Brain-computer interface relieves chronic chemotherapy-induced peripheral neuropathy: A randomized, double-blind, placebo-controlled trial.

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

Outcomes of older adults with early-stage triple-negative breast cancer (TNBC) receiving chemotherapy: a single-institution experience.

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

Axillary Nodal Metastases Conversion and Perioperative Complications with Neoadjuvant Pembrolizumab Therapy in Triple-Negative Breast Cancer.

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

Monitoring response to neoadjuvant chemotherapy in triple negative breast cancer using circulating tumor DNA.

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

Patient-Reported Quality of Life at Diagnosis in Adolescent and Young Adults With Cancer.

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

Prediction of breast cancer-related lymphedema by dermal backflow detected with near-infrared fluorescence lymphatic imaging.

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

Clinical Course of Breast Cancer Patients with Local-Regional Progression During Neoadjuvant Systemic Therapy.

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

Sociodemographic Factors Associated With Rapid Relapse in Triple-Negative Breast Cancer: A Multi-Institution Study.

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

Impact of Delayed Neoadjuvant Systemic Chemotherapy on Overall Survival Among Patients with Breast Cancer.

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

A phase Ib study of entinostat plus lapatinib with or without trastuzumab in patients with HER2-positive metastatic breast cancer that progressed during trastuzumab treatment.

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

Ductal Carcinoma In Situ and Margins <2 mm: Contemporary Outcomes With Breast Conservation.

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

Long-Term Survival of De Novo Stage IV Human Epidermal Growth Receptor 2 (HER2) Positive Breast Cancers Treated with HER2-Targeted Therapy.

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

Lapatinib activity in metastatic human epidermal growth factor receptor 2-positive breast cancers that received prior therapy with trastuzumab, pertuzumab, and/or ado-trastuzumab emtansine (T-DM1).

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

Adaptive group-sequential design with population enrichment in phase 3 randomized controlled trials with two binary co-primary endpoints.

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

Potentially inappropriate medication use in older patients with breast and colorectal cancer.

BACKGROUND: The objective of this study was to determine patient characteristics associated with potentially inappropriate medication (PIM) use and its impact on outcomes for patients with breast or colorectal cancer receiving adjuvant chemotherapy. METHODS: The Surveillance, Epidemiology, and End Results database, linked to Medicare claims, was used. The cohort included patients who were 66 years old or older and were diagnosed with stage II or III breast or colorectal cancer between July 1, 2007, and December 31, 2009. The Drugs to Avoid in the Elderly (DAE) list and the Beers criteria were used to identify PIM use. Univariate/multivariate logistic regression determined the association of baseline PIMs with covariates. Event-free survival (EFS) was defined as the time from chemotherapy initiation to the first emergency room (ER) visit, hospitalization, death, or a composite until 3 months after chemotherapy. Cox proportional hazards modeling determined the association of PIMs with EFS. RESULTS: The analysis included 1595 patients with breast cancer and 1528 patients with colorectal cancer. The baseline PIM frequencies were 22.2% (according to the DAE list) and 27.6% (according to the Beers criteria) in the breast cohort and 15.5% (according to the DAE list) and 24.8% (according to the Beers criteria) in the colorectal cohort. Among patients with breast cancer, 37.5% had at least 1 adverse outcome; associations included the use of ≥5 medications, an advanced stage, higher comorbidity, and prior ER visits/hospitalizations. Baseline PIM use according to the DAE list was associated with an increased risk of death in patients with breast cancer. Among patients with colorectal cancer, 45% had at least 1 adverse outcome, and associations included the use of ≥5 medications, older age, female sex, and higher comorbidity. A time-to-event analysis revealed no association between baseline PIM use and most outcomes. CONCLUSIONS: These findings require further prospective confirmation, but they support a correlation between polypharmacy and adverse outcomes for cancer patients and call into question the association with PIMs. Cancer 2018;124:3000-7. © 2018 American Cancer Society.

Genetic Counseling Referral Rates in Long-Term Survivors of Triple-Negative Breast Cancer.

