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PurposeThe KRISTINE study compared neoadjuvant trastuzumab emtansine plus pertuzumab (T-DM1+P) with docetaxel, carboplatin, trastuzumab plus P (TCH+P) for the treatment human epidermal growth factor receptor 2-positive stage II to III breast cancer. T-DM1+P led to a lower pathologic complete response rate (44.4% v 55.7%; P = .016), but fewer grade 3 or greater and serious adverse events (AEs). Here, we present 3-year outcomes from KRISTINE.MethodsPatients were randomly assigned to neoadjuvant T-DM1+P or TCH+P every 3 weeks for six cycles. Patients who received T-DM1+P continued adjuvant T-DM1+P, and patients who received TCH+P received adjuvant trastuzumab plus pertuzumab. Secondary end points included event-free survival (EFS), overall survival, patient-reported outcomes (measured from random assignment), and invasive disease-free survival (IDFS; measured from surgery).ResultsOf patients, 444 were randomly assigned (T-DM1+P, n = 223; TCH+P, n = 221). Median follow-up was 37 months. Risk of an EFS event was higher with TDM-1+P (hazard ratio [HR], 2.61 [95% CI, 1.36 to 4.98]) with more locoregional progression events before surgery (15 [6.7%] v 0). Risk of an IDFS event after surgery was similar between arms (HR, 1.11 [95% CI, 0.52 to 2.40]). Pathologic complete response was associated with a reduced risk of an IDFS event (HR, 0.24 [95% CI, 0.09 to 0.60]) regardless of treatment arm. Overall, grade 3 or greater AEs (31.8% v 67.7%) were less common with T-DM1+P. During adjuvant treatment, grade 3 or greater AEs (24.5% v 9.9%) and AEs leading to treatment discontinuation (18.4% v 3.8%) were more common with T-DM1+P. Patient-reported outcomes favored T-DM1+P during neoadjuvant treatment and were similar to trastuzumab plus pertuzumab during adjuvant treatment.ConclusionCompared with TCH+P, T-DM1+P resulted in a higher risk of an EFS event owing to locoregional progression events before surgery, a similar risk of an IDFS event, fewer grade 3 or greater AEs during neoadjuvant treatment, and more AEs leading to treatment discontinuation during adjuvant treatment.

Background: The 21-gene recurrence score (RS) assay (Oncotype DX) is used to guide adjuvant chemotherapy use for patients with hormone receptor-positive, HER2 (human epidermal growth factor receptor 2)-negative, axillary node-negative breast cancer. Its role, however, in providing prognostic information for late distant recurrence when added to clinicopathologic prognostic factors is unknown. Methods: A patient-specific meta-analysis including 10,004 women enrolled in three trials was updated using extended follow-up data from TAILORx, integrating the RS with histologic grade, tumor size, and age at surgery for the RSClin tool. Cox models integrating clinicopathologic factors and the RS were compared by using likelihood ratio (LR) tests. External validation of prognosis for distant recurrence in years 0 to 10 and 5 to 10 was performed in an independent cohort of 1098 women in a real-world registry. Results: RSClin provided significantly more prognostic information than either the clinicopathologic factors (ΔLR chi-square, 86.2; P<0.001) or RS alone (ΔLR chi-square, 131.0; P<0.001). The model was prognostic in an independent cohort for distant recurrence by 10 years after diagnosis (standardized hazard ratio, 1.56; 95% confidence interval, 1.25 to 1.94), was associated with late distant recurrence risk between 5 and 10 years after diagnosis (standardized hazard ratio, 1.78; 95% confidence interval, 1.25 to 2.55), and approximated the observed 10-year distant recurrence risk (Lin concordance, 0.87) and 5- to 10-year distant recurrence risk (Lin concordance, 0.92). Conclusions: The 21-gene RS is prognostic for distant recurrence and overall survival in early breast cancer. A model integrating the 21-gene RS and clinicopathologic factors improved estimates of distant recurrence risk compared with either used individually and stratified late distant recurrence risk. (Funded by the National Cancer Institute, National Institutes of Health [U10CA180820, U10CA180794, UG1CA189859, U10CA180868, and U10CA180822] and others.) [ABSTRACT FROM AUTHOR]

PurposeAnthracycline-induced congestive heart failure (CHF) is a rare but serious toxicity associated with this commonly employed anticancer therapy. The ability to predict which patients might be at increased risk prior to exposure would be valuable to optimally counsel risk-to-benefit ratio for each patient. Herein, we present a genome-wide approach for biomarker discovery with two validation cohorts to predict CHF from adult patients planning to receive anthracycline.Experimental designWe performed a genome-wide association study in 3,431 patients from the randomized phase III adjuvant breast cancer trial E5103 to identify single nucleotide polymorphism (SNP) genotypes associated with an increased risk of anthracycline-induced CHF. We further attempted candidate validation in two independent phase III adjuvant trials, E1199 and BEATRICE.ResultsWhen evaluating for cardiologist-adjudicated CHF, 11 SNPs had a P value

