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© 2015 Galbán et al.Purpose: To evaluate diffusion weighted MRI (DW-MR) as a response metric for assessment of neoadjuvant chemotherapy (NAC) in patients with primary breast cancer using prospective multi-center trials which provided MR scans along with cl

The purpose of this study was to determine the maximum tolerated dose (MTD) of gemcitabine when given concurrently with standard radiotherapy for the treatment of chest wall recurrences, and to compare actuarial rates of local-regional control with those achieved in historical controls. Patients with unresectable chest wall recurrences were enrolled in a phase I trial of concurrent gemcitabine and radiotherapy. Gemcitabine was increased at 150 mg/m2/week increments, starting at 300 mg/m2/ week. Radiotherapy was delivered to the chest wall and regional nodes to a total of 60 to 70 Gy in 2 Gy daily fractions. Treatment toxicity was assessed and a comparison of treatment outcome was performed between study patients and historical groups treated with either radiotherapy alone or excision followed by radiotherapy. The dose-limiting toxicities of neutropenia and thrombocytopenia occurred at the second planned dose of 450 mg/m2/week after accrual of only six patients, resulting in a MTD of 300 mg/m2/ week. Myelosuppression and skin desquamation were commonly observed. Actuarial rates of local-regional control were 100%, 50%, and 90% at 2 years for the gemcitabine with radiotherapy, radiotherapy alone, and excision followed by radiotherapy groups, respectively (p = 0.105).The difference among the Kaplan-Meier curves for overall local-regional control was statistically significant at p = 0.007 in favor of combined gemcitabine and radiotherapy. The MTD of gemcitabine is 300 mg/m2/week when gemcitabine is delivered concurrently with radiotherapy for unresectable chest wall failures. This novel approach suggests excellent local-regional control when compared to historical controls. A phase II trial is warranted. [ABSTRACT FROM AUTHOR]

Background: The phase III RxPONDER trial has impacted treatment for node-positive(1-3), hormone receptor-positive, HER2-negative breast cancer with 21-gene recurrence score (RS) ≤ 25. We investigated how these findings apply to different racial and ethnic groups within the trial., Methods: The trial randomized women to endocrine therapy (ET) or to chemotherapy plus ET. The primary clinical outcome was invasive disease-free survival (IDFS) with distant relapse-free survival (DRFS) as a secondary outcome. Multivariable Cox models were used to evaluate the association between race/ethnicity and survival outcomes, adjusting for clinicopathologic characteristics, RS, and treatment., Results: A total of 4,048 women with self-reported race/ethnicity were included: Hispanic (15.1%), non-Hispanic Black (NHB)(6.1%), Native American/Pacific Islander (0.8%), Asian (8.0%), and non-Hispanic White (NHW)(70%). No differences in RS distribution, tumor size, or number of positive nodes were observed by race/ethnicity. Relative to NHWs, IDFS was worse for NHBs (5-year IDFS 91.6% vs 87.1%, HR = 1.37; 95% CI 1.03-1.81) and better for Asians (91.6% vs 93.9%, HR = 0.64; 95% CI 0.46-0.91). Relative to NHW, DRFS was worse for NHBs (5-year DRFS 95.8% vs 91.0%, HR = 1.65; 95% CI 1.17-2.32) and better for Asians (95.8% vs 96.7%, HR = 0.59; 95% CI 0.37-0.95). Adjusting for clinical characteristics, particularly body mass index, diminished the effect of race on outcomes. Chemotherapy treatment efficacy did not differ by race/ethnicity., Conclusions: NHB women had worse clinical outcomes compared to NHWs in the RxPONDER trial despite similar RS and comparable treatment. Our study emphasizes the persistent racial disparities in breast cancer outcomes while highlighting complex interactions among contributing factors., Trial Registration: ClinicalTrials.gov: NCT01272037., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Although barriers to trial accrual are well-reported, few studies have explored trial eligibility and trial offers as potential drivers of disparities in cancer clinical trial enrollment., Methods: We identified patients with gastrointestinal (GI) or head/neck (HN) malignancies who were seen as new patients at the University of Michigan Health Rogel Cancer Center in 2016. By exhaustive review of the electronic medical record, we assessed the primary outcomes: (1) eligibility for, (2) documented offer of, and (3) enrollment in a clinical trial. All 41 of the clinical trials available to these patients were considered. Independent variables included clinical and non-clinical patient-related factors. We assessed associations between these variables and the primary outcomes using multivariable regression., Results: Of 1446 patients, 43% were female, 15% were over age 75, 6% were Black. 305 (21%) patients were eligible for a clinical trial. Among eligible patients, 154 (50%) had documentation of a trial offer and 90 (30%) enrolled. Among the GI cohort, bivariate analyses demonstrated that older age was associated with decreased trial eligibility. Bivariate analyses also demonstrated that Black race was associated with increased trial offer. After adjustment, patients 75 or older were less likely to be eligible for a clinical trial in the GI cohort; however, we found no significant associations between race and any of the outcomes after adjustment. Among eligible GI patients, we found no significant associations between non-clinical factors and enrollment. Among the HN cohort, bivariate analyses demonstrated that female sex, older age, Black race, and unpartnered marital status were associated with decreased likelihood of trial offer; however, we found no significant associations between race, age, and marital status and any of the outcomes after adjustment. We found no significant associations between non-clinical factors and eligibility after adjustment; however, women were less likely to be offered and to enroll in a clinical trial in the HN cohort., Conclusion: Factors associated with eligibility, documented offer, and enrollment differed between disease site cohorts at our institution. Future work is needed to ensure the equitable inclusion of women and elderly patients in clinical trials., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Clinical trials are critical components of modern health care and infrastructure. Trials benefit society through scientific advancement and individual patients through trial participation. In fact, billions of dollars are spent annually in support of these benefits. Despite the massive investments, clinical trials often fail to accomplish their primary aims and trial enrollment rates remain low. Prior efforts to improve trial conduct and enrollment have had limited success, perhaps due to oversimplification of the complex, multilevel nature of trials. For these reasons, the authors propose applying implementation science to the clinical trials context. In this commentary, the authors posit clinical trials as complex, multilevel evidence-based interventions with significant societal and individual benefits yet with persistent gaps in implementation. An application of implementation science concepts to the clinical trials context as means to build common vocabulary and establish a platform for applying implementation science and practice to improve clinical trial conduct is introduced. Applying implementation science to the clinical trials context can augment improvement efforts and build capacity for better and more efficient evidence-based care for all patients and trial stakeholders throughout the clinical trials enterprise., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: Metastatic hormone receptor (HR)-positive, HER2-negative breast cancer is an important cause of cancer mortality. Endocrine treatment with or without additional targeted therapies has been the mainstay of treatment. This trial was designed to evaluate the combination of fulvestrant plus everolimus versus fulvestrant, everolimus, and anastrozole compared with fulvestrant alone in the first-line treatment of advanced HR-positive, HER2-negative breast cancer., Patients and Methods: This randomized placebo-controlled trial included postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had received no prior systemic therapy for metastatic disease. Participants were randomized to one of three treatment arms and the primary outcome was progression-free survival (PFS), comparing combinations of fulvestrant and everolimus with or without anastrozole with fulvestrant alone. Circulating tumor cells (CTC), as measured with two different methods, and circulating tumor DNA (ctDNA) were evaluated serially prior to treatment and the beginning of the second cycle of therapy., Results: Due in part to changes in clinical practice, the study was closed after accruing only 37 participants. There was no evidence that everolimus-containing combination treatment improved PFS or overall survival relative to fulvestrant alone. When modeled continuously, an association was observed of baseline CTC and ctDNA with poorer survival., Conclusions: Although power of the study was limited, the findings were unable to support the routine use of everolimus combination endocrine therapy in the first-line treatment of advanced hormone-sensitive breast cancer. Prognostic impact of baseline ctDNA and copy-number variations in CTC was demonstrated., (©2021 American Association for Cancer Research.)

