing the extent to which expression of PARP-1 by [18F]-FTT can predict response to PARP inhibitors and measure target engagement during therapy. Citation Format: McDonald ES, Carlin S, Maxwell KN, Nayak A, Doot RK, Pantel AR, Farwell MD, Pryma DA, Clark AS, Shah P, DeMichele AM, Ziober A, Schubert EK, Palmer K, Lee HS, Matro J, de la Cruz L, Tchou J, Anderson DN, Feldman MD, Sheffer RE, Knollman H, Schnall MD, Makvandi M, Domchek S, Hubbard RA, Mach RH, Mankoff DA. PET imaging of PARP-1 expression in 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 PD4-07.

Background: CB-839 is an investigational first-in-class, potent, oral inhibitor of glutaminase (GLS), a mitochondrial enzyme that controls a critical step in tumor cell utilization of glutamine. TNBC is associated with high GLS expression and depends on GLS conversion of glutamine to glutamate for tumor cell survival and proliferation. Higher glutamine utilization has been observed in TNBC tumors from patients (pts) of African ancestry (AA), compared to those of European ancestry. CB-839 has demonstrated preclinical antitumor activity in both in vitro and in vivo models of TNBC and synergizes with paclitaxel (Pac) by reversing GLS-dependent mechanisms that lead to taxane resistance. In a phase 1 study, the Pac+CB-839 combination was well tolerated and demonstrated clinical activity in a cohort of heavily pretreated pts with TNBC (22% overall response rate [ORR]; 59% disease control rate [DCR] at ≥600 mg BID dose [n=37]), including those with taxane-refractory disease or of AA (Kalinsky et al. SABCS 2017). Here we present initial findings from an ongoing phase 2 study of Pac+CB-839 in pts with advanced TNBC (NCT03057600). Methods: Key eligibility criteria included advanced/metastatic TNBC with ECOG PS 0-1 and either 0 (1L) or ≥2 prior lines (3L+) of therapy for metastatic disease were eligible (N=112 pts max). Prior taxane therapy for the 3L+ cohorts was required. For the 1L cohorts, prior neo/adjuvant therapy (including taxanes) was allowed if time to recurrence was >12 months (mo). Pts were allocated to cohorts by line of therapy (1L or 3L+) and ancestry (AA or non-AA) in order to ensure sufficient enrollment to each of these subgroups. Pts received oral CB-839 (800 mg BID) in combination with intravenous Pac (80 mg/m2 on days 1, 8, 15 of each 28-day cycle). The primary endpoint was ORR. Other endpoints included overall survival, duration of response, clinical benefit rate, biomarker analyses, and safety. Results: As of the June 15, 2018 data cutoff, 44 pts have been enrolled (median age, 59 yrs; 41% AA; n=22 each in 1L or 3L+). In the 1L cohort, 64% and 36% had ECOG PS of 0 and 1, respectively. In the 3L+ cohort, 36% and 55% had ECOG PS of 0 and 1, respectively (9% unknown). Of 14 evaluable 1L pts, ORR was 43% and DCR (partial response [PR] + stable disease ≥8 weeks [SD]) was 79% (n=6 PR; n=5 SD). Of 16 evaluable 3L+ pts, ORR was 6% and DCR was 25% (n=1 PR; n=3 SD). Most common CB-839- or Pac-related treatment-emergent adverse events (TEAE) occurring in >15% included fatigue (34%), diarrhea (23%), nausea (18%), neuropathy (18%), alopecia (16%), anemia (16%), AST increased (16%), and hypophosphatemia (16%). Treatment-related grade ≥3 TEAEs occurred in 8 (18%) pts; the most common (occurring in >1 pt) were hypophosphatemia and neutrophil count decreased (n=2 each). No events of febrile neutropenia were reported. Conclusions: Early analyses of this phase 2 study show that Pac+CB-839 has clinical activity and is well tolerated in pts with advanced/metastatic TNBC. Updated data including exploratory biomarker analysis will be presented. Citation Format: Vidal G, Kalinsky K, Stringer-Reasor E, Lynce F, Cole J, Valdes-Albini F, Soliman H, Nikolinakos P, Silber A, DeMichele A, Ali H, Graham D, Giguere J, Brufsky A, Liang Y, Holland S, Fiji G, O'Keeffe B, Gogineni K. Efficacy and safety of CB-839, a small molecule inhibitor of glutaminase, in combination with paclitaxel in patients with advanced triple negative breast cancer (TNBC): Initial findings from a multicenter, open-label phase 2 study [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 P6-20-07.