Background: The relationship between Ki67 assessed by immunohistochemistry (IHC) and the Oncotype DX Recurrence Score (RS) is unclear. The objective of this study was to determine the correlation between the 21-gene RS and IHC-measured Ki67 with the prognostic classification groups recommended by the International Ki67 Working Group (IKWG).Methods: The authors performed a retrospective chart review of women who had hormone receptor (HR)-positive, human epidermal growth factor receptor 2-negative early breast cancer with zero to three positive lymph nodes and both Ki67 and the 21-gene RS performed at their institution from 2013 to 2021. Patients were categorized into low (≤5%), intermediate (6%-29%), and high Ki67 groups (≥30%) according to IKWG recommendations. Overall agreement and risk-stratified agreement between Ki67 and RS were assessed with the proportion of agreement and the κ statistic.Results: The study included 525 patients with HR-positive breast cancer. Among the 49% of patients with intermediate Ki67 values of 6%-29%, the distribution of low (0-10), intermediate (11-25), and high RS (26-100) was 19%, 66%, and 15%, respectively. There was slight agreement (κ = 0.01-0.20) between Ki67 and RS (κ = 0.027) in the overall population, although this was not significant (p = .1985). There was fair agreement (κ = 0.21-0.40) between high Ki67 and RS values (κ = 0.280; p < .0001). A higher progesterone receptor percentage was associated with lower RS values (p > .0001) but not lower Ki67 values. A positive nodal status and a larger tumor size were associated with higher Ki67 values (p = .0059 and p < .0001) but not with RS.Conclusions: In this group of patients selected to have a 21-gene RS, there was no significant correlation between Ki67 and RS in the overall population, and there was fair agreement between high Ki67 and high RS values.Lay Summary: In patients with early-stage, hormone receptor-positive breast cancer, decisions on adjuvant chemotherapy are based on certain biological features of the cancer and genomic assays such as the Oncotype DX Recurrence Score (RS). The goal of this study was to determine the correlation between Ki67, a marker of proliferation, and the Oncotype DX RS, a 21-gene assay demonstrated to be predictive of an adjuvant chemotherapy benefit in patients with early-stage breast cancer. In 525 patients, the authors did not find a significant correlation between Ki67 and RS. [ABSTRACT FROM AUTHOR]

Background: TAILORx (Trial Assigning Individualized Options for Treatment) prospectively assessed fatigue and endocrine symptoms among women with early‐stage hormone receptor–positive breast cancer and a midrange risk of recurrence who were randomized to endocrine therapy (E) or chemotherapy followed by endocrine therapy (CT+E). Methods: Participants completed the Functional Assessment of Chronic Illness Therapy–Fatigue, the Patient‐Reported Outcomes Measurement Information System–Fatigue Short Form, and the Functional Assessment of Cancer Therapy–Endocrine Symptoms at the baseline and at 3, 6, 12, 24, and 36 months. Linear regression was used to model outcomes on baseline symptoms, treatment, and other factors. Results: Participants (n = 458) in both treatment arms reported greater fatigue and endocrine symptoms at early follow‐up in comparison with the baseline. The magnitude of change in fatigue was significantly greater for the CT+E arm than the E arm at 3 and 6 months but not at 12, 24, or 36 months. The CT+E arm reported significantly greater changes in endocrine symptoms from the baseline to 3 months in comparison with the E arm; change scores were not significantly different at later time points. Endocrine symptom trajectories by treatment differed by menopausal status, with the effect larger and increasing for postmenopausal patients. Conclusions: Adjuvant CT+E was associated with greater increases in fatigue and endocrine symptoms at early time points in comparison with E. These differences lessened over time, and this demonstrated early chemotherapy effects more than long‐term ones. Treatment arm differences in endocrine symptoms were more evident in postmenopausal patients. Lay Summary: Participants in TAILORx (Trial Assigning Individualized Options for Treatment) with early‐stage hormone receptor–positive breast cancer and an intermediate risk of recurrence were randomly assigned to endocrine or chemoendocrine therapy.Four hundred fifty‐eight women reported fatigue and endocrine symptoms at the baseline and at 3, 6, 12, 24, and 36 months.Both groups reported greater symptoms at early follow‐up versus the baseline.Increases in fatigue were greater for the chemoendocrine group than the endocrine group at 3 and 6 months but not later.The chemoendocrine group reported greater changes in endocrine symptoms in comparison with the endocrine group at 3 months but not later. Participants in TAILORx (Trial Assigning Individualized Options for Treatment) randomized to chemoendocrine therapy report significant increases in fatigue and endocrine symptoms 3 months after randomization, which decrease through 36 months. Those randomized to endocrine therapy also report increased symptoms from the baseline, although of a lesser magnitude. [ABSTRACT FROM AUTHOR]