Background: The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary lymph-node-negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear., Methods: In a prospective trial, we randomly assigned women with hormone-receptor-positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease-free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse-free survival., Results: A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease-free survival differed according to menopausal status (P = 0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease-free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P = 0.89). Among premenopausal women, invasive disease-free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P = 0.002), with a similar increase in distant relapse-free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P = 0.009). The relative chemotherapy benefit did not increase as the recurrence score increased., Conclusions: Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease-free survival and distant relapse-free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037.)., (Copyright © 2021 Massachusetts Medical Society.)

Purpose: CXCR1, one of the receptors for CXCL8, has been identified as a druggable target on breast cancer cancer stem cells (CSC). Reparixin (R), an investigational oral inhibitor of CXCR1, was safely administered to metastatic breast cancer patients in combination with paclitaxel (P) and appeared to reduce CSC in a window-of-opportunity trial in operable breast cancer. The fRida trial (NCT02370238) evaluated the addition of R to weekly as first-line therapy for metastatic (m) TNBC., Subjects and Methods: Subjects with untreated mTNBC were randomized 1:1 to R or placebo days 1-21 in combination with weekly P 80 mg/m 2 on days 1, 8, 15 of 28-day cycles. The primary endpoint was PFS by central review., Results: 123 subjects were randomized (62 to R + P and 61 to placebo + P). PFS was not different between the 2 groups (median 5.5 and 5.6 months for R + P and placebo + P, respectively; HR 1.13, p = 0.5996). ALDH + and CD24 - /CD44 + CSC centrally evaluated by IHC were found in 16 and 34 of the 54 subjects who provided a metastatic tissue biopsy at study entry. Serious adverse events (21.3 and 20% of subjects) and grade ≥ 3 adverse reactions (ADR) (9.1 and 6.3% of all ADRs) occurred at similar frequency in both groups., Conclusion: fRida is the first randomized, double-blind clinical trial of a CSC-targeting agent in combination with chemotherapy in breast cancer. The primary endpoint of prolonged PFS was not met., Clinical Trial Registration/date of Registration: NCT01861054/February 24, 2015., (© 2021. The Author(s).)

Purpose: We developed and tested a multi-level intervention, ConnectedCancerCare (CCC), which includes a tailored website and appointment reminder system for women with early-stage breast cancer and a provider summary letter sent to their medical oncologist and primary care provider to improve the delivery of team-based survivorship care., Methods: We conducted a pilot randomized controlled trial to establish the feasibility and acceptability of CCC. Women diagnosed with stages 0-II breast cancer within one year of completing primary treatment were randomized to CCC (intervention) or a static online survivorship care plan (control). Participants completed baseline and 3-month follow-up surveys online. Post-trial interviews with 5 PCPs, 6 oncology providers, and 8 intervention patients were conducted., Results: Of the 160 eligible women invited to participate, 66 completed the baseline survey and were randomized (41%) and 54 completed a follow-up survey (83%). Participants in the intervention arm found the CCC content to be acceptable, with 82% reporting it was easy to use and 86% reporting they would recommend it to other patients. Women randomized to CCC (vs. control) more often reported scheduling a PCP follow-up visit (64% vs. 42%), communicating with their PCP about provider roles (67% vs. 18%), and higher mean team-based cancer care knowledge scores (3.7 vs. 3.4)., Conclusion: Deploying CCC in medical oncology practices was feasible, and the intervention content was acceptable. CCC shows promise for improving patient knowledge and patient-provider communication about provider roles in team-based cancer care and encouraging patients to engage with their PCP early in the survivorship period., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: Use of next-generation sequencing (NGS) to identify clinically actionable genomic targets has been incorporated into routine clinical practice in the management of advanced solid tumors; however, the clinical utility of this testing remains uncertain., Objective: To determine which patients derived the greatest degree of clinical benefit from NGS profiling., Design, Setting, and Participants: Patients in this cohort study underwent fresh tumor biopsy and blood sample collection for genomic profiling of paired tumor and normal DNA (whole-exome or targeted-exome capture with analysis of 1700 genes) and tumor transcriptome (RNA) sequencing. Somatic and germline genomic alterations were annotated and classified according to degree of clinical actionability. Results were returned to treating oncologists. Data were collected from May 1, 2011, to February 28, 2018, and analyzed from May 1, 2011, to April 30, 2020., Main Outcomes and Measures: Patients' subsequent therapy and treatment response were extracted from the medical record to determine clinical benefit rate from NGS-directed therapy at 6 months and exceptional responses lasting 12 months or longer., Results: During the study period, NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%) (MET1000 cohort) (538 men [53.0%]; mean [SD] age, 57.7 [13.3] years). Potentially clinically actionable genomic alterations were discovered in 817 patients (80.5%). Of these, 132 patients (16.2%) received sequencing-directed therapy, and 49 had clinical benefit (37.1%). Exceptional responses were observed in 26 patients (19.7% of treated patients). Pathogenic germline variants (PGVs) were identified in 160 patients (15.8% of cohort), including 49 PGVs (4.8% of cohort) with therapeutic relevance. For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), and sequencing-directed therapy in 13 patients resulted in clinical benefit in 7 instances (53.8%), including 5 exceptional responses., Conclusions and Relevance: The high rate of therapeutically relevant PGVs identified across diverse cancer types supports a recommendation for directed germline testing in all patients with advanced cancer. The high frequency of therapeutically relevant somatic and germline findings in patients with carcinoma of unknown primary origin and other rare cancers supports the use of comprehensive NGS profiling as a component of standard of care for these disease entities.

