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Background: The impact of human epidermal growth factor receptor 2 (HER2) expression determined by immunohistochemistry (IHC) on outcomes in early-stage triple-negative breast cancer (eTNBC) is unclear. Using a large, multi-institutional cohort, we evaluated outcomes by HER2 IHC status in patients with eTNBC who received neoadjuvant therapy (NAT)., Patients and Methods: Patients with stage I-III TNBC who received NAT and underwent surgery from January 2016 to June 2019 were identified from three databases. HER2 expression was defined as low (IHC1+ or 2+/FISH not amplified) or HER2 IHC score 0 by local testing at diagnosis. Pathological complete response (pCR) rates were compared using logistic regression adjusted for multiple factors. Survival outcomes were estimated using Kaplan-Meier and Cox proportional hazards models., Results: Among 977 consecutive patients, 388 (39.7%) had HER2-low and 589 (60.3%) had HER2 IHC score 0 tumors. Median age at eTNBC diagnosis was 50.3 years (range 21.0-83.4 years). At baseline, clinical nodal positivity rate was significantly higher in HER2-low (55.0%) versus HER2 IHC score 0 tumors (46.6%) (P = 0.011); pCR rates were similar (32.0% versus 32.6%; adjusted P = 0.924). At a median follow-up of 3.5 years, recurrence-free survival (RFS) did not vary significantly between HER2-low versus HER2 IHC score 0 among patients with pCR (adjusted P = 0.368) or residual disease (RD) after NAT (adjusted P = 0.573). Distant RFS and overall survival (OS) did not differ by HER2 category for patients with pCR [distant RFS (DRFS), adjusted P = 0.509; OS, adjusted P = 0.514] or RD (DRFS, adjusted P = 0.812; OS, P = 0.285). Discordance of tumor HER2 status was seen in 31.1% of HER2 IHC score 0 cases, with HER2 expression observed post-treatment; 34.8% of HER2-low cases showed discordance, with absent HER2 expression in RD., Conclusions: In this large cohort of patients with eTNBC treated with NAT, HER2-low status was not associated with pCR or survival after adjusting for clinical factors. The discordance in HER2 IHC pre- and post-NAT likely reflects challenges in HER2 quantification and heterogeneity., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Prior evidence suggests a progression-free survival (PFS) benefit from adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy for patients with some oligometastatic solid tumors. Randomized trials testing this hypothesis in breast cancer have yet to be published. We sought to determine whether adding MDT to SOC systemic therapy improves PFS in oligometastatic breast cancer., Methods: EXTEND is a multicenter phase II randomized basket trial testing the addition of MDT to SOC systemic therapy in patients with ≤5 metastases (NCT03599765). Patients were randomized 1:1 to MDT (definitive local treatment to all sites of disease, plus SOC systemic therapy) or to SOC systemic therapy only. Primary endpoint was PFS, and secondary endpoints included overall survival (OS), time to subsequent line of systemic therapy, and time to the appearance of new metastases. Exploratory analyses included quality of life (QOL) and systemic immune response measures., Results: From September 2018 through July 2022, 22 and 21 patients were randomized to the MDT and no-MDT arms, respectively. At a median follow-up of 24.8 months, PFS was not improved with the addition of MDT to SOC systemic therapy (median PFS 15.6 months MDT vs 24.9 months no-MDT [hazard ratio {HR} 0.91; 95% CI 0.34-2.48, p=0.86]). Similarly, MDT did not improve OS, time to subsequent line of systemic therapy, or time to the appearance of new metastases (all p>0.05). No significant differences were found in QOL measures, systemic T-cell activation, or T-cell stimulatory cytokine concentration., Conclusion: Among patients with oligometastatic breast cancer, the addition of MDT to SOC systemic therapy did not improve PFS. These findings suggest that MDT may have no systemic benefit in otherwise unselected oligometastatic breast cancer patients, although this trial was limited by a heterogenous and small sample size and overperformance of both treatment arms., Competing Interests: Declaration of competing interest Mr Fellman reported receiving grants from the National Institutes of Health (NIH) to The University of Texas MD Anderson Cancer Center during the conduct of the study. Dr Haymaker reported receiving grants from Avenge Bio, Sanofi, Dragonfly, BTG, Iovance Biotherapeutics, and TriSalus Life Sciences; receiving personal fees from Nanobiotix; receiving speaker honoraria from the Southwest Oncology Group and the Society for Immunotherapy of Cancer; and receiving stock options from BriaCell as a member of the scientific advisory board outside the submitted work. Dr Smith reported receiving salary support from Varian Medical Systems for a strategic alliance between MD Anderson Cancer Center and Varian Medical Systems outside the submitted work and royalty and equity interest in Oncora Medical. Dr Shaitelman reported funding from the Emerson Collective Foundation and contracted research agreements with Alpha Tau, Exact Sciences, TAE Life Sciences, and Artios Pharmaceuticals, outside the submitted work. Dr. Chun declares in the past 36 months support from grants or contracts from NIH R50 CA275822 and MD Anderson; consulting fees from Curio Science, Norton Healthcare, and AstraZeneca; honoraria from Binaytara Foundation, Curio Science, Henry Ford Health Systems, Japanese Society for Radiation Oncology and Hong Kong Precision Oncology society; and support for attending meetings and/or travel from ViewRay, American Board of Radiology, Binaytara Foundation, Japanese Society for Radiation Oncology, and AstraZeneca outside the submitted work. Dr Reuben reported receiving consulting fees and honoraria from Adaptive Biotechnologies outside the submitted work. Dr Ghia reported receiving consulting fees and honoraria from Brainlab outside the submitted work. Dr. Woodward reported personal fees from Exact Sciences and Epic Sciences, outside the submitted work. Dr Gomez reported receiving grants from AstraZeneca, Merck, Varian, and Bristol Myers Squibb and receiving consulting fees and honoraria from Grail, AstraZeneca, Olympus, Johnson & Johnson, Varian, Medtronic, and Med Learning Group outside the submitted work. Dr Tang reported receiving grants from the Cancer Prevention & Research Institute of Texas (CPRIT) and the Andrew Sabin Family Foundation and being an Andrew Sabin Scholar during the conduct of the study and receiving royalties from Wolters Kluwer and consulting fees and honoraria from Bayer, Diffusion Pharmaceuticals, and The Osler Institute Lecture Series outside the submitted work. No other disclosures were reported., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Many young adult (YA) breast cancer survivors (BCS) experience psychosocial distress during and after treatment, but do not utilize supportive care resources to maximize their health outcomes. The purpose of this pilot study was to test the feasibility and acceptability of a brief, internet-based expressive writing (EW) intervention intended to improve psychosocial health among YA BCS. Methods: Thirty YA BCS were remotely recruited via a hospital patient database and randomly assigned to the EW ( n = 20) or neutral writing ( n = 10) group. The EW intervention included delivery of positive messages and a weekly 30-minute EW activity for 3 weeks. Feasibility, acceptability, patient-reported satisfaction, and health outcomes were evaluated at baseline and 1-month follow-up. Results: The database-focused recruitment strategies (40% response) appeared to be feasible. Almost all (93%) participants adhered to at least one writing task and 67% to at least two writing tasks. Participants perceived the study as enjoyable and helpful for reducing stress. The difference in QOL of the intervention versus control group was medium to large (d = 0.73). Conclusion: This is the first study to test the feasibility of an internet-based EW for YA BCS. The online EW pilot intervention demonstrated evidence of feasibility and acceptability to YA BCS; its potential to improve health outcomes should be evaluated in an adequately powered prospective randomized controlled trial (RCT). Online EW may be offered to YA BCS in low-resource settings to address their unique physical and psychological challenges.

Purpose: The addition of pembrolizumab to chemotherapy in high-risk early triple-negative breast cancer (TNBC) improves cancer outcomes. However, pembrolizumab induces varied immune-related adverse events (irAEs) where some can be severe or lifelong. This retrospective study describes real-world patterns of irAEs in patients with TNBC who received pembrolizumab., Methods: We evaluated irAEs in patients with TNBC from a comprehensive cancer center and a community hospital who received pembrolizumab with chemotherapy between 2021 and 2023, excluding those enrolled in clinical trials. We used national guidelines to grade toxicities. Logistic regression assessed the effect of clinicopathologic variables on irAEs adjusting for covariates., Results: We identified 233 patients with a median age of 51 years, 62% had stage II TNBC, 35% had stage III TNBC, 25% were Hispanic, 21% were Black, and 42% were White. Eighty patients (34%) developed 100 separate irAEs. The most common irAEs were endocrinopathies (52%) and GI (23%); there were 26 grade ≥3 irAEs, which all resulted in hospitalization, the most common being GI (13 instances); 45 required systemic steroids, 16 required additional immunosuppressive therapy, and 32 patients discontinued pembrolizumab because of irAEs. Two patients who developed colitis eventually died due to complications. Most (67 instances) irAEs were unresolved at the time of last follow-up, but 55% (37/67) had improved to grade 1. No clinicopathologic factors were associated with the development or severity of irAEs., Conclusion: In this real-world diverse population, we observed rates of irAEs comparable with KEYNOTE-522, where endocrinopathies were the most prevalent, but GI irAEs were also prevalent and severe. This emphasizes a critical issue as pembrolizumab is increasingly being used in early TNBC and could have long-term survivorship implications.