Background: Inherited BRCA gene mutations (pathogenic variants) cause 10% of breast cancers. BRCA pathogenic variants predispose carriers to triple-negative breast cancer (TNBC); around 30% of patients with TNBC carry BRCA pathogenic variants. The 2018 NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian recommend genetic counseling referrals for patients with TNBC diagnosed at age ≤60 years. This study sought to describe genetic counseling referral patterns among long-term TNBC survivors at The University of Texas MD Anderson Cancer Center. Methods: This single-institution retrospective analysis of female long-term (disease-free for ≥5 years) TNBC survivors sought to determine the rate of genetic counseling referral among patients diagnosed at age ≤60 years between 1992 and 2008. Patients who underwent treatment and surveillance visits at our institution and were followed until 2017 were included. We collected BRCA pathogenic variant status among tested patients. Descriptive statistical methods and a univariate analysis were used to identify patient characteristics associated with genetic counseling referral. Results: We identified 646 female long-term TNBC survivors with a median age at diagnosis of 47 years. Of these, 245 (38%) received a recommendation for a genetic counseling referral. Among those referred, 156 (64%) underwent genetic testing, and 35% of those tested had BRCA pathogenic variants. Interestingly, among those referred, 20% declined genetic testing. The rate of genetic referrals improved over time, from 25% among TNBC survivors whose last surveillance visit was between 2011 and 2013 to 100% among those whose last surveillance visit was between 2014 or later. Younger age and premenopausal status at diagnosis and a family history of breast or ovarian cancer were associated with an increased rate of referral for genetic counseling. Conclusions: Among long-term TNBC survivors, the rate of referral to genetic counseling increased over time, and among those tested, 35% carried a BRCA pathogenic variant. Survivorship care provides an excellent opportunity to refer eligible patients for genetic counseling.

Outcomes in patients with early-stage breast cancer who underwent a 21-gene expression assay.

BACKGROUND: Invasive disease-free survival (IDFS) rates are excellent in patients with breast cancer (BC) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), axillary lymph node-negative (LN-) tumors with a 21-gene expression assay recurrence score (RS) of 0 to 10. However, to the authors' knowledge, the outcomes among patients with an RS of 11 to 25 who are treated with endocrine therapy alone are unknown. METHODS: In this retrospective single-institution study, the authors described the characteristics of patients with HR+, HER2-, LN- BC who underwent a 21-gene expression assay. In addition, among those individuals diagnosed between 2005 and 2011, we measured IDFS, recurrence-free survival, distant recurrence-free survival, and overall survival rates, focusing on patients with an RS of 11 to 25 by receipt of chemotherapy. The Kaplan-Meier method was used to estimate survival rates and multivariable Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals (95% CIs). RESULTS: Among 1424 patients, the RS distribution was 0 to 10 in 297 patients (21%), 11 to 25 in 894 patients (63%), and >25 in 233 patients (16%); of these, 1.7%, 15%, and 73.4% of patients, respectively, received chemotherapy. With a median follow-up of 58 months, those patients with an RS of 11 to 25 had an IDFS rate at 5 years of 92.6% (95% CI, 89.6%-94.7%), which was comparable between those who received chemotherapy and those who did not. The hazard ratios of the effect of chemotherapy were 1.64 for IDFS (95% CI, 0.73-3.71), 1.46 for recurrence-free survival (95% CI, 0.41-5.23), 1.25 for distant recurrence-free survival (95% CI, 0.32-4.92), and 2.19 for overall survival (95% CI, 0.44-11.0). CONCLUSIONS: The results of the current study demonstrate similar outcomes with or without chemotherapy in patients with HR+, HER2-, LN- BC who have an RS of 11 to 25, but a benefit from chemotherapy in this group cannot be ruled out. Cancer 2017;123:2422-31. © 2017 American Cancer Society.

Mammographic breast density is associated with the development of contralateral breast cancer.