Background: E5103 was a study designed to evaluate the efficacy and safety of bevacizumab. It was a negative trial for the end points of invasive disease–free survival and overall survival. The current work examines the tolerability of bevacizumab and other medication exposures with respect to clinical outcomes and patient‐reported outcomes (PROs). Methods: Adverse events (AEs) collected from the Common Terminology Criteria for Adverse Events were summarized to form an AE profile at each treatment cycle. All‐grade and high‐grade events were separately analyzed. The change in the AE profile over the treatment cycle was delineated as distinct AE trajectory clusters. AE‐related and any‐reason early treatment discontinuations were treated as clinical outcome measures. PROs were measured with the Functional Assessment of Cancer Therapy–Breast + Lymphedema. The relationships between the AE trajectory and early treatment discontinuation as well as PROs were analyzed. Results: More than half of all AEs (57.5%) were low‐grade. A cluster of patients with broad and mixed AE (all‐grade) trajectory grades was significantly associated with any‐reason early treatment discontinuation (odds ratio [OR], 2.87; P =.01) as well as AE‐related discontinuation (OR, 4.14; P =.001). This cluster had the highest count of all‐grade AEs per cycle in comparison with other clusters. Another cluster of patients with primary neuropathic AEs in their trajectories had poorer physical well‐being in comparison with a trajectory of no or few AEs (P <.01). A high‐grade AE trajectory did not predict discontinuations. Conclusions: A sustained and cumulative burden of across‐the‐board toxicities, which were not necessarily all recognized as high‐grade AEs, contributed to early treatment discontinuation. Patients with neuropathic all‐grade AEs may require additional attention for preventing deterioration in their physical well‐being. In this secondary data analysis study of patients with breast cancer treated with bevacizumab and chemotherapy, cumulative multiple toxicities, even of low grades, are associated with early treatment discontinuation. Peripheral neuropathy is related to poor self‐reported physical well‐being, and this suggests additional care for patients exhibiting such toxicity. [ABSTRACT FROM AUTHOR]

Background: The prognostic significance of patients with low-risk recurrence score (RS) results in the context of the American Joint Committee on Cancer (AJCC) eighth edition pathologic prognostic staging has not been investigated. We evaluated if expanded RS criteria can be considered for downstaging in AJCC pathologic prognostic staging.Methods: Using Surveillance, Epidemiology, and End Results data, we identified patients with T1-3N0-3M0 hormone receptor-positive, HER2-negative breast cancer treated from 2010 to 2015 with follow-up data through 2016. We evaluated TNM categories, grade, and RS result. The primary outcome measured was 5-year disease-specific survival (DSS) of patients with low-risk RS results not already pathologic prognostic stage IA, determined by T and N categories per AJCC eighth edition. All statistical tests were 2-sided.Results: Of 154 050 patients with median follow-up of 49 months (range = 0-83), RS results were obtained in 60 886 (39.5%): RS was less than 11 in 13 570 (22.3%); 11-17 in 22 719 (37.3%); 18-25 in 16 521 (27.1%); and 26 or higher in 8076 (13.3%). Five-year DSS for pathologic prognostic stage IA patients (n = 114 910, 74.6%) was 98.8%. Among N0-1 patients with a RS less than 18 not staged as pathologic prognostic stage IA by current criteria, 5-year DSS was excellent and not statistically significantly different than for pathologic prognostic stage IA patients (97.2%-99.7%; P > .05). For those with a RS of 18-25, there was a small decrease in DSS for T2N0 (2.3%) and modest decrease for T1-2N1 (4.2%-6.4%) compared with pathologic prognostic stage IA patients (P < .001).Conclusion: Patients with a RS less than 18 have excellent 5-year DSS regardless of T category for N0-1 disease suggesting further modification of the AJCC staging system using this cutoff. [ABSTRACT FROM AUTHOR]

To examine clinicodemographic determinants associated with breast cancer survivorship follow-up during COVID-19. We performed a retrospective, population-based cohort study including early stage (Stage I-II) breast cancer patients who underwent resection between 2006 and 2018 in a New York City hospital system. The primary outcome was oncologic follow-up prior to and during the COVID-19 pandemic. Secondary analyses compared differences in follow-up by COVID-19 case rates stratified by ZIP code. A total of 2942 patients with early-stage breast cancer were available for analysis. 1588 (54%) of patients had attended follow-up in the year prior to the COVID-19 period but failed to continue to follow-up during the pandemic, either in-person or via telemedicine. 1242 (42%) patients attended a follow-up appointment during the COVID-19 pandemic. Compared with patients who did not present for follow-up during COVID-19, patients who continued their oncologic follow-up during the pandemic were younger (p = 0.049) more likely to have received adjuvant radiation therapy (p = 0.025), and have lower household income (p = 0.031) on multivariate modeling. When patients who live in Bronx, New York, were stratified by ZIP code, there was a modest negative association (r = −0.56) between COVID-19 cases and proportion of patients who continued to follow-up during the COVID-19 period. We observed a dramatic disruption in routine breast cancer follow-up during the COVID-19 pandemic. Providers and health systems should emphasize reintegrating patients who missed appointments during COVID-19 back into regular surveillance programs to avoid significant morbidity and mortality from missed breast cancer recurrences. • A dramatic disruption in routine oncologic follow-up was observed during the COVID-19 period. • Over half of patients with breast cancer at our center did not attend routine oncologic follow-up during COVID-19. • Patients who were younger, had lower SES, and who received radiotherapy were more likely to follow-up during the pandemic. • A modest negative association was observed between local ZIP code COVID-19 infection rates and follow-up attendance rate. [ABSTRACT FROM AUTHOR]