Background: Triple negative breast cancer (TNBC) is an aggressive subtype with poor prognosis. We aimed to determine whether circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) could predict response and long-term outcomes to neoadjuvant chemotherapy (NAC)., Methods: Patients with TNBC were enrolled between 2017-2021 at The University of Texas MD Anderson Cancer Center (Houston, TX). Serial plasma samples were collected at four timepoints: pre-NAC (baseline), 12-weeks after NAC (mid-NAC), after NAC/prior to surgery (post-NAC), and one-year after surgery. ctDNA was quantified using a tumor-informed ctDNA assay (Signatera TM , Natera, Inc.) and CTC enumeration using CellSearch. Wilcoxon and Fisher's exact tests were used for comparisons between groups and Kaplan-Meier analysis used for survival outcomes., Results: In total, 37 patients were enrolled. The mean age was 50 and majority of patients had invasive ductal carcinoma (34, 91.9%) with clinical T2, (25, 67.6%) node-negative disease (21, 56.8%). Baseline ctDNA was detected in 90% (27/30) of patients, of whom 70.4% (19/27) achieved ctDNA clearance by mid-NAC. ctDNA clearance at mid-NAC was significantly associated with pathologic complete response (p = 0.02), whereas CTC clearance was not (p = 0.52). There were no differences in overall survival (OS) and recurrence-free survival (RFS) with positive baseline ctDNA and CTC. However, positive ctDNA at mid-NAC was significantly associated with worse OS and RFS (p = 0.0002 and p = 0.0034, respectively)., Conclusions: Early clearance of ctDNA served as a predictive and prognostic marker in TNBC. Personalized ctDNA monitoring during NAC may help predict response and guide treatment., (© 2024. The Author(s).)

Background: Despite lower chemotherapy use in older triple-negative breast cancer (TNBC) patients, their outcomes match younger counterparts. We compared outcomes in early-stage TNBC patients by age receiving chemotherapy at a major cancer center with a national TNBC database., Methods: Retrospective study using institutional data on stage I-III TNBC (ER/PR < 10%) women with neoadjuvant/adjuvant chemotherapy. Based on their ages at diagnosis, patients were stratified into four categories: ≤40, 41-59, 60-69, and ≥ 70 years. Demographic and clinical characteristics recorded included race, disease stage, ER/PR positivity, treatment regimen, lymphatic or vascular invasion (LVI), histologic grade, Ki-67 level, body mass index (BMI), and pathologic complete response (pCR) following neoadjuvant treatment and are summarized using descriptive statistics. The primary endpoints were overall survival (OS), disease-free survival (DFS), and distant disease-free survival (DDFS); all were estimated using the Kaplan-Meier method. Both univariate and multivariate (MV) Cox regressions were applied to evaluate the impact of important covariates on these time-to-event endpoints., Results: Of the 2336 patients studied, 492 (21.1%) were ≤ 40 years old, 1239 (53.1%) were 41-59, 461 (19.7%) were 60-69, and 144 (6.2%) were ≥ 70. In the univariate regression model of OS/DFS/DDFS, age ≥ 70 was significantly associated with worse OS (p = 0.0217); other factors associated with worse OS were non-anthracycline-based chemotherapy, higher tumor stage, and neoadjuvant chemotherapy. The multivariate Cox regression model, adjusted for race and stage, showed no significant effects of age on OS; however, patients ≥ 70 years old who received non-anthracycline treatment combinations had worse DFS (hazard ratio = 0.349 vs. 1.049, p = 0.0293) and DDFS (hazard ratio = 0.317 vs. 1.016, p = 0.0251) than patients ≤ 40 years old. DFS from MV model after adjusting for age, race, and disease stage, the hazard ratio between anthracycline + taxane treatments and anthracycline + other treatments in patients ≥ 70 years old was statistically significantly lower than in patients ≤ 40 years old (hazard ratios [HRs] = 0.349 vs. 1.049, p = 0.0293)., Conclusions: Our findings indicate that outcomes such as DFS are less favorable in older compared to younger patients with early-stage TNBC, primarily in those who did not receive an anthracycline based chemotherapy regimen., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The overall landscape of health-related quality of life (HRQoL) has not been thoroughly investigated in adolescents and young adults (AYAs) with cancer. Data are also lacking on how well HRQoL at the time of cancer diagnosis can prognosticate long-term survival in AYA survivors., Patients and Methods: We included 3,497 survivors of AYA cancer (age 15-39 years at diagnosis) who completed the Short-Form 12 Health Survey (SF-12) HRQoL questionnaire at diagnosis. Physical component summary (PCS) and mental component summary (MCS) scores were generated, with scores <50 representing poor HRQoL. Differences in HRQoL by patient characteristics and tumor type were investigated using violin plots and t tests/analysis of variance. The effect of HRQoL on overall survival was assessed using Kaplan-Meier plots and Cox proportional hazards models., Results: Overall mean PCS and MCS scores in this racially/ethnically diverse cohort (64% White, 19% Hispanic, 10% Black, and 7% other race/ethnicity) were 43.6 and 46.7, respectively. Women with breast cancer reported the most favorable PCS (50.8), and those with cervical cancer reported the lowest MCS (42.8). Age at diagnosis was associated positively with PCS (P<.001) and inversely with MCS (P<.001). Females had higher PCS yet lower MCS than males (both P<.001). Marginalized racial and ethnic populations reported lower PCS than White patients (P<.001). Physical and mental HRQoL were prognostic and associated with increased risk of poor survival (hazard ratio, 1.95; 95% CI, 1.72-2.21 for physical HRQoL, and 1.26; 95% CI, 1.13-1.40 for mental HRQoL)., Conclusions: Physical and mental HRQoL at diagnosis vary across patient characteristics in AYA cancer survivors. Poor HRQoL at diagnosis may be a prognosticator of diminished overall survival among AYA cancer survivors.

Background: Triple-negative breast cancer (TNBC) is known to portend a worse prognosis compared with same-stage, hormone receptor-positive disease. However, with the recent change in practice to include pembrolizumab in neoadjuvant chemotherapy (NAC) for TNBC, an increase in pathologic complete responses (pCRs) has been reported. The perioperative repercussions of adding pembrolizumab to standard NAC regimens for TNBC are currently unknown. We aimed to explore the perioperative implications of adding pembrolizumab to standard NAC regimens for non-metastatic TNBC., Methods: This was a retrospective review of the perioperative outcomes in patients with non-metastatic TNBC treated with pembrolizumab-NAC from January 2018 to October 2022 conducted at a high-volume cancer center. Patient demographics, comorbidities, clinical and pathological staging, NAC treatment regimen, initiation, and completion, as well as date of surgery and postoperative complications were analyzed., Results: Of 87 patients, 67.8% had an overall pCR and 86% had an axillary pCR; 37.2% of cN+ patients were spared from axillary lymph node dissection. However, 24.1% of patients experienced surgical complications, 9% of patients were receiving steroids at the time of breast surgery secondary to adverse effects of pembrolizumab-NAC, and 7% underwent a change in the initial surgical plan such as omission of reconstruction., Conclusion: Pembrolizumab-NAC has not only significant oncologic benefit but also noteworthy perioperative implications in the surgical management of TNBC., (© 2023. Society of Surgical Oncology.)

Background: Chemotherapy-induced peripheral neuropathy (CIPN) includes negative sensations that remain a major chronic problem for cancer survivors. Previous research demonstrated that neurofeedback (a closed-loop brain-computer interface [BCI]) was effective at treating CIPN versus a waitlist control (WLC). The authors' a priori hypothesis was that BCI would be superior to placebo feedback (placebo control [PLC]) and to WLC in alleviating CIPN and that changes in brain activity would predict symptom report., Methods: Randomization to one of three conditions occurred between November 2014 and November 2018. Breast cancer survivors no longer in treatment were assessed at baseline, at the end of 20 treatment sessions, and 1 month later. Auditory and visual rewards were given over 20 sessions based on each patient's ability to modify their own electroencephalographic signals. The Pain Quality Assessment Scale (PQAS) at the end of treatment was the primary outcome, and changes in electroencephalographic signals and 1-month data also were examined., Results: The BCI and PLC groups reported significant symptom reduction. The BCI group demonstrated larger effect size differences from the WLC group than the PLC group (mean change score: BCI vs. WLC, -2.60 vs. 0.38; 95% confidence interval, -3.67, -1.46 [p = .000; effect size, 1.07]; PLC, -2.26; 95% confidence interval, -3.33, -1.19 [p = .001 vs. WLC; effect size, 0.9]). At 1 month, symptoms continued to improve only for the BCI group. Targeted brain changes at the end of treatment predicted symptoms at 1 month for the BCI group only., Conclusions: BCI is a promising treatment for CIPN and may have a longer lasting effect than placebo (nonspecific BCI), which is an important consideration for long-term symptom relief. Although scientifically interesting, the ability to separate real from placebo treatment may not be as important as understanding the placebo effects differently from effects of the intervention., Plain Language Summary: Chemotherapy-induced nerve pain (neuropathy) can be disabling for cancer survivors; however, the way symptoms are felt depends on how the brain interprets the signals from nerves in the body. We determined that the perception of neuropathy can be changed by working directly with the brain. Survivors in our trial played 20 sessions of a type of video game that was designed to change the way the brain processed sensation and movement. In this, our second trial, we again observed significant improvement in symptoms that lasted after the treatment was complete., (© 2023 American Cancer Society.)