Background: Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) negatively impact adherence to and persistence with therapy. In SWOG S1202, patients with AIMSS who were treated with duloxetine, a serotonin norepinephrine reuptake inhibitor, reported improvement in pain by 12 weeks compared with placebo. Based on the authors' prior observation that responses to pain interventions differ between obese and nonobese patients, the current study examined whether response to duloxetine therapy differed by obesity status., Methods: In SWOG S1202, a total of 299 AI-treated postmenopausal women with stage I to III (AJCC 7th Edition) breast cancer who developed new or worsening average pain were enrolled, randomized to duloxetine or placebo, and treated for 12 weeks. Patient-reported outcomes were obtained at baseline and through 12 weeks. Patients were categorized into nonobese (body mass index [BMI] <30 kg/m 2 ) or obese (BMI ≥30 kg/m 2 ). The authors tested the interaction between intervention and obesity with respect to average pain at 12 weeks in the 289 eligible patients, using a P value of .05 to indicate statistical significance., Results: In approximately 54% of evaluable patients with a BMI ≥30 kg/m 2 , the reduction in the mean average pain score between baseline and 12 weeks was statistically significantly greater for patients treated with duloxetine compared with those receiving placebo (-2.73 vs -1.64 points; P = .003). Conversely, in the nonobese patients, the reduction in the mean average pain score was similar in the 2 cohorts (-2.46 vs -2.34 points; P = .75). The P value for interaction was .02, thereby meeting the threshold criteria of the current study. Similar findings were evident for other pain-related patient-reported outcomes., Conclusions: In this trial, obese patients with AIMSS obtained more analgesic benefit from duloxetine compared with nonobese patients. Additional studies are warranted to determine the biologic basis for these findings., (© 2019 American Cancer Society.)

Purpose: Extending adjuvant endocrine therapy (ET) beyond 5 years has been shown to improve outcomes in breast cancer; however, limited data are available about if and why women pursue extended ET. The primary objective was to estimate the proportion of women who were willing to receive extended ET if recommended by their physician and secondarily, to determine what factors were associated with this decision., Methods: This descriptive cross-sectional study surveyed 131 women with AJCC 7th Edition stages I-III breast cancer who had been taking adjuvant ET for 3-5 years. The survey inquired about the willingness to continue ET, quality of life (FACT-ES), and beliefs about medications (BMQ). Logistic regression was used to test for associations between clinical and disease factors, FACT-ES, BMQ, and the primary outcome., Results: One hundred and twelve (85%) patients reported "moderate" (n = 30, 23%), "quite a bit" (n = 41, 31%), or "extreme" (n = 41, 31%) willingness to pursue extended ET; 19 (14%) patients were "not at all" or were "unlikely" to be willing to take extended ET. On univariate analysis, lower total and social well-being FACT-ES scores, and lower perceived necessity and higher concerns on BMQ were associated with lower willingness to pursue extended ET. On multivariable analysis, greater patient perception of necessity of ET was the only factor associated with willingness to pursue extended ET (OR 1.34, 95% CI 1.15-1.57, p = 0.0005)., Conclusions: Most women who have taken ET for multiple years report being willing to pursue extended ET if recommended. When discussing extended ET, the data from this study support exploring patients' belief of medication necessity.

Aim: First, evaluate if patients carrying putatively diminished activity CYP2C8 genotype have longer paclitaxel exposure (e.g., time above threshold concentration of 0.05 μM [T c >0.05 ]). Second, screen additional pharmacogenes for associations with T c >0.05 . Methods: Pharmacogene panel genotypes were translated into genetic phenotypes for associations with T c >0.05 (n = 58)., Results: Patients with predicted low-activity CYP2C8 had shorter T c >0.05 after adjustment for age, body surface area and race (9.65 vs 11.03 hrs, β = 5.47, p = 0.02). This association was attributed to CYP2C8*3 (p = 0.006), not CYP2C8*4 (p = 0.58). Patients with predicted low-activity SLCO1B1 had longer T c >0.05 (12.12 vs 10.15 hrs, β = 0.85, p = 0.012)., Conclusion: Contrary to previous publications, CYP2C8*3 may confer increased paclitaxel metabolic activity. SLCO1B1 and CYP2C8 genotype may explain some paclitaxel pharmacokinetic variability.

