Pathologic complete response after neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers.

BRCA1 and BRCA2 pathogenic variant carriers develop breast cancers with distinct pathological characteristics and mutational signatures that may result in differential response to chemotherapy. We compared rates of pathologic complete response (pCR) after NAC between BRCA1/2 variant carriers and noncarriers in a cohort of 1426 women (92 [6.5%] BRCA1 and 73 [5.1%] BRCA2) with clinical stage I-III breast cancer treated with NAC followed by surgery from 11/2013 to 01/2022 at Memorial Sloan Kettering Cancer Center. The majority received doxorubicin/cyclophosphamide/paclitaxel therapy (93%); BRCA1/2 carriers were more likely to receive carboplatin (p < 0.001). Overall, pCR was achieved in 42% of BRCA1 carriers, 21% of BRCA2 carriers, and 26% of noncarriers (p = 0.001). Among clinically node-positive (cN+) patients, nodal pCR was more frequent in BRCA1/2 carriers compared to noncarriers (53/96 [55%] vs. 371/856 [43%], p = 0.015). This difference was seen in HR+/HER2- (36% vs. 20% of noncarriers; p = 0.027) and TN subtypes (79% vs. 45% of noncarriers; p < 0.001). In a multivariable analysis of the overall cohort, BRCA1 status, and TN and HER2+ subtypes were independently associated with pCR. These data indicate that BRCA1 carriers may be more likely to achieve overall and nodal pCR in response to NAC compared with BRCA2 carriers and patients with sporadic disease. Further studies with a larger cohort of BRCA1/2 mutation carriers are needed, as a small sample size may have a restricted ability to detect a significant association between mutational status and pCR in sensitivity analyses stratified by subtype and adjusted for clinically relevant factors.

Ductal Carcinoma In Situ.

In breast cancer (BC) pathogenesis models, normal cells acquire somatic mutations and there is a stepwise progression from high-risk lesions and ductal carcinoma in situ to invasive cancer. The precancer biology of mammary tissue warrants better characterization to understand how different BC subtypes emerge. Primary methods for BC prevention or risk reduction include lifestyle changes, surgery, and chemoprevention. Surgical intervention for BC prevention involves risk-reducing prophylactic mastectomy, typically performed either synchronously with the treatment of a primary tumor or as a bilateral procedure in high-risk women. Chemoprevention with endocrine therapy carries adherence-limiting toxicity.

Financial Toxicity Among Women with Breast Cancer Varies by Age and Race.

INTRODUCTION: Financial toxicity negatively affects clinical outcomes in breast cancer. Underrepresented demographics may be at higher risk for financial toxicity. We characterized disparities on the basis of age and other factors. PATIENTS AND METHODS: Surveys completed by women with stage 0-IV breast cancer treated at Memorial Sloan Kettering Cancer Center between 06/2022 and 05/2023 were analyzed. The comprehensive score for financial toxicity (COST) scale was used to assess financial toxicity. Descriptive statistics were calculated for differences in financial toxicity/related factors, and outcomes by age and race. Associations between variables of interest and COST scores were analyzed using linear regression. RESULTS: Of 8512 respondents (75% white, 9.3% Asian, 8.4% Black), most (68%) had clinical stage 0/I disease. Stratified by age, young Black women had higher financial toxicity than young white or Asian women (p < 0.001). On multivariable analysis, women age < 45 years experienced higher financial toxicity than older women (coefficient - 2.0, 95% CI - 2.8 to - 1.1, p < 0.001). Compared with white women, financial toxicity was greater among Black (coefficient - 6.8, 95% CI - 7.8 to - 5.8) and Asian women (coefficient - 3.5, 95% CI - 4.4 to - 2.5). Cost-related medication non-adherence was more frequent among Black and Asian women (p < 0.001). Asian women more often paid for treatment with savings than white and Black women (p < 0.001). Young women reported using savings for treatment-related costs more than older (45% vs. 32%); p < 0.001). CONCLUSIONS: Racial minorities and young patients are disproportionately affected by financial toxicity. Further studies are planned to determine how financial toxicity evolves over time and whether referral to financial services effectively reduces toxicity.

Arm morbidity and financial difficulty in breast cancer survivors.