Background: In women with breast cancer receiving neoadjuvant chemotherapy, residual cancer burden (RCB) predicts distant recurrence and survival. In those with high risk tumors, locoregional recurrence (LRR) remains a concern, and has been associated with type of local therapy received. We evaluated the impact of local therapy on LRR in the ISPY-2 TRIAL. Methods: Data were analyzed in Stata 14.2, using Chi2 test, log rank test, and a Cox proportional hazards model. RCB was considered a categorical variable (0/1 versus 2/3), as described in prior publications. Breast surgery categories were lumpectomy +/- radiotherapy, or mastectomy +/- radiotherapy. Axillary surgery was defined as sentinel lymph node (SLN) surgery (≤6 nodes removed) or axillary dissection (>6 nodes). Results: Follow up data from the I-SPY2 TRIAL were available for 630 patients (median follow up 2.76 yrs, range 0.4-7.2). Type of local therapy was significantly associated with clinical stage at presentation, with stage III patients most frequently undergoing mastectomy + radiation (p In a Cox model adjusting for clinical stage, tumor subtype, surgical therapy, RCB status, nodal radiation, and age, significant predictors for LRR were tumor subtype and RCB status. Hazard ratio (HR) for LRR in those with RCB 0/1 was 0.39 compared to those with RCB 2/3 (95% CI 0.17-0.87, p=0.021). There was no difference in LRR between breast conservation and mastectomy; within the breast conservation group, those who had lumpectomy alone had higher hazard of LRR compared to those having lumpectomy + radiation (HR 3.1, 95% CI 1.1-9.2, p=0.043). Conclusions: Extent of surgical therapy was not associated with local tumor control, regardless of advanced tumor stage at presentation. Rather, tumor biology and response to therapy were the best predictors of LRR. These data highlight the opportunity to minimize the morbidity of extensive surgical therapy for patients with excellent response to systemic therapy. LRR rates by clinical features and treatment status FrequencyLRR RateP valueClinical Stage 0.5I240 (47.5%)5.8% II185 (36.6%)8.7% III80 (15.8%)6.3% Tumor Subtype 0.014ER+PR+Her2-161 (26.4%)3.1% ER+PR-Her2-56 (9.2%)3.6% Her2+176 (28.9%)6.3% Triple negative216 (35.5%)11.1% Local therapy 0.169Lumpectomy85 (13.5%)11.8% Lumpectomy with radiation198 (31.4%)5.6% Mastectomy173 (27.5%)5.2% Mastectomy with radiation174 (27.6%)8.6% Axillary surgery 0.23None5 (0.8%)20% SLN329 (52.2%)5.8% ALND296 (47%)8.5% Axillary radiation 0.535Yes42 (6.7%)9.5% No588 (93.3%)7.0% Axillary management 0.2No surgery or radiation5 (0.8%)20.0% SLN312 (50%)5.3% SLN+Axillary radiation17 (2.7%)8.3% ALND271 (43%)10.3% ALND+Axillary radiation25 (4%)5.4% RCB 0.0020/1293 (50.1%)3.8% 2/3292 (49.9%)10.3% Citation Format: Silverstein J, Suleiman L, Yau C, Price ER, Singhrao R, Yee D, DeMichele A, Isaacs C, Albain KS, Chien AJ, Forero-Torres A, Wallace AM, Pusztai L, Ellis ED, Elias AD, Lang JE, Lu J, Han HS, Clark AS, Korde L, Nanda R, Northfelt DW, Khan QJ, Viscusi RK, Euhus DM, Edmiston KK, Chui SY, Kemmer K, Wood WC, Park JW, Liu MC, Olopade O, Leyland-Jones B, Tripathy D, Moulder SL, Rugo HS, Schwab R, Lo S, Helsten T, Beckwith H, I-SPY 2 TRIAL Consortium, Berry DA, Asare SM, Esserman LJ, Boughey JC, Mukhtar RA. The impact of local therapy on locoregional recurrence in women with high risk breast cancer in the neoadjuvant I-SPY2 TRIAL [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-14-01.