Background: Bone-targeted therapy (BTT) including zoledronic acid (ZA) and denosumab decreases the risk of skeletal-related events (SREs) in patients with metastatic breast cancer (MBC) and bone metastasis. The impacts from prolonged BTT on SREs and BTT-associated harms are unknown and are becoming important to understand as these patients survive for longer periods., Methods and Materials: We conducted a retrospective study of 224 patients with MBC and bone metastasis who survived for more than 2 years after diagnosis and received treatment at our institution between 2016 and 2021. We defined 3 BTT patterns: (1) ZA only, (2) denosumab only, (3) both ZA and denosumab. The association between these BTT patterns and SREs and harms was assessed using Fisher exact test and logistic regression., Results: Rates of SREs overall were 21.2% of patients given ZA only, 8.8% of those given denosumab only, and 20% of those given both, without statistically significant differences (p = .32). However, those treated with denosumab only had significantly fewer compression fractures (0.7%) (p = .02). BTT-associated harm was observed in 5.8% of the ZA-only group, 11.7% of the denosumab-only group, and 14.3% of the group given both, without statistically significant differences (p = .37)., Conclusion: Oncologists may have increased flexibility regarding the frequency of administration of BTT along with their choice of agent. Our study showed no significant difference in the prevention of overall SRE or development of BTT-associated harms between the BTT regimens evaluated., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: We examined how breast cancer-related lymphedema (BCRL) affects health-related quality of life (HRQOL), productivity, and compliance with therapeutic interventions to guide structuring BCRL screening programs., Methods: We prospectively followed consecutive breast cancer patients who underwent axillary lymph node dissection (ALND) with arm volume screening and measures assessing patient-reported health-related quality of life (HRQOL) and perceptions of BCRL care. Comparisons by BCRL status were made with Mann-Whitney U, Chi-square, Fisher's exact, or t tests. Trends over time from ALND were assessed with linear mixed-effects models., Results: With a median follow-up of 8 months in 247 patients, 46% self-reported ever having BCRL, a proportion that increased over time. About 73% reported fear of BCRL, which was stable over time. Further in time from ALND, patients were more likely to report that BCRL screening reduced fear. Patient-reported BCRL was associated with higher soft tissue sensation intensity, biobehavioral, and resource concerns, absenteeism, and work/activity impairment. Objectively measured BCRL had fewer associations with outcomes. Most patients reported performing prevention exercises, but compliance decreased over time; patient-reported BCRL was not associated with exercise frequency. Fear of BCRL was positively associated with performing prevention exercises and using compressive garments., Conclusions: Both incidence and fear of BCRL were high after ALND for breast cancer. Fear was associated with improved therapeutic compliance, but compliance decreased over time. Patient-reported BCRL was more strongly associated with worse HRQOL and productivity than was objective BCRL. Screening programs must support patients' psychological needs and aim to sustain long-term compliance with recommended interventions., Competing Interests: Declaration of competing interest SFS has funding from the Emerson Collective Foundation and contracted research agreements with Alpha Tau, Exact Sciences, TAE Life Sciences, and Artios Pharmaceuticals. WAW receives personal fees from Exact Sciences and Epic Sciences. BDS has grant funding from Varian Medical Systems and royalty and equity interest in Oncora Medical. RL serves as a consultant for Monte Rosa Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Most metastatic recurrences of triple negative breast cancer (TNBC) occur within five years of diagnosis, yet late relapses of TNBC (lrTNBC) do occur. Our objective was to develop a risk prediction model of lrTNBC using readily available clinicopathologic and sociodemographic features., Methods: We included patients diagnosed with stage I-III TNBC between 1998 and 2012 at ten academic cancer centers. lrTNBC was defined as relapse or mortality greater than 5 years from diagnosis. Features associated with lrTNBC were included in a multivariable logistic model using backward elimination with a p < 0.10 criterion, with a final multivariable model applied to training (70%) and independent validation (30%) cohorts., Results: A total 2210 TNBC patients with at least five years follow-up and no relapse before 5 years were included. In final multivariable model, lrTNBC was significantly associated with higher stage at diagnosis (adjusted Odds Ratio [aOR] for stage III vs I, 10.9; 95% Confidence Interval [CI], 7.5-15.9; p < 0.0001) and BMI (aOR for obese vs normal weight, 1.4; 95% CI, 1.0-1.8; p = 0.03). Final model performance was consistent between training (70%) and validation (30%) cohorts., Conclusions: A risk prediction model incorporating stage, BMI, and age at diagnosis offers potential utility for identification of patients at risk of development of lrTNBC and warrants further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for HER2-positive early-stage and metastatic breast cancer. Diarrhea is the most frequent side effect and the most common reason for early discontinuation. The phase II CONTROL trial investigated antidiarrheal prophylaxis or neratinib dose escalation (DE) for prevention of diarrhea. We present complete study results including final data for two DE strategies., Methods: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year. Early cohorts investigated mandatory prophylaxis with loperamide, then additional budesonide or colestipol. Final cohorts assessed neratinib DE over the first 2 (DE1) or 4 weeks (DE2). The primary endpoint was incidence of grade ≥3 diarrhea. Health-related quality of life (HRQoL) was assessed using FACT-B and EQ-5D-5L., Results: 563 patients were enrolled into six cohorts. All strategies reduced grade ≥3 diarrhea with the lowest incidence in DE1 (DE1 13%; colestipol + loperamide [CL] 21%, DE2 27%; budesonide + loperamide [BL] 28%; loperamide [L] 31%; colestipol + loperamide as needed [CL-PRN] 33%). Diarrhea-related discontinuations occurred early and were lowest in DE1 (DE1 3%; CL 4%; DE2 6%; CL-PRN 8%; BL 11%; L 20%). More patients stayed on neratinib for the prescribed period versus historical controls. Prior pertuzumab use did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration. Early transient reductions in HRQoL scores were observed., Conclusions: These complete results from CONTROL show improved neratinib tolerability with proactive management at the start of therapy. Two-week neratinib DE with loperamide as needed was particularly effective., Gov Registration Number: NCT02400476., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Arlene Chan: no competing interests to declare. Manuel Ruiz-Borrego: no competing interests to declare. Gavin Marx: no competing interests to declare. A. Jo Chien: Contracted research (personal) from Puma Biotechnology Inc. Hope S. Rugo: Research support for clinical trials through the University of California: Pfizer, Merck, Novartis, Lilly, Roche, Daiichi, Seattle Genetics, Macrogenics, Sermonix, Boehringer Ingelheim, Polyphor, AstraZeneca, Astellas, and Gilead. Honoraria from: Puma, Samsung, Chugai, Blueprint, and NAPO. Travel: GE Healthcare. Adam Brufsky: Consulting fees (personal) from Puma Biotechnology Inc. Michael Thirlwell: no competing interests to declare. Maureen Trudeau: no competing interests to declare. Ron Bose: Research grant from Puma Biotechnology, and consulting from Genentech. José A. García-Sáenz: consultative and advisory services for Seagen, Gilead, and Sanofi; consultancy/speaker fees from Novartis, Celgene, Eli Lilly, EISAI, AstraZeneca, Daiichi Sankyo, MSD, and Pierre Fabre; institution research funding from AstraZeneca; travel support from Novartis, Roche, and Pfizer. Daniel Egle: advisory services for AstraZeneca, Daiichi Sankyo, MSD, Seagen, Gilead, Novartis, Roche, Pfizer, and Lilly; consultancy/speaker fees from Roche, Pfizer, Novartis, Lilly, AstraZeneca, Daiichi Sankyo, MSD, Seagen, and Gilead; travel support from AstraZeneca and Pfizer. Barbara Pistilli: Consulting fees (personal) from Puma Biotechnology Inc., Pierre Fabre. Contracted research (personal) for Puma Biotechnology Inc. Johanna Wassermann: no competing interests to declare. Kerry A. Cheong: no competing interests to declare. Benjamin Schnappauf: no competing interests to declare. Dieter Semsek: no competing interests to declare. Christian F. Singer: no competing interests to declare. Navid Foruzan: Full-time employment Puma Biotechnology Inc. Ownership interest (stock, stock options) Puma Biotechnology Inc. Daniel DiPrimeo: Full-time employment Puma Biotechnology Inc. Ownership interest (stock, stock options) Puma Biotechnology Inc. Leanne McCulloch: Full-time employment Puma Biotechnology Inc. Ownership interest (stock, stock options) Puma Biotechnology Inc. Sara A. Hurvitz: Contracted research paid to institution: Ambrx, Amgen, Arvinas, AstraZeneca, Bayer, Cytomx, Daiichi Sankyo, Dantari, Dignitana, Genentech/Roche, G1-Therapeutics, Gilead, GSK, Immunomedics, Eli Lilly, Macrogenics, Novartis, OBI Pharma, Orinove, Pfizer, Phoenix Molecular Designs, Ltd., Pieris, PUMA, Radius, Samumed, Sanofi, Seattle Genetics/Seagen, Zymeworks; Travel expenses paid to SAH: Lilly (2019); speaking: Daiichi Sankyo (2021). Carlos H. Barcenas: no competing interests to declare., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Mild breast cancer-related lymphedema (BCRL) is clinically diagnosed as a 5%-10% increase in arm volume, typically measured no earlier than 3-6 months after locoregional treatment. Early BCRL treatment is associated with better outcomes, yet amid increasing evidence that lymphedema exists in a latent form, treatment is typically delayed until arm swelling is obvious. In this study, we investigated whether near-infrared fluorescence lymphatic imaging (NIRF-LI) surveillance could characterize early onset of peripheral lymphatic dysfunction as a predictor of BCRL., Methods: In a prospective, longitudinal cohort/observational study (NCT02949726), subjects with locally advanced breast cancer who received axillary lymph node dissection and regional nodal radiotherapy (RT) were followed serially, between 2016 and 2021, before surgery, 4-8 weeks after surgery, and 6, 12, and 18 months after RT. Arm volume was measured by perometry, and lymphatic (dys) function was assessed by NIRF-LI., Results: By 18 months after RT, 30 of 42 study subjects (71%) developed mild-moderate BCRL (i.e., ≥ 5% arm swelling relative to baseline), all manifested by "dermal backflow" of lymph into lymphatic capillaries or interstitial spaces. Dermal backflow had an 83% positive predictive value and 86% negative predictive value for BCRL, with a sensitivity of 97%, specificity of 50%, accuracy of 83%, positive likelihood ratio of 1.93, negative likelihood ratio of 0.07, and odds ratio of 29.00. Dermal backflow appeared on average 8.3 months, but up to 23 months, before the onset of mild BCRL., Conclusion: BCRL can be predicted by dermal backflow, which often appears months before arm swelling, enabling early treatment before the onset of edema and irreversible tissue changes., (© 2022. The Author(s).)

