Neoadjuvant Trebananib plus Paclitaxel-based Chemotherapy for Stage II/III Breast Cancer in the Adaptively Randomized I-SPY2 Trial-Efficacy and Biomarker Discovery.

PURPOSE: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. PATIENTS AND METHODS: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy "graduates" if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. RESULTS: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%-99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. CONCLUSIONS: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.

Changes in Surgical Management of the Axilla Over 11 Years - Report on More Than 1500 Breast Cancer Patients Treated with Neoadjuvant Chemotherapy on the Prospective I-SPY2 Trial.

BACKGROUND: Axillary surgery after neoadjuvant chemotherapy (NAC) is becoming less extensive. We evaluated the evolution of axillary surgery after NAC on the multi-institutional I-SPY2 prospective trial. METHODS: We examined annual rates of sentinel lymph node (SLN) surgery with resection of clipped node, if present), axillary lymph node dissection (ALND), and SLN and ALND in patients enrolled in I-SPY2 from January 1, 2011 to December 31, 2021 by clinical N status at diagnosis and pathologic N status at surgery. Cochran-Armitage trend tests were calculated to evaluate patterns over time. RESULTS: Of 1578 patients, 973 patients (61.7%) had SLN-only, 136 (8.6%) had SLN and ALND, and 469 (29.7%) had ALND-only. In the cN0 group, ALND-only decreased from 20% in 2011 to 6.25% in 2021 (p = 0.0078) and SLN-only increased from 70.0% to 87.5% (p = 0.0020). This was even more striking in patients with clinically node-positive (cN+) disease at diagnosis, where ALND-only decreased from 70.7% to 29.4% (p < 0.0001) and SLN-only significantly increased from 14.6% to 56.5% (p < 0.0001). This change was significant across subtypes (HR-/HER2-, HR+/HER2-, and HER2+). Among pathologically node-positive (pN+) patients after NAC (n = 525) ALND-only decreased from 69.0% to 39.2% (p < 0.0001) and SLN-only increased from 6.9% to 39.2% (p < 0.0001). CONCLUSIONS: Use of ALND after NAC has significantly decreased over the past decade. This is most pronounced in cN+ disease at diagnosis with an increase in the use of SLN surgery after NAC. Additionally, in pN+ disease after NAC, there has been a decrease in use of completion ALND, a practice pattern change that precedes results from clinical trials.

Breast Conservation Surgery and Mastectomy Have Similar Locoregional Recurrence After Neoadjuvant Chemotherapy: Results From 1462 Patients on the Prospective, Randomized I-SPY2 Trial.

Neoadjuvant chemotherapy (NAC) increases rates of successful breast-conserving surgery (BCS) in patients with breast cancer. However, some studies suggest that BCS after NAC may confer an increased risk of locoregional recurrence (LRR). We assessed LRR rates and locoregional recurrence-free survival (LRFS) in patients enrolled on I-SPY2 (NCT01042379), a prospective NAC trial for patients with clinical stage II to III, molecularly high-risk breast cancer. Cox proportional hazards models were used to evaluate associations between surgical procedure (BCS vs mastectomy) and LRFS adjusted for age, tumor receptor subtype, clinical T category, clinical nodal status, and residual cancer burden (RCB). In 1462 patients, surgical procedure was not associated with LRR or LRFS on either univariate or multivariate analysis. The unadjusted incidence of LRR was 5.4% after BCS and 7.0% after mastectomy, at a median follow-up time of 3.5 years. The strongest predictor of LRR was RCB class, with each increasing RCB class having a significantly higher hazard ratio for LRR compared with RCB 0 on multivariate analysis. Triple-negative receptor subtype was also associated with an increased risk of LRR (hazard ratio: 2.91, 95% CI: 1.8-4.6, P < 0.0001), regardless of the type of operation. In this large multi-institutional prospective trial of patients completing NAC, we found no increased risk of LRR or differences in LRFS after BCS compared with mastectomy. Tumor receptor subtype and extent of residual disease after NAC were significantly associated with recurrence. These data demonstrate that BCS can be an excellent surgical option after NAC for appropriately selected patients.

Association of Residual Ductal Carcinoma In Situ With Breast Cancer Recurrence in the Neoadjuvant I-SPY2 Trial.