Background: Palbociclib (PAL) in combination with endocrine therapy (ET) is a preferred treatment option for untreated and previously treated patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2 (HER2)–negative ABC. Patients with bone only disease could derive prolong disease control with single agent ET. Further understanding the predictive markers for sensitivity to ET alone and P+ET in both endocrine sensitive and resistant settings could help guide clinical treatment sequencing decision. We performed biomarker (BM) analysis of baseline tumor tissues in both PALOMA-2 (P2) and PALOMA-3 (P3) in bone only (BO) vs non-bone (NBO) only patients. Methods: Postmenopausal women (N=666) with no prior systemic therapy for ER+/HER2-ABC were randomized 2:1 to receive PAL+LET or matching placebo (PBO)+LET in P2. In P3 women (N=521) who progressed on prior endocrine therapy were randomized 2:1 to receive PAL+ FUL vs matching PBO+FUL. All pts including those with BO disease had to consent to provide tumor tissues to participate the current study. EdgeSeq Oncology Biomarker Panel (HTG Molecular Diagnostics; Tucson, AZ) was used for mRNA profiling. Cox regression analysis was used to evaluate the association of BO disease with treatment effect as well as the association of gene expression with treatment effect in BO vs NBO pts. Results: Treatment effect in the BM population from each study was consistent with that observed in the respective ITT population. In ITT population, BO disease was reported in 151 (23%) pts of P2 with mPFS 36.2mo PAL+LET arm (n=103) vs 11.2mo LET arm (n=48), HR=0.40 (0.26-0.62) and in 124 (24%) pts of P3 with mPFS 14.3mo PAL+FUL arm (n=86) vs 9.2mo FUL arm (n=38), HR=0.64(0.38-1.06). BO disease was reported in 107 (24%) pts in P2 and 81 (27%) pts in P3 BM population. In P2, longer mPFS was seen with PAL+ LET vs PBO+LET in BO vs NBO disease (30.6 mo vs 11.2 mo; HR=0.42 (0.25-0.69) in BO pts and 22.1 mo vs 13.8 mo HR=0.67 (0.52-0.88) in NBO pts) although the interaction effect was not statistically significant. Similar results were also observed in P3 with longer mPFS in PAL+FUL vs PBO+FUL in BO vs NBO disease (16.6 mo vs 11.2 mo HR=0.79 (0.40-1.56) in BO pts and 11.1mo vs 3.5 mo HR=0.47 (0.34-0.66) in NBO pts) with insignificant interaction effect. In both studies, BO pts had higher incidence of luminal A disease (BO vs NBO: P2=62% vs 47%; P3=54% vs 40%) and lower rate of luminal B disease (P2=19% vs 33%; P3: 26% vs 33%). In both studies, baseline ESR1, Cyclin E and CDK 4 gene expression level were comparable between BO vs NBO pts. Elevated CDK4 gene expression level was associated with resistance to LET in P2 and lower Cyclin E gene expression predicts the effect of PAL in P3. Conclusion: mPFS was significantly prolonged in BO pts with the addition of PAL to ET. BO disease was more frequently associated with luminal A subtype in ABC setting. CDK4 expression level was similar to NBO disease pts but associated with resistance to single agent LET. Citation Format: Finn RS, Turner NC, Liu Y, Rugo HS, Loibl S, Diéras V, Slamon DJ, André F, Gelmon K, DeMichele A, Loi S, Zhang Z, Giorgetti C, Gauthier E, Huang Bartlett C, Cristofanilli M. Biomarker analysis of CDK 4/6 and endocrine pathways in hormone-receptor positive (HR+) advanced breast cancer (ABC) bone only disease patients: A joint analysis of PALOMA-2 and PALOMA-3 studies [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 P6-18-03.