Current gold standard for absolute quantitation of a specific DNA sequence is droplet digital PCR (ddPCR), which has been applied to copy number variation (CNV) detection. However, the number of quantitation modules in ddPCR is limited by fluorescence channels, which thus limits the CNV sensitivity due to sampling error following Poisson distribution. Here we develop a PCR-based molecular barcoding NGS approach, quantitative amplicon sequencing (QASeq), for accurate absolute quantitation scalable to over 200 quantitation modules. By attaching barcodes to individual target molecules with high efficiency, 2-plex QASeq exhibits higher and more consistent conversion yield than ddPCR in absolute molecule count quantitation. Multiplexed QASeq improves CNV sensitivity allowing confident distinguishment of 2.05 ploidy from normal 2.00 ploidy. We apply multiplexed QASeq to serial longitudinal plasma cfDNA samples from patients with metastatic ERBB2+ (HER2+ ) breast cancer seeking association with tumor progression. We further show an RNA QASeq panel for targeted expression profiling., (© 2022. The Author(s).)

Background: Smoking negatively affects overall survival after successful breast cancer (BC) treatment. We hypothesized that smoking cessation would improve survival outcomes of BC patients who were smokers at the time of diagnosis., Methods: This was a retrospective analysis of self-identified smokers with BC treated at The University of Texas MD Anderson Cancer Center. Patient demographics, date of diagnosis, tumor stage, tobacco treatment program (TP) participation, and time to death were extracted from our departmental databases and institutional electronic health records. We examined associations between tobacco abstinence status and survival using survival models, with and without interactions, adjusted for personal characteristics and biomarkers of disease., Results: Among all 31,069 BC patients treated at MD Anderson between 2006 and 2017, we identified 2126 smokers (6.8%). From those 2126 self-identified smokers, 665 participated in the TP, reporting a conservative estimate of 31% abstinence (intent-to-treat) 9 months into the program. Patients without reported follow-up abstinence status (including TP and non-TP participants) were handled in the analyses as smokers. Survival analysis controlled for multiple factors, including disease characteristics and participation in the TP, indicated that abstainers were more likely to be alive with no evidence of disease compared to non-abstainers (HR, 0.593; 95% CI, 0.386-0.911; p = 0.017)., Conclusion: Our results suggest that quitting smoking is associated with improved survival among BC patients who were smokers at time of diagnosis across all tumor stages. Comprehensive approaches for smoking cessation in patients diagnosed with BC may prolong survival when started as early as the time of diagnosis.

Purpose: Patients with breast cancer and ipsilateral supraclavicular (SCV) node involvement at the time of diagnosis (TNM cN3c) have historically had poor outcomes. Radiation therapy (RT) has an important role because SCV nodes are not routinely surgically dissected. However, optimal locoregional management, contemporary outcomes, and prognostic factors are not well defined., Methods and Materials: We reviewed the data of patients with cN3c breast cancer treated at our institution between 2014 and 2019 with curative intent, including neoadjuvant chemotherapy, surgery, and adjuvant RT. All patients received comprehensive regional RT, including to the SCV nodes. Institutional guidelines recommend a 10-Gy or 16-Gy boost to resolved and unresolved N3 nodes, respectively. Overall survival (OS), recurrence-free survival (RFS), locoregional recurrence-free survival (LRRFS), and supraclavicular recurrence-free survival (SCRFS) were analyzed., Results: Data from 173 consecutive patients were analyzed with a median follow-up time of 2.8 years. The median age was 54 years, 76 patients (44%) were estrogen receptor positive/human epidermal growth factor receptor 2 negative, 100 patients (58%) had T3/4 disease, and 10 patients (6%) underwent a neck dissection. In addition, 156 patients (90%) received a cumulative SCV dose of ≥60 Gy. The 5-year OS, SCRFS, LRRFS, and RFS rates were 73%, 95%, 86%, and 50%, respectively. The 5-year OS rate for a cumulative SCV dose of ≥60 Gy versus <60 Gy was 75% versus 39% (P = .04). In the multivariable analysis, a cumulative SCV dose of ≥60 Gy, extranodal extension, receptor status, and Eastern Cooperative Oncology Group performance status were associated with OS. The 5-year SCRFS rates with and without neck dissection were 100% versus 95% (P = .57). Among patients with a postchemotherapy SCV node size of ≥1 cm without neck dissection, the 5-year SCRFS rate was 83%., Conclusions: In one of the largest series of patients with cN3c breast cancer, multimodality therapy using adjuvant RT with a SCV boost resulted in a 5-year LRRFS rate of 86%. There is a limited role for neck dissection as the 5-year SCRFS rate was 95% overall and 83% for residual SCV disease ≥1 cm after chemotherapy with RT alone. A cumulative SCV dose of ≥60 Gy was associated with improved OS, but not SCRFS, LRRFS, or RFS. A SCV boost should be considered in these patients as treatment was well-tolerated. Despite advances in systemic therapy, nearly half of patients developed distant metastases, highlighting the need for close observation after treatment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Oncogenic mutations in PIK3CA are prevalent in diverse cancers and can be targeted with inhibitors of the phosphoinositide-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Analysis of circulating tumor DNA (ctDNA) provides a minimally invasive approach to detect clinically actionable PIK3CA mutations., Patients and Methods: We analyzed PIK3CA hotspot mutation frequency by droplet digital PCR (QX 200; BioRad) using 16 ng of unamplified plasma-derived cell-free DNA from 68 patients with advanced solid tumors (breast cancer, n = 41; colorectal cancer, n = 13; other tumor types, n = 14). Results quantified as variant allele frequencies (VAFs) were compared with previous testing of archival tumor tissue and with patient outcomes., Results: Of 68 patients, 58 (85%) had PIK3CA mutations in tumor tissue and 43 (74%) PIK3CA mutations in ctDNA with an overall concordance of 72% (49/68, κ = 0.38). In a subset analysis, which excluded samples from 26 patients known not to have disease progression at the time of sample collection, we found an overall concordance of 91% (38/42; κ = 0.74). PIK3CA-mutated ctDNA VAF of ≤8.5% (5% trimmed mean) showed a longer median survival compared with patients with a higher VAF (15.9 versus 9.4 months; 95% confidence interval 6.7-17.1 months; P = 0.014). Longitudinal analysis of ctDNA in 18 patients with serial plasma collections (range 2-22 time points, median 5) showed that those with a decrease in PIK3CA VAF had a longer time to treatment failure (TTF) compared with patients with an increase or no change (10.7 versus 2.6 months; P = 0.048)., Conclusions: Detection of PIK3CA mutations in ctDNA is concordant with testing of archival tumor tissue. Low quantity of PIK3CA-mutant ctDNA is associated with longer survival and a decrease in PIK3CA-mutant ctDNA on therapy is associated with longer TTF., Competing Interests: Disclosure FJ has research support from Novartis, Genentech, BioMed Valley Discoveries, Astellas, Agios, Plexxikon, Deciphera, PIQUR, Symphogen, Bristol-Myers Squibb, Asana, and Upsher-Smith Laboratories; is or has been on the Scientific Advisory Boards of Guardant Health, IFM Therapeutics, Synlogic, and Deciphera; is a paid consultant for Cardiff Oncology and ImmunoMet; and has ownership interests in Cardiff Oncology. MF reports grants and personal consulting fees through 06/04/18 from Seattle Genetics and salary and stocks from 10/01/18 following the start of her employment with Seattle Genetics; grants and personal fees from Takeda, Celgene, BMS, and Merck through 06/04/18; grants from ADC Therapeutics, Molecular Templates, MedImmune, Gilead, and Genentech through 06/04/18; and personal fees from Bayer and Spectrum through 06/04/18. VS has research funding/grant support for clinical trials (to institution) from Novartis, Bayer, Berghealth, Incyte, Fujifilm, PharmaMar, D3, Pfizer, MultiVir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology, MedImmune, Altum, Dragonfly Therapeutics, Takeda and, National Comprehensive Cancer Network, NCI-CTEP, UT MD Anderson Cancer Center, Turning point therapeutics, and Boston Pharmaceuticals; travel funding from Novartis, PharmaMar, ASCO, ESMO, Helsinn, Incyte; and serves on the advisory board of Helsinn, LOXO Oncology/ Eli Lilly, R-Pharma US, INCYTE, QED pharma, Astra-Zeneca/Medimmune, Novartis, Signant Health. The remaining authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Neratinib is an irreversible, pan-human epidermal growth factor inhibitor that has shown efficacy across human epidermal growth factor receptor 2 (HER2)-positive breast cancer settings. Neratinib is indicated for use as extended adjuvant therapy for HER2-positive early-stage breast cancer or, in combination with capecitabine, in the treatment of HER2-positive metastatic breast cancer. The primary tolerability concern with neratinib is diarrhea, and severe diarrhea early in treatment can lead to a substantial proportion of patients discontinuing neratinib, which may lead to reduced or nonexistent efficacy. In order to establish a set of treatment recommendations for use of neratinib, on May 12, 2020, an expert panel of oncologists and gastroenterologists met virtually to discuss the role of neratinib in the treatment of patients with HER2-positive breast cancer. The panel reviewed the current data on neratinib, including efficacy across settings and diarrhea management strategies. Based on these data and their clinical experience, the panelists developed a set of recommendations to guide selection of patients for neratinib, implement weekly dose escalation at initiation of therapy, and prophylactically manage diarrhea., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Neoadjuvant systemic therapy (NST) is standard for locally advanced breast cancer and is now frequently considered for those with early-stage and node-positive disease. We aimed to evaluate the treatment course and outcomes in patients with disease progression during NST., Methods: Patients diagnosed with unilateral stage I-III breast cancer between 2005 and 2015 with documented local-regional progression while receiving NST, by clinical examination and/or imaging after two or more cycles of chemotherapy, were identified from a prospective database, stratified by receipt of surgery and outcomes analyzed., Results: Of 6362 patients treated with NST during the study period, 124 (1.9%) developed disease progression. At a median live follow-up of 71 months, 23.4% were alive without disease and 70.2% had died from breast cancer. Median overall survival (OS) time for patients with progression was 26 months and median distant disease-free survival (DFS) was 14 months. Triple-negative breast cancer was associated with a higher likelihood of death (p < 0.001) and development of distant metastasis (p = 0.002). Among patients who had surgery (104, 89.3%), 40 (38.5%) developed local-regional recurrence, 67 (64.4%) developed distant metastasis, and 69 (66.3%) died from breast cancer. Median OS and median distant DFS in this subgroup was 31 and 16 months, respectively., Conclusions: High rates of local-regional and distant failure were seen following disease progression while receiving NST. This suggests aggressive tumor biology and the need to study novel systemic therapies. Poor survival outcomes despite surgical management highlight the importance of careful patient selection when considering operative intervention after progression while receiving NST., (© 2021. Society of Surgical Oncology.)