Importance: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in breast cancer strongly correlates with overall survival and has become the standard end point in neoadjuvant trials. However, there is controversy regarding whether the definition of pCR should exclude or permit the presence of residual ductal carcinoma in situ (DCIS). Objective: To examine the association of residual DCIS in surgical specimens after neoadjuvant chemotherapy for breast cancer with survival end points to inform standards for the assessment of pathologic complete response. Design, Setting, and Participants: The study team analyzed the association of residual DCIS after NAC with 3-year event-free survival (EFS), distant recurrence-free survival (DRFS), and local-regional recurrence (LRR) in the I-SPY2 trial, an adaptive neoadjuvant platform trial for patients with breast cancer at high risk of recurrence. This is a retrospective analysis of clinical specimens and data from the ongoing I-SPY2 adaptive platform trial of novel therapeutics on a background of standard of care for early breast cancer. I-SPY2 participants are adult women diagnosed with stage II/III breast cancer at high risk of recurrence. Interventions: Participants were randomized to receive taxane and anthracycline-based neoadjuvant therapy with or without 1 of 10 investigational agents, followed by definitive surgery. Main Outcomes and Measures: The presence of DCIS and EFS, DRFS, and LRR. Results: The study team identified 933 I-SPY2 participants (aged 24 to 77 years) with complete pathology and follow-up data. Median follow-up time was 3.9 years; 337 participants (36%) had no residual invasive disease (residual cancer burden 0, or pCR). Of the 337 participants with pCR, 70 (21%) had residual DCIS, which varied significantly by tumor-receptor subtype; residual DCIS was present in 8.5% of triple negative tumors, 15.6% of hormone-receptor positive tumors, and 36.6% of ERBB2-positive tumors. Among those participants with pCR, there was no significant difference in EFS, DRFS, or LRR based on presence or absence of residual DCIS. Conclusions and Relevance: The analysis supports the definition of pCR as the absence of invasive disease after NAC regardless of the presence or absence of DCIS. Trial Registration: ClinicalTrials.gov Identifier NCT01042379.

Single Center Oncoplastic Experience and Patient Satisfaction Reported via Patient Reported Outcomes.

Oncoplastic breast surgery (OPS) is gaining in popularity compared with traditional breast conserving surgery due to wider resections and better satisfaction with cosmetic outcomes. This study analyzed OPS versus traditional breast conserving surgery outcomes: wound complications, reoperations for margins or fat necrosis, and ipsilateral recurrence. Methods: This retrospective review compared 191 OPS and traditional breast conserving surgery patients on patient-related factors, primary outcomes, and patient reported outcome measures results. A propensity score method analysis using 1:1 to nearest neighbor was also performed. Results: OPS patients were younger, less likely to be smokers, more likely to be ER+ and PR+, and had larger specimen volumes than did traditional breast conserving surgery patients (P < 0.05). There were also differences in distribution of invasive ductal carcinoma and noninvasive disease (P < 0.05). After the propensity score method, the differences observed between the cohorts disappeared. No differences were observed between groups for wound complication, reoperation for positive margins or fat necrosis, or ipsilateral recurrence. Results of patient reported outcome measures showed greater satisfaction with breast surgery in OPS patients (P < 0.01). Conclusions: We showed that OPS is a noninferior technique that should be discussed with appropriate patients. Operative planning should involve patient preferences in optimizing long-term cosmetic outcomes.

HDAC inhibition prevents transgene expression downregulation and loss-of-function in T-cell-receptor-transduced T cells.

T cells that are gene-modified with tumor-specific T cell receptors are a promising treatment for metastatic melanoma patients. In a clinical trial, we treated seven metastatic melanoma patients with autologous T cells transduced to express a tyrosinase-reactive T cell receptor (TCR) (TIL 1383I) and a truncated CD34 molecule as a selection marker. We followed transgene expression in the TCR-transduced T cells after infusion and observed that both lentiviral- and retroviral-transduced T cells lost transgene expression over time, so that by 4 weeks post-transfer, few T cells expressed either lentiviral or retroviral transgenes. Transgene expression was reactivated by stimulation with anti-CD3/anti-CD28 beads and cytokines. TCR-transduced T cell lentiviral and retroviral transgene expression was also downregulated in vitro when T cells were cultured without cytokines. Transduced T cells cultured with interleukin (IL)-15 maintained transgene expression. Culturing gene-modified T cells in the presence of histone deacetylase (HDAC) inhibitors maintained transgene expression and functional TCR-transduced T cell responses to tumor. These results implicate epigenetic processes in the loss of transgene expression in lentiviral- and retroviral-transduced T cells.