Background: Expression-based signatures have been shown to predict neoadjuvant therapy response; but further studies are needed to deconvolve the contribution of different immune cell types. The I-SPY 2 TRIAL is a standing neoadjuvant platform trial which evaluates experimental agents/combinations when added to standard chemotherapy. In this study, we compared published T/B cell-related signatures at 3 different levels of resolution as predictors of response in the I-SPY 2 TRIAL: (1) a combined T/B-cell co-expression module, correlated with general lymphocytic infiltrate, (2) individual T-cell and a B-cell specific signatures derived from purified immune cells and refined using tumor expression, and (3) 9 T cell subpopulation-specific signatures, including a CD8+ T resident memory phenotype (TRM) and a CD8+ T effector memory subset (TEM), generated from microdroplet-based single cell (sc) RNA sequencing of over 6000 tumor associated CD3+ T cells. Methods: Expression data from 989 I-SPY 2 patients randomized to one of 9 possible experimental arms or the standard chemotherapy control were available for analysis. Pre-treatment biopsies were assayed using Agilent gene expression arrays. All I-SPY 2 biomarker analyses follow a pre-specified analysis plan. We used logistic modeling to assess each signature as a predictor of pCR within each arm (likelihood ratio test p Results: In the population as a whole, immune signatures predict response across multiple classes of agents (8/10 arms), including the checkpoint inhibitor Pembrolizumab (Pembro). However, the cell-type and subpopulation-specific signatures most predictive of response vary by subtype and agent. For instance, the T/B-cell co-expression module associates with response to Pembro and the Angiopoetin-1/-2 inhibitor AMG-386 in both HR-HER2- and HR+ERHHER2- subtypes. However, in the HR-HER2- subtype, the T-cell signature and the sc-derived CD8-TRM signature are most predictive; whereas in the HR+HER2- subtype, it is the B-cell, CD8-TRM and a novel CD4 signature that are most strongly associated with response. In the HER2+ subtype, the T/B-cell module and B-cell signature is associated with response to the AKT-inhibitor MK2206. Interestingly, among the sc-derived signatures, it is the CD8-TEM and multiple CD4 population-specific signatures, rather than CD8-TRM, that associate with response. Conclusion: Our exploratory study suggests that immune signatures are associated with response to multiple I-SPY 2 experimental agents and implicates different immune cell types as response-predictive within breast cancer subtypes. Single cell sequencing derived population specific signatures may help further de-convolute how different immune cell types contribute to therapy responsiveness. Citation Format: Yau C, Wolf DM, Campbell M, Savas P, Lin S, Brown-Swigart L, Hirst G, Asare S, Zhu Z, I-SPY 2 TRIAL Consortium, Loi S, DeMichele A, Yee D, Berry D, Esserman L, van 't Veer L. Expression-based immune signatures as predictors of neoadjuvant targeted-/chemo-therapy response: Experience from the I-SPY 2 TRIAL of ˜1000 patients across 10 therapies [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 P3-10-06.

Background: The explosion in new treatment options targeting immune checkpoints, HER signaling, DNA repair deficiency, AKT, and other pathways calls for updated breast cancer subtypes beyond HR and HER2 status to predict which patients will respond to which treatments. Here we leverage the I-SPY 2 TRIAL biomarker program over the past 8 years across 10 treatment arms to elucidate a minimal set of biomarkers that may improve response prediction in a modern treatment context, and to investigate which new patient phenotypes are identified by these response-predictive biomarkers. Methods: 986 patients were considered in this analysis. Treatments included paclitaxel alone (or with trastuzumab (H) in HER2+) or combined with investigational agents: veliparib/carboplatin (VC); neratinib; MK2206; ganitumab; ganetespib; AMG386; TDM1/pertuzumab (P); H/P; and pembrolizumab (Pembro). 24 prospectively defined, mechanism-of-action and pathway-based expression and phospho-protein signatures/biomarkers assayed from pre-treatment biopsies were previously found to be predictive in a particular agent/arm in pre-specified analysis. Here we evaluate these biomarkers in all patients. We assessed association between each biomarker and response in the population as a whole and within each arm and HR/HER2 subtype using a logistic model. To identify optimal dichotomizing thresholds for select biomarkers, 2-fold cross-validation was repeated 500 times. Our analysis is exploratory and does not adjust for multiplicities. Results: Our initial set of 24 predictive biomarkers reflects DNA repair deficiency (n=2), immune activation (n=7), ER signaling (n=2), HER2 signaling (n=4), proliferation (n=2), phospho-activation of AKT/mTOR (n=2), and ANG/TIE2 (n=1) pathways, among others. Biomarkers reflecting similar biology are correlated and cluster together. We make use of this correlation structure to reduce the dimensionality of the biomarker set to five predictive signals: proliferation, DNA repair deficiency (DRD), immune-engaged (Immune+), luminal/ER (lum), and HER2-activated. These biomarkers, when dichotomized, identify patient groups with differential predicted sensitivities to I-SPY 2 agents and are present at different proportions within receptor subtypes. For instance, in the HER2- subset, Immune+/DRD+ patients are predicted sensitive to both VC and Pembro, and account for 39% of TN, but only 12% of HR+HER2-. On the other end of the spectrum, only 17% of TN are Immune-/DRD-, compared to the majority (56%) of HR+HER2-. There are also subsets of patients positive for only one marker. For the HER2+ subset, 67% are HER2-activated+, and 25% lum+; of these HER2-activated+ patients are more likely to be Immune+ (44%), vs 23% in lum+. HER2-activated+/Immune+ patients have higher predicted sensitivity to HER2-targeted agents than lum+ or Immune- patients. In all, these molecular phenotypes predict sensitivity to one or more I-SPY 2 investigational agents for 75% of the ˜ 1000 patients. Conclusion: Molecular phenotypes reflecting proliferation, immune engagement, HER2-activation, luminal/ER-signaling, and DNA repair deficiency may provide a roadmap to guide treatment prioritization for emerging therapeutics. Citation Format: Wolf DM, Yau C, Wulfkuhle J, Petricoin E, Campbell M, Brown-Swigart L, Hirst G, Asare S, Zhu Z, Lee EP, Delson A, Pohlmann P, I-SPY 2 TRIAL Consortium, Hylton N, Liu MC, Symmans F, DeMichele A, Yee D, Berry D, Esserman L, van 't Veer L. Identifying breast cancer molecular phenotypes to predict response in a modern treatment landscape: Lessons from ˜1000 patients across 10 arms of the I-SPY 2 TRIAL [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 P3-10-02.