Purpose: Metastatic breast cancer (MBC) has a heterogeneous clinical course. We sought to develop a prognostic model for overall survival (OS) that incorporated contemporary tumor and clinical factors for estimating individual prognosis., Methods: We identified patients with MBC from our institution diagnosed between 1998 and 2017. We developed OS prognostic models by Cox regression using demographic, tumor, and treatment variables. We assessed model predictive accuracy and estimated annual OS probabilities. We evaluated model discrimination and prediction calibration using an external validation data set from the National Comprehensive Cancer Network., Results: We identified 10,655 patients. A model using age at diagnosis, race or ethnicity, hormone receptor and human epidermal growth factor receptor 2 subtype, de novo versus recurrent MBC categorized by metastasis-free interval, Karnofsky performance status, organ involvement, frontline biotherapy, frontline hormone therapy, and the interaction between variables significantly improved predictive accuracy (C-index, 0.731; 95% CI, 0.724 to 0.739) compared with a model with only hormone receptor and human epidermal growth factor receptor 2 status (C-index, 0.617; 95% CI, 0.609 to 0.626). The extended Cox regression model consisting of six independent models, for < 3, 3-14, 14-20, 20-33, 33-61, and ≥ 61 months, estimated up to 5 years of annual OS probabilities. The selected multifactor model had good discriminative ability but suboptimal calibration in the group of 2,334 National Comprehensive Cancer Network patients. A recalibration model that replaced the baseline survival function with the average of those from the training and validation data improved predictions across both data sets., Conclusion: We have generated and validated a robust prognostic OS model for MBC. This model can be used in clinical decision making and stratification in clinical trials., Competing Interests: Carlos H. BarcenasResearch Funding: Puma Biotechnology Rashmi K. MurthyHonoraria: Puma Biotechnology, Genentech, Seattle Genetics, Novartis, AstraZenecaConsulting or Advisory Role: Genentech/Roche, Puma Biotechnology, Seattle Genetics, AstraZeneca, NovartisResearch Funding: Genentech/Roche, Daiichi Sankyo, Pfizer, EMD Serono, Seattle Genetics, AstraZenecaTravel, Accommodations, Expenses: Seattle Genetics, Genentech Robert W. CarlsonEmployment: Flatiron Health (I)Patents, Royalties, Other Intellectual Property: Patents relating to inventions as employee of NCCNOther Relationship: National Comprehensive Cancer Network Debu TripathyConsulting or Advisory Role: Novartis, Pfizer, GlaxoSmithKline, Genomic Health, AstraZeneca, OncoPepResearch Funding: Novartis, PolyphorTravel, Accommodations, Expenses: Novartis, AstraZeneca Gabriel N. HortobagyiConsulting or Advisory Role: NovartisResearch Funding: NovartisTravel, Accommodations, Expenses: NovartisNo other potential conflicts of interest were reported.

(1) Background: The relatively high rate of contralateral prophylactic mastectomy (CPM) among women with early stage unilateral breast cancer (BC) has raised concerns. We sought to assess the influence of partners, physicians, and the media on the decision of women with unilateral BC to undergo CPM and identify clinicopathological variables associated with the decision to undergo CPM. (2) Patients and Methods: Women with stage 0 to III unilateral BC who underwent CPM between January 2010 and December 2017. Patients were surveyed regarding factors influencing their self-determined decision to undergo CPM. Partner, physician, and media influence factors were modeled by logistic regressions with adjustments for a family history of breast cancer and pathological stage. (3) Results: 397 (29.6%) patients completed the survey and were included in the study. Partners, physicians, and the media significantly influenced patients' decision to undergo CPM. The logistic regression models showed that, compared to self-determination alone, overall influence on the CPM decision was significantly higher for physicians ( p = 0.0006) and significantly lower for partners and the media ( p < 0.0001 for both). Fifty-nine percent of patients' decisions were influenced by physicians, 28% were influenced by partners, and only 17% were influenced by the media. The model also showed that patients with a family history of BC had significantly higher odds of being influenced by a partner than did those without a family history of BC ( p = 0.015). (4) Conclusions: Compared to self-determination, physicians had a greater influence and partners and the media had a lower influence on the decision of women with unilateral BC to undergo CPM. Strong family history was significantly associated with a patient's decision to undergo CPM.

Background: Triple-negative breast cancer (TNBC) accounts for disproportionately poor outcomes in breast cancer, driven by a subset of rapid-relapse TNBC (rrTNBC) with marked chemoresistance, rapid metastatic spread, and poor survival. Our objective was to evaluate clinicopathologic and sociodemographic features associated with rrTNBC., Methods: We included patients diagnosed with stage I-III TNBC in 1996 through 2012 who received chemotherapy at 1 of 10 academic cancer centers. rrTNBC was defined as a distant metastatic recurrence event or death ≤24 months after diagnosis. Features associated with rrTNBC were included in a multivariable logistic model upon which backward elimination was performed with a P<.10 criterion, with a final multivariable model applied to training (70%) and independent validation (30%) cohorts., Results: Among all patients with breast cancer treated at these centers, 3,016 fit the inclusion criteria. Training cohort (n=2,112) bivariable analyses identified disease stage, insurance type, age, body mass index, race, and income as being associated with rrTNBC (P<.10). In the final multivariable model, rrTNBC was significantly associated with higher disease stage (adjusted odds ratio for stage III vs I, 16.0; 95% CI, 9.8-26.2; P<.0001), Medicaid/indigent insurance, lower income (by 2000 US Census tract), and younger age at diagnosis. Model performance was consistent between the training and validation cohorts. In sensitivity analyses, insurance type, low income, and young age were associated with rrTNBC among patients with stage I/II but not stage III disease. When comparing rrTNBC versus late relapse (>24 months), we found that insurance type and young age remained significant., Conclusions: Timing of relapse in TNBC is associated with stage of disease and distinct sociodemographic features, including insurance type, income, and age at diagnosis.

Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for extended adjuvant treatment in early-stage HER2-positive breast cancer based on the phase III ExteNET study. In that trial, in which no antidiarrheal prophylaxis was mandated, grade 3 diarrhea was observed in 40% of patients and 17% discontinued due to diarrhea. The international, open-label, sequential-cohort, phase II CONTROL study is investigating several strategies to improve tolerability., Patients and Methods: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year plus loperamide prophylaxis (days 1-28 or 1-56). Sequential cohorts evaluated additional budesonide or colestipol prophylaxis (days 1-28) and neratinib dose escalation (DE; ongoing). The primary end point was the incidence of grade ≥3 diarrhea., Results: Final data for loperamide (L; n = 137), budesonide + loperamide (BL; n = 64), colestipol + loperamide (CL; n = 136), and colestipol + as-needed loperamide (CL-PRN; n = 104) cohorts, and interim data for DE (n = 60; completed ≥six cycles or discontinued; median duration 11 months) are available. No grade 4 diarrhea was observed. Grade 3 diarrhea rates were lower than ExteNET in all cohorts and lowest in DE (L 31%, BL 28%, CL 21%, CL-PRN 32%, DE 15%). Median number of grade 3 diarrhea episodes was one; median duration per grade 3 episode was 1.0-2.0 days across cohorts. Most grade 3 diarrhea and diarrhea-related discontinuations occurred in month 1. Diarrhea-related discontinuations were lowest in DE (L 20%, BL 8%, CL 4%, CL-PRN 8%, DE 3%). Decreases in health-related quality of life did not cross the clinically important threshold., Conclusions: Neratinib tolerability was improved with preemptive prophylaxis or DE, which reduced the rate, severity, and duration of neratinib-associated grade ≥3 diarrhea compared with ExteNET. Lower diarrhea-related treatment discontinuations in multiple cohorts indicate that proactive management can allow patients to stay on neratinib for the recommended time period. CLINICALTRIALS.GOV: NCT02400476., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Delays in the initiation of therapy among patients with early stage breast cancer (BC) can negatively affect outcomes. Patients treated with neoadjuvant systemic chemotherapy (NSC) usually display tumors with high-risk features. Considering these high-risk characteristics and the evidence supporting adverse outcomes associated with delays in adjuvant chemotherapy initiation, we sought to determine whether a delay in NSC initiation is associated with overall survival (OS)., Methods: We identified patients diagnosed between January 1995 and December 2015 with invasive primary BC (stage I-III) who received NSC at MD Anderson Cancer Center. Patients were categorized according to their time from BC diagnosis to NSC (in days) into three subgroups: 0-30, 31-60, and ≥61 days. Primary endpoint was OS. Descriptive statistics and Cox's proportional hazard models were used., Results: A total of 5,137 patients were included. Median follow-up was 6.5 years. The 5-year OS estimates according to time to NSC were 87%, 85%, and 83% in patients who received NSC within 0-30, 31-60, and ≥61 days after diagnosis, respectively (p = .006). In multivariable analysis, compared with time to NSC of 0-30 days, delayed NSC ≥61 days was associated with an increased risk of death (31-60 days: hazard ratio [HR] = 1.05 [95% confidence interval (CI) 0.92-1.19]; ≥61 days, HR = 1.28 [95% CI 1.06-1.54]). In stratified analyses, the association between delay in NSC initiation and increased risk of death was statistically significant for patients with stage I and II BC (31-60 days: HR = 1.22 [95% CI 1.02-1.47]; ≥61 days, HR = 1.41 [95% CI 1.07-1.86]) and among patients with HER2-positive tumors ( ≥61 days, HR = 1.86 [95% CI 1.21-2.86])., Conclusion: A delay in NSC initiation of more than 61 days after BC diagnosis was associated with an increased risk of death. Early initiation of NSC should be a priority; multidisciplinary teams must focus on coordination of care and patient-centered, timely treatment planning and delivery., Implications for Practice: The results of this study showed that a delay in neoadjuvant systemic chemotherapy initiation of more than 61 days after breast cancer diagnosis is associated with an increased risk of death; therefore, efforts must focus on early initiation of therapy, which should be a priority. Multidisciplinary teams must enhance coordination of care and patient-centered, timely treatment planning and delivery., (© AlphaMed Press 2020.)

Introduction: The role of surgery for breast cancer liver metastases (BCLM) remains controversial. This study aimed to analyze survival in patients treated with hepatectomy plus systemic therapy or systemic therapy alone for BCLM and to determine selection factors to guide surgical therapy., Materials and Methods: Patients who underwent hepatectomy plus systemic therapy (n = 136) and systemic therapy alone for isolated BCLM (n = 763) were compared. Overall survival (OS) was analyzed after propensity score matching. Intrinsic subtypes were defined as: luminal A (estrogen receptor [ER]+ and/or progesterone receptor positive [PR]+, human epidermal growth factor receptor 2 [HER2]-), luminal B (ER and/or PR+, HER2+), HER2-enriched (ER and PR-, HER2+), and basal-like (ER, PR, HER2-)., Results: After hepatectomy, independent predictors of poor OS were number and size of liver metastases, and intrinsic subtype (hazard ratios, 1.11, 1.16, and 4.28, respectively). Median OS was 75 and 81 months among patients with luminal B and HER2-enriched subtypes, compared with 17 and 53 months among patients with basal-like and luminal A subtypes (P < .001). Median progression-free survival (PFS) was 60 months with the HER2-enriched subtype, compared with 17, 16, and 5 months with luminal A, luminal B, and basal-like subtypes, respectively (P < .001). After propensity score matching, 5-year OS rates were 56% vs. 40% in the surgery vs. systemic therapy alone groups (P = .018)., Conclusion: Surgical resection of BCLM yielded higher OS compared with systemic therapy alone and prolonged PFS among patients with the HER2-enriched subtype. These findings support the use of surgical therapy in appropriately selected patients, based on intrinsic subtypes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Tumor cells with a mesenchymal phenotype and/or cancer stem-like cells (CSCs) are known to contribute to metastasis and drug resistance. Circulating tumor cells (CTCs) undergoing epithelial-mesenchymal transition (EMT) and CTCs reflecting a dedifferentiated CSC phenotype may not be detected using only an anti-EpCAM antibody to capture them. We used an antibody-independent CTC enrichment platform, ApoStream®, which does not rely on any antibody, including anti-EpCAM, to capture EMT- and CSC-CTCs in breast cancer patients who received neoadjuvant chemotherapy and correlated them to pathological complete response (pCR)., Methods: Blood samples from newly diagnosed breast cancer patients were prospectively collected before neoadjuvant chemotherapy (T0), after chemotherapy but before surgery (T1), and after surgery (T2) and processed using ApoStream. CTCs detected were stained with additional markers to define 3 CTC subsets with the following phenotypes: epithelial CTCs (CK+, EpCAM+ or E-cadherin+), EMT-CTCs (β-catenin+ or vimentin+), and CSC-CTCs (CD44+ and CD24low)., Results: We enrolled 55 patients, 47 of which had data for analysis. EMT-CTCs were detected in 57%, 62%, and 72% and CSC-CTCs in 9%, 22%, and 19% at the T0, T1, and T2 time points, respectively. Counts of epithelial (P = 0.225) and EMT (P = 0.522) phenotypes of CTCs at T0 did not significantly predict pCR. Moreover, no correlation between CTC count change and pCR was demonstrated., Conclusions: ApoStream was successful in detecting EMT-CTCs among patients after neoadjuvant chemotherapy. However, EMT-/CSC-CTC counts did not correlate with pCR. Due to the small sample size and heterogeneity of this patient population, further study in a larger cohort of molecularly homogeneous patients is warranted., Competing Interests: ApoCell provided support in the form of salaries for authors (DWD, WW). The commercial affiliation to Apocell does not alter our adherence to PLOS ONE policies on sharing data and materials.