Do high-volume centers mitigate complication risk and reduce costs associated with performing pancreaticoduodenectomy in ethnic minorities?

INTRODUCTION: Few studies examine the impact of ethnicity on post-operative outcomes and costs associated with pancreaticoduodenectomy (PD). METHODS: Multivariable regression (MVR) was used to perform a risk-adjusted comparison of patients within the Healthcare Cost and Utilization Project Databases undergoing PD. RESULTS: 4742 patients underwent PD. 3871 (81%) were white, 456 (10%) black, and 415 (9%) Hispanic. Black and Hispanics were less likely than whites to undergo PD in high volume centers. Blacks and Hispanics had a higher risk of select post-operative complications, prolonged lengths of stay, and high-cost outliers. When PDs done in high volume centers were evaluated separately, blacks and Hispanics had a lower adjusted-risk of any serious morbidity (OR 0.44, 95% CI [0.33, 0.57], OR 0.56, 95% CI [0.43, 0.73]) than whites but costs for PD among the three ethnic groups were statistically identical. CONCLUSION: Racial and ethnic minorities undergoing PD are less likely to receive care at high-volume centers, are at an increased risk of post-operative morbidity, and have higher odds of being high-cost outliers than NHW.

MK-2206 and Standard Neoadjuvant Chemotherapy Improves Response in Patients With Human Epidermal Growth Factor Receptor 2-Positive and/or Hormone Receptor-Negative Breast Cancers in the I-SPY 2 Trial.

PURPOSE: The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer. PATIENTS AND METHODS: I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week. RESULTS: MK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform). CONCLUSION: The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.

Enhanced recovery after surgery: A clinical review of implementation across multiple surgical subspecialties.

Enhanced recovery after surgery (ERAS) is a multimodal protocol applied towards perioperative patient care. ERAS programs are implemented by a multidisciplinary team centered around the patient, incorporating outpatient clinical staff, preoperative nurses, anesthesiologists, operative nurses, postoperative recovery staff, floor inpatient nurses, dieticians, physical therapists, social workers, and surgeons. Initial studies on perioperative care measures focused on cardiac surgery. Subsequently, the development of the ERAS Study Group in 2001 focused on colorectal surgery and postoperative outcome measures. Today, ERAS protocols have been implemented across many surgical subspecialties including: bariatric, breast, plastic, cardiac, colorectal, esophageal, head and neck, hepatic, gynecologic, neurosurgical, orthopedic, pancreatic, thoracic, and urologic surgery. The goal of ERAS programs is to promote rapid recovery as quantified by decreasing the length of hospital stay, complications, and cost of specific surgical interventions. In the setting of the opioid crisis in America, there is also an increasing focus on minimizing perioperative narcotic use. The purpose of this review is to compare ERAS protocols across surgical subspecialties, focusing on quantified metrics of improvement, and to provide a clear and concise summary of the literature in regards to current ERAS practices and success rates.

The laparoscopic approach to pancreatoduodenectomy is cost neutral in very high-volume centers.

BACKGROUND: Little is known regarding the impact of minimally invasive approaches to pancreatoduodenectomy on the aggregate costs of care for patients undergoing pancreatoduodenectomy. METHODS: We queried the Healthcare Cost and Utilization Project State Inpatient Database to identify patients undergoing elective laparoscopic or open pancreatoduodenectomy between 2014 and 2016. RESULTS: In this database, 488 (10%) patients underwent elective laparoscopic; 4,544 (90%) underwent open pancreatoduodenectomy. On adjusted analysis, the risk of perioperative morbidity and overall duration of hospitalization for patients undergoing elective laparoscopic were identical to those for patients undergoing open pancreatoduodenectomy. Patients undergoing elective laparoscopic in low (+$10,399, 95% confidence interval [$3,700, $17,098]) and moderate to high (+$4,505, 95% confidence interval [$528, $8,481]) volume centers had greater costs than those undergoing open pancreatoduodenectomy in the same centers. In very high-volume centers (>127 pancreatoduodenectomies/year), aggregate costs of care for patients undergoing elective laparoscopic were essentially identical to those undergoing open pancreatoduodenectomy in the same centers (+$815, 95% confidence interval [-$1,530, $3,160]). CONCLUSION: Rates of morbidity and overall duration of hospitalization for patients undergoing elective laparoscopic are not different than those undergoing open pancreatoduodenectomy. At low to moderate and high-volume centers, elective laparoscopic is associated with greater aggregate costs of care relative to open pancreatoduodenectomy. At very high-volume centers, elective laparoscopic is cost-neutral.