Multigene expression assays are prognostic for recurrence in hormone-receptor positive 2 (HER-2) negative breast cancer, and, in some cases, predictive of benefit from chemotherapy or extended endocrine therapy. The results of these assays may be used to guide treatment recommendations for early HER-2 negative breast cancer. We review the results of trials establishing the clinical utility of several commercially available gene expression assays. [ABSTRACT FROM AUTHOR]

Background: Early discontinuation is a substantial barrier to the delivery of endocrine therapies (ETs) and may influence recurrence and survival. The authors investigated the association between early discontinuation of ET and social determinants of health, including insurance coverage and the neighborhood deprivation index (NDI), which was measured on the basis of patients' zip codes, in breast cancer. Methods: In this retrospective analysis of a prospective randomized clinical trial (Trial Assigning Individualized Options for Treatment), women with hormone receptor–positive, human epidermal growth factor receptor 2–negative breast cancer who started ET within a year of study entry were included. Early discontinuation was calculated as stopping ET within 4 years of its start for reasons other than distant recurrence or death via Kaplan‐Meier estimates. A Cox proportional hazards joint model was used to analyze the association between early discontinuation of ET and factors such as the study‐entry insurance and NDI, with adjustments made for other variables. Results: Of the included 9475 women (mean age, 55.6 years; White race, 84%), 58.0% had private insurance, whereas 11.7% had Medicare, 5.8% had Medicaid, 3.8% were self‐pay, and 19.1% were treated at international sites. The early discontinuation rate was 12.3%. Compared with those with private insurance, patients with Medicaid (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.23‐1.92) and self‐pay patients (HR, 1.65; 95% CI, 1.25‐2.17) had higher early discontinuation. Participants with a first‐quartile NDI (highest deprivation) had a higher probability of discontinuation than those with a fourth‐quartile NDI (lowest deprivation; HR, 1.34; 95% CI, 1.11‐1.62). Conclusions: Patients' insurance and zip code at study entry play roles in adherence to ET, with uninsured and underinsured patients having a high rate of treatment nonadherence. Early identification of patients at risk may improve adherence to therapy. Lay Summary: In this retrospective analysis of 9475 women with breast cancer participating in a clinical trial (Trial Assigning Individualized Options for Treatment), Medicaid and self‐pay patients (compared with those with private insurance) and those in the highest quartile of neighborhood deprivation scores (compared with those in the lowest quartile) had a higher probability of early discontinuation of endocrine therapy.These social determinants of health assume larger importance with the expected increase in unemployment rates and loss of insurance coverage in the aftermath of the coronavirus disease 2019 pandemic. Early identification of patients at risk and enrollment in insurance optimization programs may improve the persistence of therapy. Patients' insurance status and geographic residence play important roles in the persistence of endocrine therapy use. Early identification of patients at risk may improve adherence to therapy. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the impact of insurance and neighborhood SES (nSES) on chemotherapy completion and overall mortality among participants in breast cancer clinical trials. The data sources for this study were two adjuvant breast cancer trials (ECOG E1199 and E5103) collectively including 9790 women. Insurance status at trial registration was categorized into private, government (Medicaid, Medicare, and other government type insurance), and self‐pay. An Agency for Healthcare Research Quality (AHRQ) nSES index was calculated using residential zip codes linked to county level data on occupation, income, poverty, wealth, education, and crowding. Logistic regression and Cox Proportional Hazard models estimated odds ratios (OR) for chemotherapy treatment completion and hazard ratios (HR) for mortality, respectively, for insurance status and nSES. The models adjusted for: race, age, tumor size, nodal status, hormone receptor status, and primary surgery. The majority of patients had private insurance at trial registration: E1199: 85.6% (4154/4854) and E5103: 82.4% (3987/4836); median SES index was 53.8 (range: 41.8‐66.8) and 54.1 (range: 44.5‐66.1), respectively. Patients with government insurance were less likely to complete chemotherapy treatment (E1199 OR (95%CI): 0.73 (0.57‐0.94); E5103 0.76 (0.64‐0.91)) and had an increased risk of death (E1199 HR (95%CI): 1.44 (1.22‐1.70); E5103 1.29 (1.06‐1.58)) compared to the privately insured patients. There was no association between nSES and chemotherapy completion or overall mortality. Patients with government insurance at trial registration appeared to face barriers in chemotherapy completion and had a higher overall mortality compared to their privately insured counterparts. [ABSTRACT FROM AUTHOR]