PURPOSE: Long-term upper extremity symptoms after breast cancer treatment may impact patient-reported financial difficulty. In this cross-sectional investigation, we hypothesized that severity of arm symptoms would be associated with greater financial difficulty. METHODS: Stage 0-III breast cancer patients treated at our institution from 2002 to 2012 were recruited for a 2018 survey study appraising disease-specific patient-centered outcomes using EORTC-QLQ-BR23 and EORTC-QLQ-C30 questionnaires. The association between Arm Symptom (AS) score and Financial Impact (FI) score was assessed, adjusting for clinically relevant variables. RESULTS: Of 1126 interested participants, 882 (78%) responded to surveys. Three hundred fourteen (36%) with incomplete responses were excluded. Median time from surgery was 9 years; 181 (32%) and 117 (21%) had mastectomy with or without reconstruction, 126 (22%) received postmastectomy radiation (PMRT), and 221 (39%) underwent axillary lymph node dissection. 76 (13%) reported some degree of financial difficulty; 10 (2%) the highest degree of difficulty. Of 217 (38%) patients experiencing arm symptoms, 60 (28%) had severe symptoms. Seven (70%) of those with highest degree of financial difficulty had severe arm symptoms. Younger age at surgery (p = .029), mastectomy with reconstruction (p = 0.003), Hispanic ethnicity (p < 0.001), PMRT (p = 0.027), recurrence (p < 0.001), and higher AS score (p < 0.001) were associated with greater financial difficulty. On multivariable analysis, AS score, younger age, Hispanic ethnicity, and recurrence remained associated with financial difficulty. CONCLUSION: In this study, younger age, Hispanic ethnicity, and arm morbidity were associated with increased risk for financial difficulty. Clarifying how treatment-related adverse events such as arm morbidity increase financial hardship may guide interventions to mitigate this burden.

Dose dense doxorubicin plus cyclophosphamide in a modified KEYNOTE522 regimen for triple negative breast cancer.

The KEYNOTE-522 (KN522) regimen for neoadjuvant treatment of triple negative breast cancer (TNBC) utilized q3week dosing for doxorubicin plus cyclophosphamide (AC); however, dose-dense AC (ddAC) has demonstrated superior overall survival (OS) compared to q3week AC in anthracycline and taxane-based regimens. We performed a retrospective analysis assessing the use of ddAC in KN522 and the impact of sequencing ddAC before or after carboplatin/paclitaxel (CbT) plus pembrolizumab on multiple outcomes. 128 patients with TNBC were included. Overall pathologic complete response (pCR) rate of 56%. Sequencing of ddAC vs CbT first showed no difference in pCR rate (ddAC 55% vs. CbT 58%, p = 0.77). However, ddAC first compared to CbT first correlated with a significant increase in the incidence of overall treatment delays (ddAC 70% vs. CbT 51%, p = 0.03), with cytopenias most frequent (ddAC 59% vs. CbT 31%, p = 0.001). ddAC in a modified KN522 regimen is safe, tolerable, and effective. Efficacy is comparable regardless of chemotherapy sequencing, but ddAC first is significantly associated with higher rates of treatment delays and cytopenias.

Impact of Neoadjuvant Chemoimmunotherapy on Surgical Outcomes and Time to Radiation in Triple-Negative Breast Cancer.

BACKGROUND: We examined the association between immunotherapy-containing and standard chemotherapy regimens with treatment delays and postoperative complications in stage II-III triple-negative breast cancer. The effect of immune-related adverse events (irAEs) was compared. PATIENTS AND METHODS: We compared 139 women treated with neoadjuvant pembrolizumab plus chemotherapy (KEYNOTE-522 regimen) from August 2021 to September 2022 with 287 consecutive patients who received neoadjuvant chemotherapy alone prior to July 2021 and underwent surgery. Baseline characteristics, time to treatments, and surgical complications were compared using two-sample non-parametric tests. Linear regression evaluated association of irAEs with time to surgery and radiation. Logistic regression identified factors associated with surgical complications. RESULTS: Age, body mass index, race, American Society of Anesthesiologists (ASA) class, and mastectomy rates were similar among cohorts. No clinically relevant difference in time from end of neoadjuvant treatment to surgery was observed [KEYNOTE-522: median 32 (IQR 27, 43) days; non-KEYNOTE-522: median 31 (IQR 26, 37) days; P = 0.048]. Time to radiation did not differ (P = 0.7). A total of 26 patients (9%; non-KEYNOTE-522) versus 11 (8%; KEYNOTE-522) experienced postoperative complications (P = 0.6). In the KEYNOTE-522 cohort, 59 (43%) of 137 patients experienced 82 irAEs; 40 (68%) required treatment. Older age (P = 0.018) and ASA class 4 (P = 0.007) were associated with delays to surgery after adjusting for clinical factors. Experiencing ≥ 1 irAE was associated with delay to radiation (P = 0.029). IrAEs were not associated with surgical complications (P = 0.4). CONCLUSIONS: We observed no clinically meaningful difference between times to surgery/adjuvant radiation or postoperative complications and type of preoperative chemotherapy. IrAEs were associated with delay to adjuvant radiation but not with postoperative complications or delay to surgery.