Purpose: Paclitaxel exposure, specifically the maximum concentration ( C max ) and amount of time the concentration remains above 0.05 μmol/L ( T c >0.05 ), has been associated with the occurrence of paclitaxel-induced peripheral neuropathy. The objective of this study was to validate the relationship between paclitaxel exposure and peripheral neuropathy. Experimental Design: Patients with breast cancer receiving paclitaxel 80 mg/m 2 × 12 weekly doses were enrolled in an observational clinical study (NCT02338115). Paclitaxel plasma concentration was measured at the end of and 16-26 hours after the first infusion to estimate C max and T c >0.05 Patient-reported peripheral neuropathy was collected via CIPN20 at each dose, and an 8-item sensory subscale (CIPN8) was used in the primary analysis to test for an association with T c >0.05 Secondary analyses were conducted using C max as an alternative exposure parameter and testing each parameter with a secondary endpoint of the occurrence of peripheral neuropathy-induced treatment disruption. Results: In 60 subjects included in the analysis, the increase in CIPN8 during treatment was associated with baseline CIPN8, cumulative dose, and relative dose intensity ( P < 0.05), but neither T c >0.05 ( P = 0.27) nor C max ( P = 0.99). In analyses of the secondary endpoint, cumulative dose (OR = 1.46; 95% confidence interval (CI), 1.18-1.80; P = 0.0008) and T c >0.05 (OR = 1.79; 95% CI, 1.06-3.01; P = 0.029) or C max (OR = 2.74; 95% CI, 1.45-5.20; P = 0.002) were associated with peripheral neuropathy-induced treatment disruption. Conclusions: Paclitaxel exposure is predictive of the occurrence of treatment-limiting peripheral neuropathy in patients receiving weekly paclitaxel for breast cancer. Studies are warranted to determine whether exposure-guided dosing enhances treatment effectiveness and/or prevents peripheral neuropathy in these patients. Clin Cancer Res; 24(15); 3602-10. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Purpose Locoregional control for inflammatory breast cancers and chest wall recurrences is suboptimal, which has motivated interest in radiosensitization to intensify therapy. Preclinical studies have suggested a favorable therapeutic index when poly (ADP-ribose) polymerase inhibitors are used as radiosensitizers; clinical investigation is necessary to establish appropriate dosing and confirm safety. Patients and Methods We conducted a multi-institutional phase I study of veliparib and concurrent radiotherapy (RT) to the chest wall and regional lymph nodes in 30 patients with inflammatory or locally recurrent breast cancer after complete surgical resection. RT consisted of 50 Gy to the chest wall and regional lymph nodes plus a 10-Gy boost. A Bayesian time-to-event continual reassessment method escalated dose through four levels, with a 30% targeted rate of dose-limiting toxicity (DLT) measured during the 6 weeks of treatment plus 4 weeks of follow-up. DLTs were defined as confluent moist desquamation > 100 cm 2 , nonhematologic toxicity grade ≥ 3, toxicity that requires an RT dose delay > 1 week, absolute neutrophil count < 1,000/mm 3 , platelet count < 50,000/mm 3 , or hemoglobin < 8.0 g/dL if possibly, probably, or definitely related to study treatment. Results Five DLTs occurred: Four were moist desquamation (two each at 100 and 150 mg twice a day), and one was neutropenia (at 200 mg twice a day). The crude rate of any grade 3 toxicity (regardless of attribution) was 10% at year 1, 16.7% at year 2, and 46.7% at year 3. At year 3, six of 15 surviving patients had severe fibrosis in the treatment field. Conclusion Although severe acute toxicity did not exceed 30% even at the highest tested dose, nearly half of surviving patients demonstrated grade 3 adverse events at 3 years, which underscores the importance of long-term monitoring of toxicity in trials of radiosensitizing agents.

Addressing drug resistance is a core challenge in cancer research, but the degree of heterogeneity in resistance mechanisms in cancer is unclear. In this study, we conducted next-generation sequencing (NGS) of circulating tumor cells (CTC) from patients with advanced cancer to assess mechanisms of resistance to targeted therapy and reveal opportunities for precision medicine. Comparison of the genomic landscapes of CTCs and tissue metastases is complicated by challenges in comprehensive CTC genomic profiling and paired tissue acquisition, particularly in patients who progress after targeted therapy. Thus, we assessed by NGS somatic mutations and copy number alterations (CNA) in archived CTCs isolated from patients with metastatic breast cancer who were enrolled in concurrent clinical trials that collected and analyzed CTCs and metastatic tissues. In 76 individual and pooled informative CTCs from 12 patients, we observed 85% concordance in at least one or more prioritized somatic mutations and CNA between paired CTCs and tissue metastases. Potentially actionable genomic alterations were identified in tissue but not CTCs, and vice versa. CTC profiling identified diverse intra- and interpatient molecular mechanisms of endocrine therapy resistance, including loss of heterozygosity in individual CTCs. For example, in one patient, we observed CTCs that were either wild type for ESR1 ( n = 5/32), harbored the known activating ESR1 p.Y537S mutation ( n = 26/32), or harbored a novel ESR1 p.A569S ( n = 1/32). ESR1 p.A569S was modestly activating in vitro , consistent with its presence as a minority circulating subclone. Our results demonstrate the feasibility and potential clinical utility of comprehensive profiling of archived fixed CTCs. Tissue and CTC genomic assessment are complementary, and precise combination therapies will likely be required for effective targeting in advanced breast cancer patients. Significance: These findings demonstrate the complementary nature of genomic profiling from paired tissue metastasis and circulating tumor cells from patients with metastatic breast cancer. Cancer Res; 78(4); 1110-22. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Purpose Adherence to aromatase inhibitor (AI) therapy for early-stage breast cancer is limited by AI-associated musculoskeletal symptoms (AIMSS). Duloxetine is US Food and Drug Administration approved for treatment of multiple chronic pain disorders. We hypothesized that treatment of AIMSS with duloxetine would improve average joint pain compared with placebo. Methods This randomized, double-blind, phase III trial included AI-treated postmenopausal women with early-stage breast cancer and who had average joint pain score of ≥ 4 out of 10 that developed or worsened since AI therapy initiation. Patients were randomly assigned 1:1 to duloxetine or placebo for 13 weeks. The primary end point was average joint pain through 12 weeks, examined using multivariable linear mixed models, adjusted for stratification factors (baseline pain score of 4 to 6 v 7 to 10 and prior taxane use). Clinically significant change in average pain was defined as a ≥ 2-point decrease from baseline. Results Of 299 enrolled patients, 127 patients treated with duloxetine and 128 who received placebo were evaluable for the primary analysis. By 12 weeks, the average joint pain score was 0.82 points lower for patients who received duloxetine compared with those who received placebo (95% CI, -1.24 to -0.40; P = .0002). Similar patterns were observed for worst joint pain, joint stiffness, pain interference, and functioning. Rates of adverse events of any grade were higher in the duloxetine-treated group (78% v 50%); rates of grade 3 adverse events were similar. Conclusion Results of treatment with duloxetine for AIMSS were superior to those of placebo among women with early-stage breast cancer, although it resulted in more frequent low-grade toxicities.