We developed prognostic models for breast cancer-specific survival (BCSS) that consider anatomic stage and other important determinants of prognosis and survival in breast cancer, such as age, grade, and receptor-based subtypes with the intention to demonstrate that these factors, conditional on stage, improve prediction of BCSS. A total of 20,928 patients with stage I-III invasive primary breast cancer treated at The University of Texas MD Anderson Cancer Center between 1990 and 2016, who received surgery as an initial treatment were identified to generate prognostic models by Fine-Gray competing risk regression model. Model predictive accuracy was assessed using Harrell's C-index. The Aalen-Johansen estimator and a selected Fine-Gray model were used to estimate the 5-year and 10-year BCSS probabilities. The performance of the selected model was evaluated by assessing discrimination and prediction calibration in an external validation dataset of 29,727 patients from the National Comprehensive Cancer Network (NCCN). The inclusion of age, grade, and receptor-based subtype in addition to stage significantly improved the model predictive accuracy (C-index: 0.774 (95% CI 0.755-0.794) vs. 0.692 for stage alone, p  < 0.0001). Young age (<40), higher grade, and TNBC subtype were significantly associated with worse BCSS. The selected model showed good discriminative ability but poor calibration when applied to the validation data. After recalibration, the predictions showed good calibration in the training and validation data. More refined BCSS prediction is possible through a model that has been externally validated and includes clinical and biological factors., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

Purpose: Talazoparib has demonstrated efficacy in patients with BRCA -positive metastatic breast cancer. This study evaluated the pathologic response of talazoparib alone for 6 months in patients with a known germline BRCA pathogenic variant (g BRCA -positive) and operable breast cancer., Methods: Eligibility included 1 cm or larger invasive tumor and g BRCA -positive disease. Human epidermal growth factor receptor 2-positive tumors were excluded. Twenty patients underwent a pretreatment biopsy, 6 months of once per day oral talazoparib (1 mg), followed by definitive surgery. Patients received adjuvant therapy at physician's discretion. The primary end point was residual cancer burden (RCB). With 20 patients, the RCB-0 plus RCB-I response rate can be estimated with a 95% CI with half width less than 20%., Results: Twenty patients were enrolled from August 2016 to September 2017. Median age was 38 years (range, 23 to 58 years); 16 patients were g BRCA 1 positive and 4 patients were g BRCA 2 positive. Fifteen patients had triple-negative breast cancer (estrogen receptor/progesterone receptor < 10%), and five had hormone receptor-positive disease. Five patients had clinical stage I disease, 12 had stage II, and three had stage III, including one patient with inflammatory breast carcinoma and one with metaplastic chondrosarcomatous carcinoma. One patient chose to receive chemotherapy before surgery and was not included in RCB analyses. RCB-0 (pathologic complete response) rate was 53% and RCB-0/I was 63%. Eight patients (40%) had grade 3 anemia and required a transfusion, three patients had grade 3 neutropenia, and 1 patient had grade 4 thrombocytopenia. Common grade 1 or 2 toxicities were nausea, fatigue, neutropenia, alopecia, dizziness, and dyspnea. Toxicities were managed by dose reduction and transfusions. Nine patients required dose reduction., Conclusion: Neoadjuvant single-agent oral talazoparib once per day for 6 months without chemotherapy produced substantial RCB-0 rate with manageable toxicity. The substantive pathologic response to single-agent talazoparib supports the larger, ongoing neoadjuvant trial (ClinicalTrials.gov identifier: NCT03499353).

Background: Limited data are available concerning the clinical features of toxic gastrointestinal (GI) effects of taxane-based therapy. We describe the clinical, endoscopic and histologic features of taxane-induced colitis., Methods: This retrospective study included cancer patients who received taxane therapy and underwent colonoscopy for GI symptoms from 2000-2018., Results: Of the 45,527 patients who received taxane therapy during the study period, 76 (0.2%) met the inclusion criteria. Most patients (54%) received paclitaxel, 37% docetaxel, and 9% nab-paclitaxel. The median time from taxane therapy initiation to colitis symptom onset was 31 days. The median duration of colitis symptoms was 30 days. Colitis treatment comprised immunosuppressive therapy in 8 patients (11%), antibiotics in 17 (22%), antimotility agents in 18 (24%), and octreotide or somatostatin in 2 (3%). Thirty-five patients (46%) required hospitalization and seven (9%) required admission to the intensive care unit (ICU). Endoscopy revealed mucosal ulceration in 19 patients (25%), nonulcerative inflammation in 32 (42%), and normal findings in 25 (33%). Seventeen patients (22%) had features of lymphocytic colitis. One patient had spontaneous colonic perforation that required surgical intervention. Colitis symptoms recurred in 7 patients (9%) after initial improvement. Patients who received nab-paclitaxel developed GI toxicity earlier (P=0.003), required colitis-related hospitalization more frequently (P=0.005), and received intravenous fluids more frequently (P=0.025), compared with patients who received other taxanes., Conclusions: Taxane-related colitis can present with significant inflammation on colonoscopy, and in a minority of patients as microscopic colitis. Taxane-induced colitis, although uncommon, can lead to ICU admission and colonic perforation., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)

The use of co-primary endpoints in drug development allows investigators to capture an experimental intervention's multidimensional effect more comprehensively than a single primary endpoint. We propose the theoretical basis and development of an adaptive population enrichment design with co-primary endpoints, provide stage-wise boundary values for futility and efficacy, and discuss power under different efficacy configurations, subgroup prevalence, and analysis times using a pre-specified decision criterion. We considered a two-arm, two-stage, parallel group design where population enrichment occurs at the interim analysis by dropping any non-responsive subgroups. A test for efficacy is conducted only in the enriched population. Two binary endpoints are evaluated as co-primary endpoints. Our trial objective is to determine whether the experimental intervention is superior to the control intervention, with superiority required in both endpoints. We define the stopping boundary using alpha spending functions. Using a 0.025 significance level for each endpoint, we obtain the stage I threshold boundary values for futility and efficacy as -0.1040 and 2.2761, respectively, and the stage II boundary value for futility and efficacy is 2.2419. We show that in the presence of substantial heterogeneity of treatment effect, we gain more power to observe an effect in the subgroup where the benefits are greater. By allowing the dropping of non-responsive subgroups at an early stage, our design reduces the likelihood of obtaining false-negative results due to inclusion of the heterogeneous treatment effects of both subgroups, which would dilute the responsive subgroup's results., (© 2019 John Wiley & Sons, Ltd.)

Purpose: Screening for potentially inappropriate medications (PIM) is recommended in older patients with cancer receiving chemotherapy, given the concern for adverse drug reactions, drug-drug interactions and non-adherence. Our objective was to determine the impact of PIM on outcomes in patients with breast and colorectal cancers receiving chemotherapy., Methods: We used data from the SEER-Medicare database, including patients >/= 66 years old with a diagnosis of Stage II/III breast and colorectal cancer made between 7/1/2007-12/31/2009. We used modified STOPP criteria to define baseline PIM as a dichotomous variable in the 4 months prior to diagnosis. STOPP criteria was used based on its performance as a robust measure of PIM. Outcomes measures included ER visits, hospitalizations, and death within 3 months from the last chemotherapy, and a composite of the three. We used Chi-square or Fisher's exact test to determine associations of PIM with covariates and outcomes, and Cox proportional hazards (PH) model for the time-to-event analysis., Results: Final analysis included 1,595 patients with breast cancer and 1,528 patients with colorectal cancer. Frequency of baseline PIM by STOPP was 31.5% in the breast and 30.9% in the colorectal cohort. In the breast cohort, associations with the composite outcome in the Cox PH model included disease stage, comorbidity, medication number and baseline ER visits/hospitalization. Age, gender, race, comorbidity and baseline ER visits/hospitalization were associated in the colorectal cohort. PIM was not associated with outcomes in either cohort, aside from hospitalization in the breast., Conclusions: We found no consistent association between pre-chemotherapy PIM defined by STOPP and outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The risk of colorectal neoplasia in breast cancer survivors is unclear. This study aimed to determine the colonic adenoma detection rate (ADR) in patients with breast cancer., Methods: We conducted a retrospective study of patients with breast cancer who underwent a colonoscopy between 2000 and 2017. A control group (n=3295), comprising cancer-free patients undergoing their first screening colonoscopy, was used for comparison., Results: Of 62,820 breast cancer patients, 3304 met the inclusion criteria. The mean age at the time of first colonoscopy was 59 years. ADR was 55%; 1803 patients had adenomas. High-grade dysplasia was evident in 28% of polyps and invasive adenocarcinoma was detected in 172 patients (5%). The median time from breast cancer diagnosis to adenoma detection was 3 years. The ADR was 21% in patients aged <40 years (n=63) and 39% in patients aged 40-50 years (n=314). The ADR was 26% in patients <50 years with a body mass index (BMI) lower than 30 kg/m 2 or no family history of colorectal cancer. Multivariate logistic regression analysis revealed that the following independent factors were associated with a greater risk of colon adenoma: older age, higher BMI, family history of colorectal cancer, and personal history of breast cancer., Conclusions: In patients with breast cancer, the ADR was higher than the reported rates for the general population. Screening colonoscopy should be considered soon after breast cancer diagnosis in patients <50 years of age. Further prospective studies investigating our findings are warranted., Competing Interests: Conflict of Interest: None

Purpose: Lapatinib (L) is approved in combination with capecitabine or letrozole for patients with trastuzumab-resistant HER2-positive metastatic breast cancer (MBC). However, there is no efficacy data of L in patients who received prior pertuzumab (P) and ado-trastuzumab emtansine (T-DM1), now included as standard first- and second-line therapies, respectively. The goal of this study was to assess the efficacy of L in a contemporary patient population that received prior P and/or T-DM1., Methods: We identified patients with HER2-positive MBC who received L (n = 520) between 2003 and 2017 at MD Anderson Cancer Center and selected a target cohort who received L after prior P or T-DM1 (n = 43) with the remaining included in the comparison cohort (n = 477). We evaluated outcome measures including clinical benefit rate (CBR), best tumor response (BTR), duration on L, and time to progression (TTP). Survival analyses used Kaplan-Meier statistics., Results: CBR was 28% (95% CI 10-32) for the target cohort and 40% (95% CI 36-45) for the comparison cohort. The median duration on L was 5 months (95% CI 3.0-9.0) in the target cohort and 6.7 months (5.9-8.0) in the comparison cohort. In both cohorts, the median time to progression (TTP) and overall survival (OS) were longer in patients with de novo metastatic disease compared to patients with disease recurrence., Conclusion: L-based therapy is an active therapeutic option and remains a viable option for HER2 + MBC after prior trastuzumab, P and/or T-DM1.