The laparoscopic approach to distal pancreatectomy is a value-added proposition for patients undergoing care in moderate-volume and high-volume centers.

BACKGROUND: Little is known regarding the impact of the minimally invasive approach to distal pancreatectomy on the aggregate costs of care for patients undergoing distal pancreatectomy. METHODS: We queried the Healthcare Cost and Utilization Project State Inpatient Database to identify patients undergoing elective laparoscopic distal pancreatectomy or open distal pancreatectomy between 2012 and 2014. Multivariable regression was used to evaluate postoperative outcomes including readmissions to 90 days after distal pancreatectomy. RESULTS: A total of 267 (11%) patients underwent laparoscopic distal pancreatectomy, and a total of 2,214 (89%) underwent open distal pancreatectomy. On multivariable regression, patients undergoing laparoscopic distal pancreatectomy had a decreased odds risk of having any severe adverse outcome (odds ratio 0.73, 95% confidence interval [0.54-0.97]), prolonged length of stay (odds ratio 0.49, 95% confidence interval [0.30-0.79]), and of being in the highest quartile for aggregate costs of care (odds ratio 0.46, 95% confidence interval [0.32-0.66]) relative to those undergoing open distal pancreatectomy. Patients undergoing laparoscopic distal pancreatectomy had a lower average 90-day aggregate cost of care than those undergoing open distal pancreatectomy when procedures were performed in high-volume (-$16,153, 95% CI: [-$23,342 to -$8,964]) centers. CONCLUSION: Patients undergoing laparoscopic distal pancreatectomy have a lower risk of severe adverse outcomes, prolonged overall length of stay, and lower associated costs of care relative to those undergoing open distal pancreatectomy. This association is independent of hospital volume.

Correction to: Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells.

The authors would like to make the following corrections to the published article.

Considerations for sentinel lymph node biopsy in breast cancer patients with biopsy proven axillary disease prior to neoadjuvant treatment.

BACKGROUND: Axillary disease can be downstaged with neoadjuvant treatment for breast cancer. We attempted to identify factors to consider in determining whether to perform a sentinel lymph node biopsy in patients with biopsy proven axillary metastases (cN+) prior to neoadjuvant treatment. METHODS: A retrospective chart review was conducted on patients at a single tertiary care center who underwent neoadjuvant treatment followed by surgery between 9/2013 and 2/2017. RESULTS: 47% of patients with node positive disease prior to neoadjuvant treatment were downstaged to node negative (ypN0) disease. These patients were more likely to have triple negative or Her2 positive disease than those patients who remained node positive (ypN+) as these were more likely to have hormone receptor positive disease. These patients were also more likely to demonstrate complete clinical imaging response of the primary tumor and axilla on preoperative breast MRI. CONCLUSIONS: Tumor biology and clinical response noted on breast MRI can help guide the decision to perform sentinel lymph node biopsy in patients with axillary node positive disease prior to neoadjuvant treatment.

Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells.