Purpose: Chemokine receptor 1 (CXCR1) is recognized as an actionable receptor selectively expressed by breast cancer stem cells (BCSCs). Reparixin is an investigational allosteric inhibitor of chemokine receptors 1 and 2 (CXCR1/2), and demonstrates activity against BCSCs in human breast cancer xenografts. This phase Ib clinical trial examined dose, safety, and pharmacokinetics of paclitaxel plus reparixin therapy, and explored effects of reparixin on BCSCs in patients with metastatic breast cancer (MBC) (trial registration ID: NCT02001974). Experimental Design: Eligible patients had MBC and were candidates for paclitaxel therapy. Study treatment included a 3-day run-in with reparixin oral tablets three times a day, followed by paclitaxel 80 mg/m 2 /week (days 1, 8, and 15 for 28-day cycle) + reparixin tablets three times a day for 21/28 days; three dose cohorts were examined in a 3+3 dose escalation schema. Additional patients were recruited into an expansion cohort at the recommended phase II dose to further explore pharmacokinetics, safety, and biological effects of the combination therapy. Results: There were neither G4-5 adverse events nor serious adverse events related to study therapy and no interactions between reparixin and paclitaxel to influence their respective pharmacokinetic profiles. A 30% response rate was recorded, with durable responses >12 months in two patients. Exploratory biomarker analysis was inconclusive for therapy effect on BCSCs. Conclusions: Weekly paclitaxel plus reparixin in MBC appeared to be safe and tolerable, with demonstrated responses in the enrolled population. Dose level 3, 1200 mg orally three times a day, was selected for further study in a randomized phase II trial (NCT02370238). Clin Cancer Res; 23(18); 5358-65. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Metastasis is the primary cause of cancer-related deaths. Although The Cancer Genome Atlas has sequenced primary tumour types obtained from surgical resections, much less comprehensive molecular analysis is available from clinically acquired metastatic cancers. Here we perform whole-exome and -transcriptome sequencing of 500 adult patients with metastatic solid tumours of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53, CDKN2A, PTEN, PIK3CA, and RB1. Putative pathogenic germline variants were present in 12.2% of cases of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing to identify gene fusions, pathway activation, and immune profiling. Our results show that integrative sequence analysis provides a clinically relevant, multi-dimensional view of the complex molecular landscape and microenvironment of metastatic cancers.

Neutrophils, the most abundant type of leukocytes in blood, can form neutrophil extracellular traps (NETs). These are pathogen-trapping structures generated by expulsion of the neutrophil's DNA with associated proteolytic enzymes. NETs produced by infection can promote cancer metastasis. We show that metastatic breast cancer cells can induce neutrophils to form metastasis-supporting NETs in the absence of infection. Using intravital imaging, we observed NET-like structures around metastatic 4T1 cancer cells that had reached the lungs of mice. We also found NETs in clinical samples of triple-negative human breast cancer. The formation of NETs stimulated the invasion and migration of breast cancer cells in vitro. Inhibiting NET formation or digesting NETs with deoxyribonuclease I (DNase I) blocked these processes. Treatment with NET-digesting, DNase I-coated nanoparticles markedly reduced lung metastases in mice. Our data suggest that induction of NETs by cancer cells is a previously unidentified metastasis-promoting tumor-host interaction and a potential therapeutic target., (Copyright © 2016, American Association for the Advancement of Science.)

Fulvestrant is a dose dependent selective estrogen receptor (ER) down-regulator (SERD) used in ER-positive metastatic breast cancer (MBC). Nearly all patients develop resistance. We performed molecular analysis of circulating tumor cells (CTC) to gain insight into fulvestrant resistance. Preclinical studies were performed with cultured breast cancer cells spiked into human blood and analyzed on the CellSearch(®) system. Clinical data are limited to a subset of patients with ER-positive MBC from a previously reported pilot trial whose disease was progressing on fulvestrant (N = 7) or aromatase inhibitors (AIs) (N = 10). CTCs were enumerated and phenotyped for ER and B-cell lymphoma (BCL2) using the CellSearch(®) CXC kit. In preclinical modeling, tamoxifen and AIs resulted in stabilized ER expression, whereas fulvestrant eliminated it. Five of seven patients progressing on fulvestrant had ≥5CTC/7.5 ml WB. Two of these five, treated with 500 mg/month fulvestrant, had no detectable CTC-expression of ER and BCL2 (an ER regulated gene). Three patients had heterogeneous CTC-ER and BCL2 expression indicating incomplete degradation of the ER target by fulvestrant. Two of these patients received 250 mg/month whereas the third patient received 500 mg/month fulvestrant. Her cancer harbored a mutation (Y537S) in the estrogen receptor alpha gene (ESR1). All seven ER positive patients progressing on AIs had heterogeneous CTC-ER expression. These results suggest heterogeneous mechanisms of resistance to fulvestrant, including insufficient dosage, ESR1 mutation, or conversion to dependence on non-ER pathways. CTC enumeration, phenotyping, and genotyping might identify patients who would benefit from fulvestrant dose escalation versus switching to alternative therapies., (Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