Background: Human epidermal growth factor 2 (HER2) is an effective therapeutic target in breast cancer; however, resistance to anti-HER2 agents such as trastuzumab and lapatinib develops. In a preclinical model, an HDAC inhibitor epigenetically reversed the resistance of cancer cells to trastuzumab and showed synergistic efficacy with lapatinib in inhibiting growth of trastuzumab-resistant HER2-positive (HER2+) breast cancer., Methods: A phase 1b, dose escalation study was performed to assess maximum tolerated dose, safety/toxicity, clinical efficacy and explored pharmacodynamic biomarkers of response to entinostat combined with lapatinib with or without trastuzumab., Results: The combination was safe. The MTD was lapatinib, 1000 mg daily; entinostat, 12 mg every other week; trastuzumab, 8 mg/kg followed by 6 mg/kg every 3 weeks. Adverse events included diarrhoea (89%), neutropenia (31%), and thrombocytopenia (23%). Neutropenia, thrombocytopenia and hypokalaemia were noted. Pharmacodynamic assessment did not yield conclusive results. Among 35 patients with evaluable response, PR was observed in 3 patients and CR in 3 patients, 1 maintained SD for over 6 months., Discussion: This study identified the MTD of the entinostat, lapatinib, and trastuzumab combination that provided acceptable tolerability and anti-tumour activity in heavily pre-treated patients with HER2+ metastatic breast cancer, supporting a confirmatory trial.

Background: OncotypeDX recurrence score (RS) ® has been found to predict recurrence and disease-free survival in patients with node negative breast cancer. Whether RS is useful in guiding locoregional therapy decisions is unclear. We sought to evaluate the relationship between RS and lymph node burden., Methods: Patients with invasive breast cancer who underwent sentinel lymph node dissection from 2010 to 2015 were identified from a prospectively maintained database. Patients were excluded if they were clinically node positive or if they received neoadjuvant chemotherapy. RS was classified as low (< 18), intermediate (18-30), or high (> 30). The association between RS, lymph node burden, and disease recurrence was evaluated. Statistical analyses were performed in R version 3.4.0; p < 0.05 was considered significant., Results: A positive SLN was found in 168 (15%) of 1121 patients. Completion axillary lymph node dissection was performed in 84 (50%) of SLN-positive patients. The remaining 84 (50%) patients had one to two positive SLNs and did not undergo further axillary surgery. RS was low in 58.5%, intermediate in 32.6%, and high in 8.9%. RS was not associated with a positive SLN, number of positive nodes, maximum node metastasis size, or extranodal extension. The median follow-up was 23 months. High RS was not associated with locoregional recurrence (p = 0.07) but was significantly associated with distant recurrence (p = 0.0015)., Conclusions: OncotypeDX RS is not associated with nodal burden in women with clinically node-negative breast cancer, suggesting that RS is not useful to guide decisions regarding extent of axillary surgery for these patients.

Background: An increasing proportion of human epidermal growth receptor 2 (HER2) positive (HER2+) metastatic breast cancer (MBC) is diagnosed as de novo stage IV disease. We hypothesize that a subset of these patients who achieve no evidence of disease (NED) status after multimodality HER2-targeted treatments may have prolonged progression-free survival (PFS) and overall survival (OS)., Materials and Methods: Patients with de novo stage IV, HER2+ MBC ( n = 483) diagnosed between 1998 and 2015 were identified at two institutions (Yale and MD Anderson Cancer Centers). Clinical variables, treatment details, and survival outcomes were compared between those who achieved NED and those who did not., Results: All patients received trastuzumab, and 20% also received pertuzumab as first-line therapy. The median OS was 5.5 years (95% confidence interval [Cl]: 4.8-6.2). Sixty-three patients (13.0%) achieved NED; their PFS and OS rates were 100% and 98% (95% CI: 94.6%-100%), respectively, at 5 years and remained the same at 10 years. For patients with no NED ( n = 420), the PFS and OS rates were 12% (95% CI: 4.5%-30.4%) and 45% (95% CI: 38.4%-52.0%) at 5 years and 0% and 4% (95% CI, 1.3%-13.2%) at 10 years, respectively. NED patients more frequently had solitary metastasis (79% vs. 51%, p = .005) and surgery to resect cancer (59% vs. 22%, p ≤ .001). In multivariate analysis, NED status (hazard ratio [HR]: 0.014, p = .0002) and estrogen receptor positive status (HR: 0.72; p = .04) were associated with prolonged OS., Conclusion: Among patients with de novo stage IV, HER2+ MBC, those who achieve NED status have a very high PFS and OS. Further randomized studies are required to fully understand the impact of systemic or locoregional therapy on achieving these excellent long-term outcomes., Implications for Practice: In this retrospective review at two institutions, it was demonstrated that 13% of patients with de novo stage IV, human epidermal growth receptor 2 positive metastatic breast cancer achieved no evidence of disease (NED) status with trastuzumab-based therapy plus/minus local therapies, and these patients had a very high progression-free survival (100%) and overall survival (98%) at both the 5- and 10-year time points. Achieving NED status may be an important therapeutic goal. However, further randomized studies are required to fully understand the impact of systemic or locoregional therapy on achieving these excellent long-term outcomes., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Objective: To determine the relationship between negative margin width and locoregional recurrence (LRR) in a contemporary cohort of ductal carcinoma in situ (DCIS) patients., Background: Recent national consensus guidelines recommend an optimal margin width of 2 mm or greater for the management of DCIS; however, controversy regarding re-excision remains when managing negative margins <2 mm., Methods: One thousand four hundred ninety-one patients with DCIS who underwent breast-conserving surgery from 1996 to 2010 were identified from a prospectively managed cancer center database and analyzed using univariate and multivariate Cox proportional hazard models to determine the relationship between negative margin width and LRR with or without adjuvant radiation therapy (RT)., Results: A univariate analysis revealed that age <40 years (n = 89; P = 0.02), no RT (n = 298; P = 0.01), and negative margin width <2 mm (n = 120; P = 0.005) were associated with LRR. The association between margin width and LRR differed by adjuvant RT status (interaction P = 0.02). There was no statistical significant difference in LRR between patients with <2 mm and ≥2 mm negative margins who underwent RT (10-yr LRR rate, 4.8% vs 3.3%, respectively; hazard ratio, 0.8; 95% CI, 0.2-3.2; P = 0.72). For patients who did not undergo RT, those with margins <2 mm were significantly more likely to develop a LRR than were those with margins ≥2 mm (10-yr LRR rate, 30.9% vs 5.4%, respectively; hazard ratio, 5.5; 95% CI, 1.8-16.8, P = 0.003)., Conclusions: Routine additional surgery may not be justified for patients with negative margins <2 mm who undergo RT but should be performed in patients who forego RT.

Introduction: Several human epidermal growth factor 2 (HER2)-targeted regimens are used to treat HER2-positive (HER2 + ) breast cancer (BC). The goal of this study was to retrospectively determine the pathologic complete response (pCR) rate for trastuzumab and pertuzumab (HP)-containing regimens compared with trastuzumab (H)-containing regimens for stage II to III HER2 + BC., Patients and Methods: Patients (n = 977) with stage II to III HER2 + BC who received neoadjuvant HER2-targeted therapy from 2005 to 2016 and underwent definitive breast and axillary lymph node surgery were identified. pCR was defined as ypT0/is, ypN0. Univariate/multivariate logistic regression and the χ 2 test for comparing proportions was used for the statistical analysis., Results: The pCR rate was higher for the HP group (n = 170) compared with the H group (n = 807): 59% versus 46% (odds ratio, 1.7; 95% confidence interval, 1.21-2.37; P = .0021). After adjustment for clinically important factors (age, date of diagnosis, stage, tumor grade, nodal status, hormone receptor [HR] status, menopausal status, and chemotherapy backbone) the adjusted odds ratio was 2.25 (95% confidence interval, 1.08-4.73; P = .032). In multivariate analysis, a significant predictor of pCR in both groups included HR status (HR-negative > HR-positive)., Conclusion: These results demonstrate that HP-containing regimens yield higher pCR rates compared with H-containing regimens in patients with stage II to III HER2 + BC in clinical practice regardless of chemotherapy backbone., (Copyright © 2018 Elsevier Inc. All rights reserved.)