PURPOSE:Multiple studies have demonstrated the negative impact of cancer care delays during the COVID-19 pandemic, and transmission mitigation techniques are imperative for continued cancer care delivery. We aimed to gauge the effectiveness of these measures at the University of Pennsylvania.METHODS:We conducted a longitudinal study of SARS-CoV-2 antibody seropositivity and seroconversion in patients presenting to infusion centers for cancer-directed therapy between May 21, 2020, and October 8, 2020. Participants completed questionnaires and had up to five serial blood collections.RESULTS:Of 124 enrolled patients, only two (1.6%) had detectable SARS-CoV-2 antibodies on initial blood draw, and no initially seronegative patients developed newly detectable antibodies on subsequent blood draw(s), corresponding to a seroconversion rate of 0% (95% CI, 0.0 TO 4.1%) over 14.8 person-years of follow up, with a median of 13 health care visits per patient.CONCLUSION:These results suggest that patients with cancer receiving in-person care at a facility with aggressive mitigation efforts have an extremely low likelihood of COVID-19 infection.

Circulating tumor cells (CTC) are prognostic in metastatic breast cancer (MBC). The CTC-endocrine therapy index (CTC-ETI), consisting of CTC-ER (estrogen receptor), BCL2, human epidermal growth factor receptor (HER2), and Ki67 expression, might predict resistance to endocrine therapy (ET) in patients with ER-positive MBC. One hundred twenty-one patients with ER-positive/HER2-negative MBC initiating a new ET after ≥1 lines of ET were enrolled in a prospective, multi-institutional clinical trial. CTC-ETI and clinical/imaging follow-up were performed at baseline and serial time points. Progression-free survival (PFS) and rapid progression (RP; determined at the 3-month time point) were primary endpoints. Associations with clinical outcomes used logrank and Fisher’s exact tests. At baseline, 36% (38/107) of patients had ≥5 CTC/7.5 ml whole blood (WB). Patients with ≥5 vs. P = 0.03). Elevated CTC at 1 month was associated with even worse PFS (1.9 vs. 5.0 months from the 1-month sample, P P = 0.008). Patients with high vs. low CTC and CTC-ETI more frequently experienced RP (CTC: 66% vs. 41%; P = 0.03; CTC-ETI: 79% vs. 40%; P = 0.002). In conclusion, CTC enumeration and the CTC-ETI assay are prognostic at baseline and follow-up in patients with ER-positive/HER2-negative MBC starting new ET. CTC at first follow-up might identify a group of patients with ER-positive MBC that could forego ET, but CTC-ETI did not contribute further.