Design and Evaluation of a Bilateral Semi-Rigid Exoskeleton to Assist Hip Motion.

This study focused on designing and evaluating a bilateral semi-rigid hip exoskeleton. The exoskeleton assisted the hip joint, capitalizing on its proximity to the body's center of mass. Unlike its rigid counterparts, the semi-rigid design permitted greater freedom of movement. A temporal force-tracking controller allowed us to prescribe torque profiles during walking. We ensured high accuracy by tuning control parameters and series elasticity. The evaluation involved experiments with ten participants across ten force profile conditions with different end-timings and peak magnitudes. Our findings revealed a trend of greater reductions in metabolic cost with assistance provided at later timings in stride and at greater magnitudes. Compared to walking with the exoskeleton powered off, the largest reduction in metabolic cost was 9.1%. This was achieved when providing assistance using an end-timing at 44.6% of the stride cycle and a peak magnitude of 0.11 Nm kg-1. None of the tested conditions reduced the metabolic cost compared to walking without the exoskeleton, highlighting the necessity for further enhancements, such as a lighter and more form-fitting design. The optimal end-timing aligns with findings from other soft hip exosuit devices, indicating a comparable interaction with this prototype to that observed in entirely soft exosuit prototypes.

Enhancing walking performance in patients with peripheral arterial disease: An intervention with ankle-foot orthosis.

Lower extremity peripheral artery disease (PAD) is a cardiovascular condition manifesting from narrowed or blocked arteries supplying the legs. Gait is impaired in patients with PAD. Recent evidence suggests that walking with carbon fiber ankle foot orthoses (AFOs) can improve patient mobility and delay claudication time. This study aimed to employ advanced biomechanical gait analysis to evaluate the impact of AFO intervention on gait performance among patients with PAD. Patients with claudication had hip, knee, and ankle joint kinetics and kinematics assessed using a cross-over intervention design. Participants walked over the force platforms with and without AFOs while kinematic data was recorded with motion analysis cameras. Kinetics and kinematics were combined to quantify torques and powers during the stance period of the gait cycle. The AFOs effectively reduced the excessive ankle plantar flexion and knee extension angles, bringing the patients' joint motions closer to those observed in healthy individuals. After 3 months of the AFO intervention, the hip range of motion decreased, likely due to changes occurring within the ankle chain. With the assistance of the AFOs, the biological power generation required from the ankle and hip during the push-off phase of walking decreased. Wearing AFOs resulted in increased knee flexor torque during the loading response phase of the gait. Based on this study, AFOs may allow patients with PAD to maintain or improve gait performance. More investigation is needed to fully understand and improve the potential benefits of ankle assistive devices.

Social Determinants of Health Associated With the Need for Urgent Versus Elective Cholecystectomy at an Urban, Safety-Net Hospital.

Background: Benign gallstone disease is the most frequent indication for cholecystectomy in the United States. Many patients present with complicated disease requiring urgent interventions, which increases morbidity and mortality. We investigated the association between individual and population-level social determinants of health (SDoH) with urgent versus elective cholecystectomy. Patients and Methods: All patients undergoing cholecystectomy (2014-2021) for benign gallstone disease were included. Demographic and clinical data were linked to population-level SDoH characteristics using census tracts. Data were analyzed using descriptive and inferential statistics. Results: A total of 3,197 patients met inclusion criteria; 1,913 (59.84%) underwent urgent cholecystectomy, 1,204 (37.66%) underwent emergent cholecystectomy, and 80 (2.5%) underwent interval cholecystectomy. On multinomial logistic regression, patients who were older (relative risk [RR], 1.010; p < 0.001), black (RR, 1.634; p = 0.008), and living in census tracts with a higher percent of poverty (RR, 0.017; p = 0.021) had a higher relative risk of presenting for urgent cholecystectomy. Patients who were female (RR, 0.462; p < 0.001), had a primary care provider (PCP; RR, 0.821; p = 0.018), and lived in census tracts with low supermarket access (RR, 0.764; p = 0.038) had a lower relative risk of presenting for urgent cholecystectomy. Only age (RR, 1.066; p < 0.001), female gender (RR, 0.227; p < 0.001), and having a PCP (RR, 1.984; p = 0.034) were associated with presentation for interval cholecystectomy. Conclusions: Patients who were older, black, and living in census tracts with high poverty levels had a higher relative risk of presenting for urgent cholecystectomy at our institution, whereas females and patients with PCPs were more likely to undergo elective cholecystectomy. Improved access to primary care and surgical clinics for all patients at safety-net hospitals may result in improved outcomes in the management of benign gallstone disease by increasing diagnosis and treatment in the elective setting.