Breast cancer is the second most commonly diagnosed cancer in American women following skin cancer. Despite overall decrease in breast cancer mortality due to advances in treatment and earlier screening, black patients continue to have 40% higher risk of breast cancer related death compared to white patients. This disparity in outcome persists even when controlled for access to care and stage at presentation and has been attributed to differences in tumor subtypes or gene expression profiles. There is emerging evidence that the tumor microenvironment (TME) may contribute to the racial disparities in outcome as well. Here, we provide a comprehensive review of current literature available regarding race-dependent differences in the TME. Notably, black patients tend to have a higher density of pro-tumorigenic immune cells (e.g., M2 macrophages, regulatory T cells) and microvasculature. Although immune cells are classically thought to be anti-tumorigenic, increase in M2 macrophages and angiogenesis may lead to a paradoxical increase in metastasis by forming doorways of tumor cell intravasation called tumor microenvironment of metastasis (TMEM). Furthermore, black patients also have higher serum levels of inflammatory cytokines, which provide a positive feedback loop in creating a pro-metastatic TME. Lastly, we propose that the higher density of immune cells and angiogenesis observed in the TME of black patients may be a result of evolutionary selection for a more robust immune response in patients of African geographic ancestry. Better understanding of race-dependent differences in the TME will aid in overcoming the racial disparity in breast cancer mortality. [ABSTRACT FROM AUTHOR]

Background: We used two models to simulate a proposed noninferiority trial of radiotherapy (RT) omission in low-risk invasive breast cancer to illustrate how modeling could be used to predict the trial's outcomes, inform trial design, and contribute to practice debates.Methods: The proposed trial was a prospective randomized trial of no-RT vs RT in women age 40 to 74 years undergoing lumpectomy and endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, stage I breast cancer with an Oncotype DX score of 18 or lower. The primary endpoint was recurrence-free interval (RFI), including locoregional recurrence, distant recurrence, and breast cancer death. Noninferiority required the two-sided 90% confidence interval of the RFI hazard ratio (HR) for no-RT vs RT to be entirely below 1.7. Model inputs included published data. The trial was simulated 1000 times, and results were summarized as percent concluding noninferiority and mean (standard deviation) of hazard ratios for Model GE and Model M, respectively.Results: Noninferiority was demonstrated in 18.0% and 3.7% for the two models. The respective means (SD) of the RFI hazard ratios were 1.8 (0.7) and 2.4 (0.9); most were locoregional recurrences. The mean five-year RFI rates for no-RT vs RT (SD) were 92.7% (2.9%) vs 95.5% (2.2%) and 88.4% (2.0%) vs 94.5% (1.6%). Both models showed little or no difference in breast cancer-specific or overall survival. Alternative definitions of low risk based on combinations of age and grade produced similar results.Conclusions: The proposed trial was unlikely to show noninferiority of omitting radiotherapy even using alternative definitions of low-risk, as the endpoint included local recurrence. Future trials regarding radiotherapy should address absolute reduction in recurrence and impact of type of recurrence on the patient. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy after breast conservation has become the standard of care. Prior meta-analyses on effects of radiotherapy predated availability of gene expression profiling (GEP) to assess recurrence risk and/or did not include all relevant outcomes. This analysis used GEP information with pooled individual-level data to evaluate the impact of omitting radiotherapy on recurrence and mortality.Methods: We considered trials that evaluated or administered radiotherapy after lumpectomy in women with low-risk breast cancer. Women included had undergone lumpectomy and were treated with hormonal therapy for stage I, ER+ and/or PR+, HER2- breast cancer with Oncotype scores no greater than 18. Recurrence-free interval (RFI), type of RFI (locoregional or distant), and breast cancer-specific and overall survival were compared between no radiotherapy and radiotherapy using adjusted Cox models. All statistical tests were two-sided.Results: The final sample included 1778 women from seven trials. Omission of radiotherapy was associated with an overall adjusted hazard ratio of 2.59 (95% confidence interval [CI] = 1.38 to 4.89, P = .003) for RFI. There was a statistically significant increase in any first locoregional recurrence (P = .001), but not distant recurrence events (P = .90), or breast cancer-specific (P = .85) or overall survival (P = .61). Five-year RFI rate was high (93.5% for no radiotherapy vs 97.9% for radiotherapy; absolute reduction = 4.4%, 95% CI = 0.7% to 8.1%, P = .03). The effects of radiotherapy varied across subgroups, with lower RFI rates for those with Oncotype scores of less than 11 (vs 11-18), older (vs younger), and ER+/PR+ status (vs other).Conclusions: Omission of radiotherapy in hormone-sensitive patients with low recurrence risk may lead to a modest increase in locoregional recurrence event rates, but does not appear to increase the rate of distant recurrence or death. [ABSTRACT FROM AUTHOR]