PURPOSE Patients with triple-negative breast cancer (TNBC) and residual invasive disease (RD) after completion of neoadjuvant chemotherapy (NAC) have a high-risk for recurrence, which is reduced by adjuvant capecitabine. Preclinical models support the use of platinum agents in the TNBC basal subtype. The EA1131 trial hypothesized that invasive disease-free survival (iDFS) would not be inferior but improved in patients with basal subtype TNBC treated with adjuvant platinum compared with capecitabine. PATIENTS AND METHODS Patients with clinical stage II or III TNBC with ≥ 1 cm RD in the breast post-NAC were randomly assigned to receive platinum (carboplatin or cisplatin) once every 3 weeks for four cycles or capecitabine 14 out of 21 days every 3 weeks for six cycles. TNBC subtype (basal v nonbasal) was determined by PAM50 in the residual disease. A noninferiority design with superiority alternative was chosen, assuming a 4-year iDFS of 67% with capecitabine. RESULTS Four hundred ten of planned 775 participants were randomly assigned to platinum or capecitabine between 2015 and 2021. After median follow-up of 20 months and 120 iDFS events (61% of full information) in the 308 (78%) patients with basal subtype TNBC, the 3-year iDFS for platinum was 42% (95% CI, 30 to 53) versus 49% (95% CI, 39 to 59) for capecitabine. Grade 3 and 4 toxicities were more common with platinum agents. The Data and Safety Monitoring Committee recommended stopping the trial as it was unlikely that further follow-up would show noninferiority or superiority of platinum. CONCLUSION Platinum agents do not improve outcomes in patients with basal subtype TNBC RD post-NAC and are associated with more severe toxicity when compared with capecitabine. Participants had a lower than expected 3-year iDFS regardless of study treatment, highlighting the need for better therapies in this high-risk population.

Background Obesity is a chronic, relapsing, and progressive disease; it is associated with poor health-related quality of life (HRQOL) in survivors of breast cancer. Methods In this 2 × 2 factorial trial, 351 survivors of breast cancer with overweight or obesity were randomized to 1 of 4 treatment groups for 52 weeks: control, exercise alone, diet alone, or exercise plus diet. HRQOL end points were measured at baseline and at week 52 using the 36-Item Medical Outcomes Survey-Short Form (SF-36). Repeated measures analysis of covariance quantified the estimated treatment difference (ETD). Results At baseline, participants had a mean (SD) age of 59.4 years (8.7), body mass index of 34.0 kg/m2 (5.9), and 71 participants (20.2%) self-reported fair or poor general health. After 52 weeks, compared with control, the exercise plus diet improved the physical health summary score (ETD: 5.39; 95% CI, 0.55-10.22); exercise alone (ETD: -1.91; 95% CI, -6.60 to 2.79) and diet alone (ETD: 3.16; 95% CI, -1.52 to 7.83) did not change the physical health summary score. Compared with control, exercise alone (ETD: -0.27; 95% CI, -6.60 to 2.79), diet alone (ETD: 3.25; 95% CI, -1.41 to 7.91), and the exercise plus diet (ETD: 1.75; 95% CI, -2.90 to 6.39) did not change the mental health summary score. Exercise alone did not impact any HRQOL subscale; diet alone improved the vitality subscale; exercise plus diet improved the physical functioning, role-physical and vitality subscales. Conclusion In survivors of breast cancer with overweight or obesity, exercise plus diet improved select HRQOL end points at week 52.

Cancer patients have increased morbidity and mortality from Coronavirus Disease 2019 (COVID-19), but the underlying immune mechanisms are unknown. In a cohort of 100 cancer patients hospitalized for COVID-19 at the University of Pennsylvania Health System, we found that patients with hematologic cancers had a significantly higher mortality relative to patients with solid cancers after accounting for confounders including ECOG performance status and active cancer status. We performed flow cytometric and serologic analyses of 106 cancer patients and 113 non-cancer controls from two additional cohorts at Penn and Memorial Sloan Kettering Cancer Center. Patients with solid cancers exhibited an immune phenotype similar to non-cancer patients during acute COVID-19 whereas patients with hematologic cancers had significant impairment of B cells and SARS-CoV-2-specific antibody responses. High dimensional analysis of flow cytometric data revealed 5 distinct immune phenotypes. An immune phenotype characterized by CD8 T cell depletion was associated with a high viral load and the highest mortality of 71%, among all cancer patients. In contrast, despite impaired B cell responses, patients with hematologic cancers and preserved CD8 T cells had a lower viral load and mortality. These data highlight the importance of CD8 T cells in acute COVID-19, particularly in the setting of impaired humoral immunity. Further, depletion of B cells with anti-CD20 therapy resulted in almost complete abrogation of SARS-CoV-2-specific IgG and IgM antibodies, but was not associated with increased mortality compared to other hematologic cancers, when adequate CD8 T cells were present. Finally, higher CD8 T cell counts were associated with improved overall survival in patients with hematologic cancers. Thus, CD8 T cells likely compensate for deficient humoral immunity and influence clinical recovery of COVID-19. These observations have important implications for cancer and COVID-19-directed treatments, immunosuppressive therapies, and for understanding the role of B and T cells in acute COVID-19.