Malignant melanoma incidence has been increasing for over 30 years, and despite promising new therapies, metastatic disease remains difficult to treat. We describe preliminary results from a Phase I clinical trial (NCT01586403) of adoptive cell therapy in which three patients received autologous CD4+ and CD8+ T cells transduced with a lentivirus carrying a tyrosinase-specific TCR and a marker protein, truncated CD34 (CD34t). This unusual MHC Class I-restricted TCR produces functional responses in both CD4+ and CD8+ T cells. Parameters monitored on transduced T cells included activation (CD25, CD69), inhibitory (PD-1, TIM-3, CTLA-4), costimulatory (OX40), and memory (CCR7) markers. For the clinical trial, T cells were activated, transduced, selected for CD34t+ cells, then re-activated, and expanded in IL-2 and IL-15. After lymphodepleting chemotherapy, patients were given transduced T cells and IL-2, and were followed for clinical and biological responses. Transduced T cells were detected in the circulation of three treated patients for the duration of observation (42, 523, and 255 days). Patient 1 tolerated the infusion well but died from progressive disease after 6 weeks. Patient 2 had a partial response by RECIST criteria then progressed. After progressing, Patient 2 was given high-dose IL-2 and subsequently achieved complete remission, coinciding with the development of vitiligo. Patient 3 had a mixed response that did not meet RECIST criteria for a clinical response and developed vitiligo. In two of these three patients, adoptive transfer of tyrosinase-reactive TCR-transduced T cells into metastatic melanoma patients had clinical and/or biological activity without serious adverse events.

Does practice make perfect? Resident experience with breast surgery influences excision adequacy.

BACKGROUND: The adequacy of breast-conserving surgery (BCS) for invasive or in situ disease is largely determined by the final surgical margins. Although margin status is associated with various clinicopathologic features, the influence of resident involvement remains controversial. METHODS: Patients who underwent BCS for malignancy from 2009 to 2012 were identified. The effects of various clinicopathologic characteristics and resident involvement were evaluated. RESULTS: Of the 502 cases performed, a resident assisted with most surgeries (95%). The overall rate of positive margins was 30%, which was not associated with resident involvement. Interns assisting from July to September had significantly lower rates of positive margins. Margins were more likely to be positive following any given resident's first 3 cases on their breast rotation than throughout the remainder of their rotation. CONCLUSION: Although resident level alone does not influence the adequacy of BCS, experience gained over time does appear to be associated with lower rates of positive margins.

Epidemiology of breast cancer.

This article outlines the current incidence, prevalence, and mortality of breast cancer and reviews the epidemiology of the disease. Major risk factors for the development of breast cancer are covered, including reproductive, genetic, and environmental variables. Understanding the epidemiology of breast cancer will help clinicians identify high-risk patients for appropriate screening and informed disease management decisions.

Notch-1 and Notch-4 biomarker expression in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) demonstrates lack of expression of hormone receptors and human epidermal growth factor receptor. However, there is no targeted therapy for TNBC. The authors analyzed 29 TNBC cases for Notch-1 and Notch-4 biomarker expression and subcellular location, Ki67 proliferation rate, and relevant clinical/survival data. Results demonstrated an unfavorable Ki67 rate in 90% of cases, Notch-1 expression in tumor and endothelial cells in 100% of cases, and Notch-4 expression in tumor cells in 73% of cases and endothelial cells in 100% of cases. Additionally, subcellular localization of Notch-1 and Notch-4 was predominantly nuclear and cytoplasmic. In conclusion, (a) the majority of TNBCs are high-grade infiltrating ductal carcinomas with high Ki67 proliferation rate and (b) both Notch-1 and Notch-4 receptors are overexpressed in tumor and vascular endothelial cells with subcellular localization different from that of hormone-positive breast cancer. Targeting Notch signaling with gamma secretase inhibitors should to be explored to further improve the survival rate of TNBC patients.

Predictors of positive sentinel lymph node in thin melanoma.

BACKGROUND: The treatment of thin melanoma (Breslow thickness <1.0 mm) may include sentinel lymph node (SLN) biopsy (SLNB). The validity of SLNB for thin melanoma remains widely debated. The purpose of this study was to elucidate pathologic factors that are predictive of SLN positivity. METHODS: A retrospective analysis of a prospective database revealed 1,199 patients diagnosed with primary cutaneous melanoma. Multiple logistic regression was used to determine an association between pathologic factors and SLN positivity. RESULTS: Thin melanomas were identified in 469 patients (39%). Of these, 147 patients (31%) underwent SLNB. Positive SLNs were found in 16 patients (11%). Multiple logistic regression demonstrated that both ulceration (odds ratio, 5.27; P = .047) and thickness (odds ratio, 46.69; P = .022) were associated with SLN positivity. CONCLUSIONS: Patients with thin melanomas >.75 mm and/or ulceration should be considered for SLNB.