BACKGROUND: Women with dense mammographic breast density (BD) have a 2-fold increased risk of developing primary breast cancer (BC). The authors hypothesized that dense mammographic BD also is associated with an increased risk of developing contralateral breast cancer (CBC). METHODS: Among female patients treated at The University of Texas MD Anderson Cancer Center for sporadic, AJCC stage I to stage III BC between January 1997 and December 2012, the authors identified patients who had developed metachronous CBC (cases) and selected 1:2 matched controls who did not develop CBC using incidence density sampling, matched on attainted age, year of diagnosis, and hormone receptor status of the first BC. Mammographic BD, assessed at the time of first BC diagnosis, was categorized as "nondense" (American College of Radiology breast categories of fatty or scattered density) or "dense" (American College of Radiology categories of heterogeneously dense or extremely dense). Multivariable conditional logistic regression models were used for statistical analysis. RESULTS: A total of 229 cases and 451 controls were evaluated. Among the cases, approximately 39.3% had nondense breast tissue and 60.7% had dense breast tissue. Among controls, approximately 48.3% had nondense breast tissue and 51.7% had dense breast tissue. After adjustment for potential prognostic risk factors for BC, the odds of developing CBC were found to be significantly higher for patients with dense breasts (odds ratio, 1.80; 95% confidence interval, 1.22-2.64 [P<.01]) than for those with nondense breasts. Patients who received chemotherapy or endocrine therapy were less likely to develop CBC. CONCLUSIONS: In women with primary BC, mammographic BD appears to be a risk factor for the development of CBC. Cancer 2017;123:1935-1940. © 2017 American Cancer Society.

A 10-Year Experience with Mastectomy and Tissue Expander Placement to Facilitate Subsequent Radiation and Reconstruction.

BACKGROUND: An integrated approach to skin sparing mastectomy with tissue expander placement followed by radiotherapy and delayed reconstruction was initiated in our institution in 2002. The purpose of this study was to assess the surgical outcomes of this strategy. METHODS: Between September 2002 and August 2013, a total of 384 reconstructions had a tissue expander placed at the time of mastectomy and subsequently underwent radiotherapy. Rates and causes of tissue expander explantation before, during, and after radiotherapy, as well as tumor specific outcomes and reconstruction approaches, were collected. RESULTS: Median follow-up after diagnosis was 5.6 (range 1.3-13.4) years. In the study cohort, 364 patients (94.8%) had stage II-III breast cancer, and 7 patients (1.8%) had locally recurrent disease. The 5-year rates of actuarial locoregional control, disease-free survival, and overall survival were 99.2, 86.1, and 92.4%, respectively. The intended delayed-immediate reconstruction was subsequently completed in 325 of 384 mastectomies (84.6% of the study cohort). Of the remaining 59 tissue expanders, 1 was explanted before radiotherapy, 1 during radiotherapy, and 7 patients (1.8%) were lost to follow-up. Fifty patients (13.0%) required tissue expander explantation after radiation and before their planned final reconstruction, primarily due to cellulitis. Nonetheless, the cumulative rate of completed reconstructions was 89.6%. The median time from placement of the tissue expander until reconstruction was 12 (interquartile range 9-15) months. CONCLUSIONS: Tissue expander placement at skin-sparing mastectomy in patients who require radiotherapy appears to be a viable strategy for combining reconstruction and radiotherapy.

Impact of Time from Completion of Neoadjuvant Chemotherapy to Surgery on Survival Outcomes in Breast Cancer Patients.

BACKGROUND: No studies have examined the impact of the interval from conclusion of neoadjuvant chemotherapy to surgery in breast cancer patients. This study was undertaken to investigate the relationship between time interval from neoadjuvant chemotherapy to surgery and survival outcomes. METHODS: Breast cancer patients diagnosed with stage I-III disease who received neoadjuvant chemotherapy June 1995 to April 2007 were identified. The effect of neoadjuvant chemotherapy to surgery interval, defined as ≤4, 4-6, or >6 weeks, on survival outcomes was examined. Descriptive statistics and Cox proportional hazards models were used. RESULTS: A total of 1101 patients were identified. Median time to surgery was 33 (range 8-159) days; 335 patients (30.4 %) had surgery within 4 weeks of their last dose of neoadjuvant chemotherapy, 524 (47.6 %) within 4-6 weeks, and 242 (22.0 %) after more than 6 weeks. Median follow-up was 94 (range 3-178) months. The 5-year overall survival (OS) estimates were 79, 87, and 81 % in patients who underwent surgery ≤4, 4-6, and >6 weeks after neoadjuvant chemotherapy, respectively (p = 0.03). The three groups did not differ in 5-year recurrence-free survival (RFS) or locoregional recurrence-free survival (LRFS). In multivariable analysis, compared with an interval of ≤4 weeks, patients who underwent surgery at 4-6 or >6 weeks had equivalent OS, LRFS, and RFS; a sensitivity analysis suggested worse OS in patients who underwent surgery at >8 weeks. CONCLUSIONS: Patients with neoadjuvant chemotherapy to surgery intervals of up to 8 weeks had equivalent OS, RFS, and LRFS.