SWOG S0800, a randomized open-label Phase II clinical trial, compared the combination of weekly nab-paclitaxel and bevacizumab followed by dose-dense doxorubicin and cyclophosphamide (AC) with nab-paclitaxel followed or preceded by AC as neoadjuvant treatment for HER2-negative locally advanced breast cancer (LABC) or inflammatory breast cancer (IBC). Patients were randomly allocated (2:1:1) to three neoadjuvant chemotherapy arms: (1) nab-paclitaxel with concurrent bevacizumab followed by AC; (2) nab-paclitaxel followed by AC; or (3) AC followed by nab-paclitaxel. The primary endpoint was pathologic complete response (pCR) with stratification by disease type (non-IBC LABC vs. IBC) and hormone receptor status (positive vs. negative). Overall survival (OS), event-free survival (EFS), and toxicity were secondary endpoints. Analyses were intent-to-treat comparing bevacizumab to the combined control arms. A total of 215 patients were accrued including 11 % with IBC and 32 % with triple-negative breast cancer (TNBC). The addition of bevacizumab significantly increased the pCR rate overall (36 vs. 21 %; p = 0.019) and in TNBC (59 vs. 29 %; p = 0.014), but not in hormone receptor-positive disease (24 vs. 18 %; p = 0.41). Sequence of administration of nab-paclitaxel and AC did not affect the pCR rate. While no significant differences in OS or EFS were seen, a trend favored the addition of bevacizumab for EFS (p = 0.06) in TNBC. Overall, Grade 3-4 adverse events did not differ substantially by treatment arm. The addition of bevacizumab to nab-paclitaxel prior to dose-dense AC neoadjuvant chemotherapy significantly improved the pCR rate compared to chemotherapy alone in patients with triple-negative LABC/IBC and was accompanied by a trend for improved EFS. This suggests reconsideration of the role of bevacizumab in high-risk triple-negative locally advanced breast cancer.

Bone metastases from breast cancer are common, causing significant morbidity. Preclinical data of dasatinib, an oral small molecule inhibitor of multiple oncogenic tyrosine kinases, suggested efficacy in tumor control and palliation of bone metastases in metastatic breast cancer (MBC). This clinical trial aimed to determine whether treatment with either of 2 dose schedules of dasatinib results in a progression-free survival (PFS) >50 % at 24 weeks in bone metastasis predominant MBC, to evaluate the toxicity of the 2 dosing regimens, and explore whether treatment results in decreased serum bone turnover markers and patient-reported "worst pain." Subjects with bone metastasis predominant MBC were randomly assigned to either 100 mg of dasatinib once daily, or 70 mg twice daily, with treatment continued until time of disease progression or intolerable toxicity. Planned accrual was 40 patients in each arm. The primary trial endpoint was PFS, defined as time from registration to progression or death due to any cause. Median PFS for all eligible patients (79) was 12.6 weeks (95 % CI 9.1-16.7). Neither cohort met the threshold for further clinical interest. There were no significant differences in PFS by randomized treatment arm (p = 0.85). Toxicity was similar in both cohorts, with no clear trend in serum biomarkers of bone turnover or patient-reported pain. Dasatinib was ineffective in controlling bone-predominant MBC in a patient population, unselected by molecular markers. Further study of dasatinib in breast cancer should not be pursued unless performed in molecularly determined patient subsets, or rational combinations., Competing Interests: None: WB, EK, GH, JK, DL, CM, PD, AS; CV reports sponsorship of clinical trial to institution by Bayer Pharmaceuticals; DH reports Stock Ownership: Oncimmune LLC, De Soto, KS, USA – stock options (7/20/09), Inbiomotion, Barcelona, Spain – stock options (10/22/12); Lecture/Honorarium: Visiting Consultant for Lilly Oncology, Indianapolis, IN (11/7/14); Sponsored Clinical Research – Principle or co-Investigator: Merrimack Pharmaceuticals, Inc. (Parexel Intl Corp) (01/24/15-02/02/20), Eli Lilly Company (06/19/15-04/30/19), Janssen R&D, LLC (Johnson & Johnson) (12/23/08-04/28/18), Puma Biotechnology, Inc., (subcontract Wash Univ St. Louis to Univ Mich) (07/19/13-07/31/18), Pfizer (07/22/13-07/14/18), Astra Zeneca (11/01/14-10/31/16), Astra Zeneca (02/06/15-02/05/16; Royalties from licensed technology: Janssen R&D, LLC (Johnson & Johnson) (08/01/14); Patents: Title: A method for predicting progression free and overall survival at each follow-up timepoint during therapy of metastatic breast cancer patients using circulating tumor cells. Filed 14 Mar 2005 with the European Patent Office, Netherlands. Application No./Patent No. 05725638.0-1223-US2005008602. Applicant/Proprietor: Immunicon Corporation. Dr. Daniel F. Hayes is designated as inventor/co-inventor; Title: Diagnosis and Treatment of Breast Cancer. Patent No.: US 8,790,878 B2. Date of Patent: Jul. 29, 2014. Applicant Proprietor: University of Michigan. Dr. Daniel F. Hayes is designated as inventor/co-inventor; Title: Circulating Tumor Cell Capturing Techniques and Devices. Patent No.: US 8,951,484 B2. Date of Patent: Feb. 10, 2015. Applicant Proprietor: University of Michigan. Dr. Daniel F. Hayes is designated as inventor/co-inventor.