Purpose: Identification of single-gene biomarkers that are prognostic of outcome can shed new insights on the molecular mechanisms that drive breast cancer and other cancers. Methods: Exploratory analysis of 20,464 single-gene messenger RNAs (mRNAs) in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) discovery cohort indicates that low expression of FGD3 mRNA is prognostic for poor outcome. Prognostic significance of faciogenital dysplasia 3 (FGD3), SUSD3, and other single-gene proliferation markers was evaluated in breast cancer and The Cancer Genome Atlas (TCGA) cohorts. Results: A meta-analysis of Cox regression of FGD3 mRNA as a continuous variable for overall survival of estrogen receptor (ER)–positive samples in METABRIC discovery, METABRIC validation, TCGA breast cancer, and Combination Chemotherapy in Treating Women With Breast Cancer (E2197) cohorts resulted in a combined hazard ratio (HR) of 0.69 (95% CI, 0.63 to 0.75), indicating better outcome with high expression. In the ER-negative samples, the combined meta-analysis HR was 0.72 (95% CI, 0.63 to 0.82), suggesting that FGD3 is prognostic regardless of ER status. The potential of FGD3 as a biomarker for freedom from recurrence was evaluated in the Breast International Group 1-98 (BIG 1-98; Letrozole or Tamoxifen in Treating Postmenopausal Women With Breast Cancer) study (HR, 0.85; 95% CI, 0.76 to 0.93) for breast cancer–free interval. In the Hungarian Academy of Science (HAS) breast cancer cohort, splitting on the median had an HR of 0.49 (95% CI, 0.42 to 0.58) for recurrence-free survival. A comparison of the Stouffer P value in five ER-positive cohorts showed that FGD3 (P = 3.8E-14) outperformed MKI67 (P = 1.06E-8) and AURKA (P = 2.61E-5). A comparison of the Stouffer P value in four ER-negative cohorts showed that FGD3 (P = 3.88E-5) outperformed MKI67 (P =.477) and AURKA (P =.820). Conclusion: FGD3 was previously shown to inhibit cell migration. FGD3 mRNA is regulated by ESR1 and is associated with favorable outcome in six distinct breast cancer cohorts and four TCGA cancer cohorts. This suggests that FGD3 is an important clinical biomarker. [ABSTRACT FROM AUTHOR]

Background. Icrucumab (ICR) and ramucirumab (RAM) bind vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR-1 and -2), respectively. This open-label, randomized phase II study evaluated their efficacy and safety in combination with capecitabine (CAP) in patients with previously treated unresectable, locally advanced or metastatic breast cancer. Methods. Patients were randomly assigned (1:1:1) to receive CAP (1,000 mg/m2 orally twice daily, days 1-14) alone or in combination with RAM (10 mg/kg intravenously [IV], days 1 and 8) (RAM 1 CAP) or ICR (12 mg/kg IV, days 1 and 8) (ICR 1 CAP) every 21 days. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), tumor response, safety, and pharmacokinetics. Results. Of 153 patients randomized, 150 received treatment. Median PFS (95% confidence interval) was 22.1 (12.1-36.1) weeks on RAM 1 CAP, 7.3 (6.3-13.0) weeks on ICR 1 CAP, and 19.0 (12.1-24.3) weeks on CAP (hazard ratios [HRs]: 0.691, p = .1315, RAM 1 CAP versus CAP; 1.480, p = .0851, ICR 1 CAP versus CAP). Median OS was 67.4 weeks on RAM 1 CAP, 62.0 weeks on ICR 1 CAP, and 71.6 weeks on CAP (HRs: 1.833, p = .0283, RAM 1 CAP versus CAP; 1.468, p = .1550, ICR 1 CAP versus CAP). There was no statistically significant difference in PFS or OS between either combination arm and CAP. Treatment-related adverse events more frequent (by ≥10%) on RAM 1 CAP than on CAP were constipation, decreased appetite, headache, epistaxis, and hypertension. Those more frequent (by ≥10%) on ICR 1 CAP than CAP were anemia, increased lacrimation, periorbital edema, nausea, vomiting, peripheral edema, facial edema, dehydration, and dyspnea. Conclusion. Combining RAM or ICR with CAP did not improve PFS in the targeted study population. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cause of cancer and cancer death worldwide. Although most patients present with localized breast cancer and may be rendered disease-free with local therapy, distant recurrence is common and is the primary cause of death from the disease. Adjuvant systemic therapies are effective in reducing the risk of distant and local recurrence, including endocrine therapy, anti-HER2 therapy, and chemotherapy, even in patients at low risk of recurrence. The widespread use of adjuvant systemic therapy has contributed to reduced breast cancer mortality rates. Adjuvant cytotoxic chemotherapy regimens have evolved from single alkylating agents to polychemotherapy regimens incorporating anthracyclines and/or taxanes. This review summarizes key milestones in the evolution of adjuvant systemic therapy in general, and adjuvant chemotherapy in particular. Although adjuvant treatments are routinely guided by predictive factors for endocrine therapy (hormone receptor expression) and anti-HER2 therapy (HER2 overexpression), predicting benefit from chemotherapy has been more challenging. Randomized studies are now in progress utilizing multiparameter gene expression assays that may more accurately select patients most likely to benefit from adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Hispanic women have higher breast cancer mortality compared to non-Hispanic whites. We evaluated for Proliferation Axis Score differences, as determined by Onco type Dx, in Hispanic and non-Hispanic white women with newly diagnosed breast cancer. We matched 219 women, based upon age, stage, and nodal status. Compared to non-Hispanic whites, Hispanic women with hormone-sensitive, HER2-negative early-stage breast cancer had a higher Proliferation Axis Score. No differences were seen in Recurrence Score, ER, PR, or HER2 by Onco type DX. CCNB1 and AURKA were significantly higher in Hispanic women. These tumor differences may help explain breast cancer outcome differences between the two ethnicities. [ABSTRACT FROM AUTHOR]