Diagnosis of disease affecting gait with a body acceleration-based model using reflected marker data for training and a wearable accelerometer for implementation.

This paper demonstrates the value of a framework for processing data on body acceleration as a uniquely valuable tool for diagnosing diseases that affect gait early. As a case study, we used this model to identify individuals with peripheral artery disease (PAD) and distinguish them from those without PAD. The framework uses acceleration data extracted from anatomical reflective markers placed in different body locations to train the diagnostic models and a wearable accelerometer carried at the waist for validation. Reflective marker data have been used for decades in studies evaluating and monitoring human gait. They are widely available for many body parts but are obtained in specialized laboratories. On the other hand, wearable accelerometers enable diagnostics outside lab conditions. Models trained by raw marker data at the sacrum achieve an accuracy of 92% in distinguishing PAD patients from non-PAD controls. This accuracy drops to 28% when data from a wearable accelerometer at the waist validate the model. This model was enhanced by using features extracted from the acceleration rather than the raw acceleration, with the marker model accuracy only dropping from 86 to 60% when validated by the wearable accelerometer data.

Examining Race and Patient-Reported Outcomes After Contralateral Prophylactic Mastectomy with Reconstruction.

BACKGROUND: Little is known regarding racial differences in satisfaction and quality of life (QOL) after contralateral prophylactic mastectomy (CPM). In this study, we aim to characterize associations between race, and postoperative satisfaction and well-being, utilizing the validated BREAST-Q patient-reported outcome measure. PATIENTS AND METHODS: Patients were eligible if they were diagnosed with stage 0-III unilateral breast cancer and underwent mastectomy with immediate reconstruction at our institution between 2016 and 2022. BREAST-Q surveys were administered in routine clinical care preoperatively and postoperatively to assess QOL. We assessed whether the relationship between race, and domains of satisfaction with breasts and psychosocial well-being differed by receipt of CPM compared with unilateral mastectomy at 6 months, 1 year, 2 years, and 3 years following reconstruction. RESULTS: Of 3334 women, 2040 (61%) underwent unilateral mastectomy and 1294 (39%) underwent CPM. Compared with White and Asian women who received CPM, Black women who underwent CPM were more likely to have higher BMI (p < 0.001), undergo autologous reconstruction (p = 0.006), and receive postmastectomy radiation (PMRT) (p < 0.001). There was no association between race and domains of satisfaction of breasts or psychosocial well-being for women who underwent unilateral mastectomy (p = 0.6 and p > 0.9, respectively) or CPM (p = 0.8 and p = 0.9, respectively). PMRT was negatively associated with both satisfaction with breasts (p < 0.001) and psychosocial well-being (p = 0.007). CONCLUSIONS: Differences in satisfaction with breasts and psychosocial well-being at 3-year follow-up were not associated with race but rather treatment variables, particularly the receipt of PMRT. Further investigations with a larger and more diverse population are needed to validate these findings.

Lower limb revascularization leads to faster walking but with less efficient mechanics in claudicating patients.

Peripheral artery disease (PAD) is characterized by reduced blood flow to the extremities due to atherosclerosis. Studies report impaired gait mechanics in patients with lower extremity PAD. We hypothesized that revascularization surgery would improve gait mechanics when quantified by net lower limb joint work across the stance phase of walking. We performed gait analyses in 35 patients with PAD and 35 healthy, older adults. Patients with PAD performed a walking protocol prior to and six months following revascularization surgery. Healthy adults only took part in a single walking session. Lower limb joint powers were calculated using inverse dynamics and were integrated across early, middle, and late stance phases to determine the work performed during each phase (J kg-1). The work mechanical ratio between positive-producing and negative-producing phases of stance was calculated for each lower-limb joint. Self-selected walking speed significantly increased from 1.13 ± 0.2 ms-1 to 1.26 ± 0.18 ms-1 in patients following revascularization (p < 0.001). We observed a significant decrease in positive late stance work (p < 0.001) in conjunction with more negative work during early stance (p < 0.001) in patients following revascularization. Revascularization surgery led to faster walking without an increase in the ankle joint's mechanical ratio. Our results suggest faster walking was achieved via work done at the hip rather than the ankle. These findings suggest that additional therapies that facilitate the restoration of muscle, tissue, and nervous system damage caused by years of having reduced blood flow to the limbs might still be beneficial following revascularization.