Prior to availability of anti-HER2 therapies, HER2-positive metastatic breast cancer (MBC) was associated with a poor prognosis. Prospective randomized trials have demonstrated survival benefit from anti-HER2 treatments. Anecdotal observations have suggested that a small but meaningful fraction of patients with HER2-positive MBC may be "exceptional responders" with long survival. We hypothesized that demographic and/or clinicopathologic characteristics can be identified to distinguish short-term from long-term survivors. A retrospective, single-institution review of 168 patients with HER2-positive MBC who received treatment with anti-HER2 therapy in the metastatic setting was performed. Cox proportional hazards analysis was used to assess factors associated with long-term survival. Median overall survival from the time of breast cancer recurrence was 3.9 years (95 % CI 3.4-5.2). From the time of diagnosis of MBC, 56 (33 %) survived for 5 or more years and 12 (7 %) survived more than 10 years. Of the 66 patients diagnosed with central nervous system metastases, 9 (14 %) survived more than 5 years following that diagnosis. Younger age at diagnosis, lower stage, hormone receptor positive status, and only having one organ involved at diagnosis were associated with longer survival. Four patients discontinued anti-HER2 therapy and are without evidence of progression of disease after a median 7.4 years (0.2-12.0) since stopping therapy. In a cohort of patients with HER2-positive MBC treated primarily with trastuzumab and lapatinib, 7 % of patients were "exceptional responders." Combining these clinical factors with molecular determinants of prolonged survival may provide insights for individualizing treatment selection.

Rare cancers account for 27% of neoplasms diagnosed each year, and 25% of cancer-related deaths in the United States. However, rare cancers show some of the highest response rates to targeted therapies, probably due to identification of oncogenic drivers with little interpatient variability. Although the low incidence of rare cancers makes large-scale randomized trials involving single histologies difficult to perform, drugs have been successfully developed in rare cancers using clinical trial designs that combine microscopic histologies. Such trials are being pursued within the National Clinical Trials Network (NCTN), which possesses unique qualifications to perform widespread molecular screening of tumors for patient enrollment onto therapeutic clinical trials. When larger clinical trials are needed to determine optimum treatment strategies in rare cancers, the NCTN's broad reach in North America and internationally, and their ability to partner with both United States-based and international research organizations, can make these challenging studies feasible., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Endocrine therapy (ET) fails to induce a response in one half of patients with hormone receptor (HR)-positive metastatic breast cancer (MBC), and almost all will eventually become refractory to ET. Circulating tumor cells (CTC) are associated with worse prognosis in patients with MBC, but enumeration alone is insufficient to predict the absolute odds of benefit from any therapy, including ET. We developed a multiparameter CTC-Endocrine Therapy Index (CTC-ETI), which we hypothesize may predict resistance to ET in patients with HR-positive MBC., Methods: The CTC-ETI combines enumeration and CTC expression of four markers: estrogen receptor (ER), B-cell lymphoma 2 (BCL-2), Human Epidermal Growth Factor Receptor 2 (HER2), and Ki67. The CellSearch System and reagents were used to capture CTC and measure protein expression by immunofluorescent staining on CTC., Results: The feasibility of determining CTC-ETI was initially established in vitro and then in a prospective single-institution pilot study in patients with MBC. CTC-ETI was successfully determined in 44 of 50 (88%) patients. Eighteen (41%), 9 (20%), and 17 (39%) patients had low, intermediate, and high CTC-ETI scores, respectively. Interobserver concordance of CTC-ETI determination was from 94% to 95% (Kappa statistic, 0.90-0.91). Inter- and cell-to-cell intrapatient heterogeneity of expression of each of the CTC markers was observed. CTC biomarker expression was discordant from both primary and metastatic tissues., Conclusions: CTC expression of ER, BCL-2, HER2, and Ki67 can be reproducibly measured with high analytical validity using the CellSearch System. The clinical implications of CTC-ETI, and of the heterogeneity of CTC biomarker expression, are being evaluated in an ongoing prospective trial., (©2014 American Association for Cancer Research.)

This is an exciting time to be in cancer medicine. New technologies, such as next-generation sequencing (NGS), have increased our understanding of the molecular aberrations that define cancer. This, in turn, has led to the identification of cancer-specific molecular targets and potential drugs to confront these targets. As these new technologies move toward clinical application, a new vocabulary of "genome medicine" has been introduced to the field of oncology. Unfortunately, unclear or incorrect use of the new terminology has led to semantic misunderstandings that impair communication between the basic research and clinical practice arenas. These misunderstandings have led to assumptions regarding the clinical application of NGS and other technologies that may or may not be true. For example, some organizations that perform NGS testing on clinical samples have endorsed use of the results of such tests to direct specific therapies based on laboratory hypotheses, but without clinical testing of the hypotheses to show utility for these potential predictive claims. Here, we review some simple, and hopefully universally acceptable, definitions, concepts, and trial designs so that laboratory researchers and clinicians can move closer toward speaking the same language., (©2015 American Association for Cancer Research.)