BACKGROUND: Population-based studies have shown improved survival for patients diagnosed with metastatic breast cancer over time, presumably because of the availability of new and more effective therapies. The objective of the current study was to determine whether survival improved for patients who developed distant recurrence of breast cancer after receiving adjuvant therapy. METHODS: Adjuvant chemotherapy trials coordinated by the Eastern Cooperative Oncology Group that accrued patients between 1978 and 2002 were reviewed. Survival after distant disease recurrence was estimated for progressive time periods, and adjusted for baseline covariates in a Cox proportional hazards model. RESULTS: Of the 13,785 patients who received adjuvant chemotherapy in 11 trials, 3447 (25%) developed distant disease recurrence; the median survival after recurrence was 20 months (95% confidence interval, 19 months-21 months). Factors associated with inferior survival included a shorter distant recurrence-free interval (DRFI), estrogen receptor-negative and progesterone receptor-negative disease, the number of positive axillary lymph nodes present at the time of diagnosis, and black race ( P < .0001 for all). When the time period of recurrence was added to the model, it was not found to be significantly associated with survival for the general population with disease recurrence. Survival improved over time only in those patients with hormone receptor-negative disease with a DRFI ≤ 3 years, both among the 5 most recent and the entire trial data sets ( P = .01 and P = .05, respectively). CONCLUSIONS: In contrast to reports from population-based studies, no general improvement in survival was observed over the last 30 years for patients who developed distant disease recurrence after adjuvant chemotherapy after adjusting for DRFI. Improved survival for patients with hormone receptor-negative disease with a short DRFI suggests a benefit from trastuzumab. Cancer 2013. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: Obesity has been associated with inferior outcomes in operable breast cancer, but the relation between body mass index (BMI) and outcomes by breast cancer subtype has not been previously evaluated. METHODS: The authors evaluated the relation between BMI and outcomes in 3 adjuvant trials coordinated by the Eastern Cooperative Oncology Group that included chemotherapy regimens with doxorubicin and cyclophosphamide, including E1199, E5188, and E3189. Results are expressed as hazard ratios (HRs) from Cox proportional hazards models (HR >1 indicates a worse outcome). All P values are 2-sided. RESULTS: When evaluated as a continuous variable in trial E1199, increasing BMI within the obese (BMI, ≥30 kg/m2) and overweight (BMI, 25-29.9 kg/m2) ranges was associated with inferior outcomes in hormone receptor-positive, human epidermal growth receptor 2 (HER-2)/ neu-negative disease for disease-free survival (DFS; P = .0006) and overall survival (OS; P = .0007), but not in HER-2/ neu-overexpressing or triple-negative disease. When evaluated as a categorical variable, obesity was associated with inferior DFS (HR, 1.24; 95% confidence interval [CI], 1.06-1.46; P = .0008) and OS (HR, 1.37; 95% CI, 1.13-1.67; P = .002) in hormone receptor-positive disease, but not other subtypes. In a model including obesity, disease subtype, and their interaction, the interaction term was significant for OS ( P = .02) and showed a strong trend for DFS ( P = .07). Similar results were found in 2 other trials (E5188, E3189). CONCLUSIONS: In a clinical trial population that excluded patients with significant comorbidities, obesity was associated with inferior outcomes specifically in patients with hormone receptor-positive operable breast cancer treated with standard chemohormonal therapy. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background The association between black race and worse outcomes in operable breast cancer reported in previous studies has been attributed to a higher incidence of more aggressive triple-negative disease, disparities in care, and comorbidities. We evaluated associations between black race and outcomes, by tumor hormone receptor and HER2 expression, in patients who were treated with contemporary adjuvant therapy. Methods The effect of black race on disease-free and overall survival was evaluated using Cox proportional hazards models adjusted for multiple covariates in a clinical trial population that was treated with anthracycline- and taxane-containing chemotherapy. Categorical variables were compared using the Fisher exact test. All P values are two-sided. Results Of 4817 eligible patients, 405 (8.4%) were black. Compared with nonblack patients, black patients had a higher rate of triple-negative disease (31.9% vs 17.2%; P < .001) and a higher body mass index (median: 31.7 vs 27.4 kg/m2; P < .001). Black race was statistically significantly associated with worse disease-free survival (5-year disease-free survival, black vs nonblack: 76.7% vs 84.5%; hazard ratio of recurrence or death = 1.58, 95% confidence interval = 1.19 to 2.10, P = .0015) and overall survival (5-year overall survival, black vs nonblack: 87.6% vs 91.9%; hazard ratio of death = 1.49, 95% confidence interval = 1.05 to 2.12, P = .025) in patients with hormone receptor–positive HER2-negative disease but not in patients with triple-negative or HER2-positive disease. In a model that included black race, hormone receptor–positive HER2-negative disease vs other subtypes, and their interaction, the interaction term was statistically significant for disease-free survival (P = .027) but not for overall survival (P = .086). Conclusion Factors other than disparities in care or aggressive disease contribute to increased recurrence in black women with hormone receptor–positive breast cancer. [ABSTRACT FROM PUBLISHER]