Peripheral artery disease causes consistent gait irregularities regardless of the location of leg claudication pain.

BACKGROUND: The most common symptom of peripheral artery disease (PAD) is intermittent claudication that involves the calf, thigh, and/or buttock muscles. How the specific location of this leg pain is related to altered gait, however, is unknown. OBJECTIVES: We hypothesized that because the location of claudication symptoms uniquely affects different leg muscle groups in people with PAD, this would produce distinctive walking patterns. METHODS: A total of 105 participants with PAD and 35 age-matched older volunteers without PAD (CTRL) were recruited. Participants completed walking impairment questionnaires (WIQ), Gardner-Skinner progressive treadmill tests, the six-minute walk test, and we performed an advanced evaluation of the biomechanics of their overground walking. Participants with PAD were categorized into 4 groups according to their stated pain location(s): calf only (C, n = 43); thigh and calf (TC, n = 18); buttock and calf (BC, n = 15); or buttock, thigh, and calf (BTC, n = 29). Outcomes were compared between CTRL, C, TC, BC and BTC groups using a one-way ANOVA with post-hoc comparisons to identify and assess statistically significant differences. RESULTS: There were no significant differences between CTRL, C, TC, BC and BTC groups in distances walked or walking speed when either pain-free or experiencing claudication pain. Each participant with PAD had significantly dysfunctional biomechanical gait parameters, even when pain-free, when compared to CTRL (pain-free) walking data. During pain-free walking, out of the 18 gait parameters evaluated, we only identified significant differences in hip power generation during push-off (in C and TC groups) and in knee power absorption during weight acceptance (in TC and BC groups). There were no between-group differences in gait parameters while people with PAD were walking with claudication pain. CONCLUSIONS: Our data demonstrate that PAD affects the ischemic lower extremities in a diffuse manner irrespective of the location of claudication symptoms. DATABASE REGISTRATION: ClinicalTrials.gov NCT01970332.

Mutational Status is Associated with a Higher Rate of Pathologic Complete Response After Neoadjuvant Chemotherapy in Hormone Receptor-Positive Breast Cancer.

BACKGROUND: Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) occurs in up to 20% of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancers. Whether this differs among BRCA mutation carriers is uncertain. This study compared pCR between BRCA1/2 mutation carriers and matched sporadic control subjects. METHODS: From November 2013 to January 2022, this study identified 522 consecutive women with clinical stage I to III HR+/HER2- breast cancer treated with NAC and surgery. The study matched BRCA1/2 mutation carriers 1:2 to non-carriers in terms of age, clinical tumor (cT) and nodal (cN) stage, and differentiation. Two-sample non-parametric tests compared baseline characteristics. Multivariable logistic regression assessed pCR (i.e., ypT0/ispN0) by BRCA1/2 mutational status. RESULTS: Of the 522 women (median age, 50 years), 59 had BRCA1/2 mutations, 78% of which were clinically node positive. Anthracycline-based NAC was administered to 97%. More BRCA1/2 mutation carriers were younger, had cT1 tumors, and had poorly differentiated disease. After matching, 58 BRCA1/2 mutation carriers were similar to 116 non-carriers in terms of age (p = 0.6), cT (p = 0.9), cN stage (p = 0.7), and tumor differentiation (p > 0.9). Among the mutation carriers, the pCR rate was 15.5% for BRCA1/2, 38% (8/21) for BRCA1, and 2.7% (1/37) for BRCA2 versus 7.8% (9/116) for the non-carriers (p < 0.001). After NAC, 5 (41.7%) of the 12 BRCA1 mutation carriers converted to pN0 versus 10 (37%) of the 27 BRCA2 mutation carriers and 19 (20.9%) of the 91 non-carriers (p = 0.3). In the multivariable analysis, BRCA1 mutation status was associated with higher odds of pCR than non-carrier status (odds ratio [OR] 6.31; 95% confidence interval [CI] 1.95-20.5; p = 0.002), whereas BRCA2 mutation status was not (OR 0.45; 95% CI 0.02-2.67; p = 0.5). CONCLUSIONS: This study showed that BRCA1 mutation carriers with HR+/HER2- breast cancers have a higher rate of pCR than sporadic cancers and may derive greater benefit from chemotherapy. The use of NAC to downstage these patients should be considered.