Neoadjuvant chemotherapy has several appealing potential benefits compared with classic adjuvant chemotherapy. Of these, the only proven benefit is to facilitate the surgical approach, either by converting an inoperable cancer to one that is operable, or by converting a patient who is felt to be a candidate for mastectomy to one who might be treated successfully with breast conserving therapy. Randomized trials comparing neoadjuvant chemotherapy with postoperative chemotherapy have failed to demonstrate prolongation of overall survival. The benefits of monitoring apparent response during neoadjuvant chemotherapy have not been proven. Conduct of phase II drug development trials in the neoadjuvant setting may be advantageous compared with performing such trials in the metastatic setting. However, such trials raise concerns that are not unavoidable but need to be addressed., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To evaluate diffusion weighted MRI (DW-MR) as a response metric for assessment of neoadjuvant chemotherapy (NAC) in patients with primary breast cancer using prospective multi-center trials which provided MR scans along with clinical outcome information., Materials and Methods: A total of 39 patients with locally advanced breast cancer accrued from three different prospective clinical trials underwent DW-MR examination prior to and at 3-7 days (Hull University), 8-11 days (University of Michigan) and 35 days (NeoCOMICE) post-treatment initiation. Thirteen patients, 12 of which participated in treatment response study, from UM underwent short interval (<1hr) MRI examinations, referred to as "test-retest" for examination of repeatability. To further evaluate stability in ADC measurements, a thermally controlled diffusion phantom was used to assess repeatability of diffusion measurements. MRI sequences included contrast-enhanced T1-weighted, when appropriate, and DW images acquired at b-values of 0 and 800 s/mm2. Histogram analysis and a voxel-based analytical technique, the Parametric Response Map (PRM), were used to derive diffusion response metrics for assessment of treatment response prediction., Results: Mean tumor apparent diffusion coefficient (ADC) values generated from patient test-retest examinations were found to be very reproducible (|ΔADC|<0.1x10-3mm2/s). This data was used to calculate the 95% CI from the linear fit of tumor voxel ADC pairs of co-registered examinations (±0.45x10-3mm2/s) for PRM analysis of treatment response. Receiver operating characteristic analysis identified the PRM metric to be predictive of outcome at the 8-11 (AUC = 0.964, p = 0.01) and 35 day (AUC = 0.770, p = 0.05) time points (p<.05) while whole-tumor ADC changes where significant at the later 35 day time interval (AUC = 0.825, p = 0.02)., Conclusion: This study demonstrates the feasibility of performing a prospective analysis of DW-MRI as a predictive biomarker of NAC in breast cancer patients. In addition, we provide experimental evidence supporting the use of sensitive analytical tools, such as PRM, for evaluating ADC measurements.

The era of genomics-based medicine promises to provide molecular tests that will permit precision medicine. However, in 2015, it is not clear what the terms genomics-based medicine, molecular tests, or precision medicine mean. In this report, we review the definitions of these terms and other important semantics relative to what it takes to get a tumor biomarker into standard clinical practice, and the potential clinical trial designs that are being considered to determine if tumor biomarker tests based on next-generation sequencing actually provide benefit to patients with cancer.

Purpose: Increased circulating tumor cells (CTCs; five or more CTCs per 7.5 mL of whole blood) are associated with poor prognosis in metastatic breast cancer (MBC). A randomized trial of patients with persistent increase in CTCs tested whether changing chemotherapy after one cycle of first-line chemotherapy would improve the primary outcome of overall survival (OS)., Patients and Methods: Patients with MBC who did not have increased CTCs at baseline remained on initial therapy until progression (arm A). Patients with initially increased CTCs that decreased after 21 days of therapy remained on initial therapy (arm B). Patients with persistently increased CTCs after 21 days of therapy were randomly assigned to continue initial therapy (arm C1) or change to an alternative chemotherapy (arm C2)., Results: Of 595 eligible and evaluable patients, 276 (46%) did not have increased CTCs (arm A). Of those with initially increased CTCs, 31 (10%) were not retested, 165 were assigned to arm B, and 123 were randomly assigned to arm C1 or C2. No difference in median OS was observed between arm C1 and C2 (10.7 and 12.5 months, respectively; P = .98). CTCs were strongly prognostic. Median OS for arms A, B, and C (C1 and C2 combined) were 35 months, 23 months, and 13 months, respectively (P < .001)., Conclusion: This study confirms the prognostic significance of CTCs in patients with MBC receiving first-line chemotherapy. For patients with persistently increased CTCs after 21 days of first-line chemotherapy, early switching to an alternate cytotoxic therapy was not effective in prolonging OS. For this population, there is a need for more effective treatment than standard chemotherapy., (© 2014 by American Society of Clinical Oncology.)

Unlabelled: Aromatase inhibitors (AIs), which are used to treat breast cancer, inhibit estrogen production in postmenopausal women. AI-associated musculoskeletal symptoms occur in approximately half of treated women and lead to treatment discontinuation in 20 to 30%. The etiology may be due in part to estrogen deprivation. In premenopausal women, lower estrogen levels have been associated with increased pain as well as with impairment of descending pain inhibitory pathways, which may be a risk factor for developing chronic pain. We prospectively tested whether AI-induced estrogen deprivation alters pain sensitivity, thereby increasing the risk of developing AI-associated musculoskeletal symptoms. Fifty postmenopausal breast cancer patients underwent pressure pain testing and conditioned pain modulation (CPM) assessment prior to AI initiation and after 3 and 6 months. At baseline, 26 of 40 (65%) assessed patients demonstrated impaired CPM, which was greater in those who had previously received chemotherapy (P = .006). No statistically significant change in pressure pain threshold or CPM was identified following estrogen deprivation. In addition, there was no association with either measure of pain sensitivity and change in patient-reported pain with AI therapy. AI-associated musculoskeletal symptoms are not likely due to decreased pain threshold or impaired CPM prior to treatment initiation, or to effects of estrogen depletion on pain sensitivity., Perspective: This article presents our findings of the effect of estrogen deprivation on objective measures of pain sensitivity. In postmenopausal women, medication-induced estrogen depletion did not result in an identifiable change in pressure pain threshold or CPM. Impaired CPM may be associated with chemotherapy., (Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Imaging biomarkers capable of early quantification of tumor response to therapy would provide an opportunity to individualize patient care. Image registration of longitudinal scans provides a method of detecting treatment associated changes within heterogeneous tumors by monitoring alterations in the quantitative value of individual voxels over time, which is unattainable by traditional volumetric-based histogram methods. The concepts involved in the use of image registration for tracking and quantifying breast cancer treatment response using parametric response mapping (PRM), a voxel-based analysis of diffusion-weighted magnetic resonance imaging (DW-MRI) scans, are presented. Application of PRM to breast tumor response detection is described, wherein robust registration solutions for tracking small changes in water diffusivity in breast tumors during therapy are required. Methodologies that employ simulations are presented for measuring expected statistical accuracy of PRM for response assessment. Test-retest clinical scans are used to yield estimates of system noise to indicate significant changes in voxel-based changes in water diffusivity. Overall, registration-based PRM image analysis provides significant opportunities for voxel-based image analysis to provide the required accuracy for early assessment of response to treatment in breast cancer patients receiving neoadjuvant chemotherapy.