The anthracyclines are commonly used for the treatment of early stage and advanced stage breast cancer, but many patients develop resistance to therapy. The definition of anthracycline resistance varies considerably in the literature, but in most cases includes disease progression during or within 6–12 months after completion of anthracycline therapy. Some authors have distinguished true anthracycline resistance (defined as progression during anthracycline therapy) from anthracycline pretreatment (defined as progression after completion of therapy). Single agents that have demonstrated response rates of at least 15–20% in anthracycline pretreated or resistant disease include the antitubulin agents (docetaxel, paclitaxel, vinorelbine), antimetabolites (capecitabine, fluorouracil), nucleoside analogues (gemcitabine), and trastuzumab (for HER2/neu positive disease only). Phase III studies have demonstrated that docetaxel is more effective than paclitaxel, mitomycin/vinblastine, and methotrexate/fluorouracil, and that the docetaxel/capecitabine combination is more effective than docetaxel alone. The decision regarding which agent(s) to use should be based upon the patient’s prior treatment history, tumor biology (HER2/neu and hormone receptor expression), comorbid conditions (e.g. neuropathy, heart disease), and other considerations (e.g. insurance coverage for oral medication). The choice of a specific treatment regimen must be individualized based upon these considerations. [ABSTRACT FROM AUTHOR]

Purpose The Trial Assigning Individualized Options for Treatment (TAILORx) found chemotherapy could be omitted in many women with hormone receptor–positive, HER2 -negative, node-negative breast cancer and 21-gene recurrence scores (RS) 11–25, but left unanswered questions. We used simulation modeling to fill these gaps. Methods We simulated women eligible for TAILORx using joint distributions of patient and tumor characteristics and RS from TAILORx data; treatment effects by RS from other trials; and competing mortality from the Surveillance, Epidemiology, and End Results program database. The model simulations replicated TAILORx design, and then tested treatment effects on 9-year distant recurrence-free survival (DRFS) in 14 new scenarios: eight subgroups defined by age (≤50 and >50 years) and 21-gene RS (11–25/16–25/16–20/21–25); six different RS cut points among women ages 18–75 years (16–25, 16–20, 21–25, 26–30, 26–100); and 20-year follow-up. Mean hazard ratios SD, and DRFS rates are reported from 1000 simulations. Results The simulation results closely replicated TAILORx findings, with 75% of simulated trials showing noninferiority for chemotherapy omission. There was a mean DRFS hazard ratio of 1.79 (0.94) for endocrine vs chemoendocrine therapy among women ages 50 years and younger with RS 16–25; the DFRS rates were 91.6% (0.04) for endocrine and 94.8% (0.01) for chemoendocrine therapy. When treatment was randomly assigned among women ages 18–75 years with RS 26–30, the mean DRFS hazard ratio for endocrine vs chemoendocrine therapy was 1.60 (0.83). The conclusions were unchanged at 20-year follow-up. Conclusions Our results confirmed a small benefit in chemotherapy among women aged 50 years and younger with RS 16–25. Simulation modeling is useful to extend clinical trials, indicate how uncertainty might affect results, and power decision tools to support broader practice discussions. [ABSTRACT FROM AUTHOR]

Late disease recurrence (more than 5 years after initial diagnosis) represents a clinical challenge in the treatment and management of estrogen receptor-positive breast cancer (BC). An international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. The underlying biological causes of late recurrence are complex, with the processes governing cancer cell dormancy, including immunosurveillance, cell proliferation, angiogenesis, and cellular stemness, being integral to disease progression. These critical processes are described herein as well as their role in influencing risk of recurrence. Moreover, observational and interventional clinical trials are proposed, with a focus on methods to identify patients at risk of recurrence and possible strategies to combat this in patients with estrogen receptor-positive BC. Because the problem of late BC recurrence of great importance, recent advances in disease detection and patient monitoring should be incorporated into novel clinical trials to evaluate approaches to enhance patient management. Indeed, future research on these issues is planned and will offer new options for effective late recurrence treatment and prevention strategies. [ABSTRACT FROM AUTHOR]

Upon analysis of archived primary tumors of 482 patients with triple negative breast cancer (TNBC) enrolled in two randomized Phase III adjuvant chemotherapy trials, we have found that tumor infiltrating lymphocytes (TILs), as assessed and quantified by hematoxylin and eosin (H&E) staining are a robust and independent predictor of disease-free survival (DFS), distant recurrence-free interval (DRFI) and overall survival (OS).1Our findings provide confirmation of results observed in TNBC in a European adjuvant chemotherapy dataset and therefore elevate TILs as prognostic biomarker for operable TNBC to level I evidence. [ABSTRACT FROM AUTHOR]