Clipping the Positive Lymph Node in Patients with Clinically Node Positive Breast Cancer Treated with Neoadjuvant Chemotherapy: Impact on Axillary Surgery in the ISPY-2 Clinical Trial.

BACKGROUND: For patients with clinically node-positive (cN+) breast cancer undergoing neoadjuvant chemotherapy (NAC), retrieving previously clipped, biopsy-proven positive lymph nodes during sentinel lymph node biopsy [i.e., targeted axillary dissection (TAD)] may reduce false negative rates. However, the overall utilization and impact of clipping positive nodes remains uncertain. PATIENTS AND METHODS: We retrospectively analyzed cN+ ISPY-2 patients (2011-2022) undergoing axillary surgery after NAC. We evaluated trends in node clipping and associations with type of axillary surgery [sentinel lymph node (SLN) only, SLN and axillary lymph node dissection (ALND), or ALND only] and event-free survival (EFS) in patients that were cN+ on a NAC trial. RESULTS: Among 801 cN+ patients, 161 (20.1%) had pre-NAC clip placement in the positive node. The proportion of patients that were cN+ undergoing clip placement increased from 2.4 to 36.2% between 2011 and 2021. Multivariable logistic regression showed nodal clipping was independently associated with higher odds of SLN-only surgery [odds ratio (OR) 4.3, 95% confidence interval (CI) 2.8-6.8, p < 0.001]. This was also true among patients with residual pathologically node-positive (pN+) disease. Completion ALND rate did not differ based on clip retrieval success. No significant differences in EFS were observed in those with or without clip placement, both with or without successful clip retrieval [hazard ratio (HR) 0.85, 95% CI 0.4-1.7, p = 0.7; HR 1.8, 95% CI 0.5-6.0, p = 0.3, respectively]. CONCLUSION: Clip placement in the positive lymph node before NAC is increasingly common. The significant association between clip placement and omission of axillary dissection, even among patients with pN+ disease, suggests a paradigm shift toward TAD as a definitive surgical management strategy in patients with pN+ disease after NAC.

Paravertebral versus Pectoralis-II (Interpectoral and Pectoserratus) Nerve Blocks for Postoperative Analgesia after Non-Mastectomy Breast Surgery: A Randomized, Controlled, Observer-Masked Noninferiority Trial.

BACKGROUND: Pectoralis-II and paravertebral nerve blocks are both used to treat pain following breast surgery. Most previous studies involving mastectomy identified little difference of significance between the two approaches. Whether this is also accurate for non-mastectomy procedures remains unknown. METHODS: Participants undergoing uni- or bilateral non-mastectomy breast surgery anticipated to have at least moderate postoperative pain were randomized to a pectoralis-II or paravertebral block (90 mg ropivacaine/side for both). Surgeons and recovery room staff were masked to treatment group assignment, and participants were not informed of their treatment group. Injectate for pectoralis-II blocks was ropivacaine 0.3% (30 mL) per side. Injectate for paravertebral blocks was ropivacaine 0.5% (9 mL in each of 2 levels) per side. We hypothesized that pectoralis-II blocks would have noninferior (1) analgesia [Numeric Rating Scale] and (2) cumulative opioid consumption within the operating and recovery rooms combined (dual primary outcomes). The study was adequately powered with n=100, but the target enrollment was raised to n=150 to account for higher-than-anticipated variability. RESULTS: The trial was ended prematurely with 119 (79%) of the original target of 150 participants enrolled due to (masked) surgeon preference. Within the recovery room, pain scores were higher in participants with pectoralis-II (n=60) than paravertebral blocks (n=59): median [IQR] 3.3 [2.3, 4.8] vs 1.3 [0, 3.6]; 95% CI: 0.5 to 2.6; P < 0.001. Similarly, intravenous morphine equivalents were higher in the pectoralis-II group: 17.5 [12.5, 21.9] vs 10.0 mg [10, 20]; 95% CI: 0.1 to 7.5; P = 0.004. No block-related adverse events were identified in either group. CONCLUSIONS: Following non-mastectomy breast surgery, 2-level paravertebral blocks provided superior analgesia and opioid sparing compared with pectoralis-II blocks. This is a contrary finding to the majority of studies in patients having mastectomy in which little significant difference was identified between the two types of blocks.

Association of baseline ROR1 and ROR2 gene expression with clinical outcomes in the I-SPY2 neoadjuvant breast cancer trial.

PURPOSE: ROR1 and ROR2 are Type 1 tyrosine kinase-like orphan receptors for Wnt5a that are associated with breast cancer progression. Experimental agents targeting ROR1 and ROR2 are in clinical trials. This study evaluated whether expression levels of ROR1 or ROR2 correlated with one another or with clinical outcomes. METHODS: We interrogated the clinical significance of high-level gene expression of ROR1 and/or ROR2 in the annotated transcriptome dataset from 989 patients with high-risk early breast cancer enrolled in one of nine completed/graduated/experimental and control arms in the neoadjuvant I-SPY2 clinical trial (NCT01042379). RESULTS: High ROR1 or high ROR2 was associated with breast cancer subtypes. High ROR1 was more prevalent among hormone receptor-negative and human epidermal growth factor receptor 2-negative (HR-HER2-) tumors and high ROR2 was less prevalent in this subtype. Although not associated with pathologic complete response, high ROR1 or high ROR2 each was associated with event-free survival (EFS) in distinct subtypes. High ROR1 associated with a worse EFS in HR + HER2- patients with high post-treatment residual cancer burden (RCB-II/III) (HR 1.41, 95% CI = 1.11-1.80) but not in patients with minimal post-treatment disease (RCB-0/I) (HR 1.85, 95% CI = 0.74-4.61). High ROR2 associated with an increased risk of relapse in patients with HER2 + disease and RCB-0/I (HR 3.46, 95% CI = 1.33-9.020) but not RCB-II/III (HR 1.07, 95% CI = 0.69-1.64). CONCLUSION: High ROR1 or high ROR2 distinctly identified subsets of breast cancer patients with adverse outcomes. Further studies are warranted to determine if high ROR1 or high ROR2 may identify high-risk populations for studies of targeted therapies.

Outcomes and clinicopathologic characteristics associated with disseminated tumor cells in bone marrow after neoadjuvant chemotherapy in high-risk early stage breast cancer: the I-SPY SURMOUNT study.

PURPOSE: Disseminated tumor cells (DTCs) expressing epithelial markers in the bone marrow are associated with recurrence and death, but little is known about risk factors predicting their occurrence. We detected EPCAM+/CD45- cells in bone marrow from early stage breast cancer patients after neoadjuvant chemotherapy (NAC) in the I-SPY 2 Trial and examined clinicopathologic factors and outcomes. METHODS: Patients who signed consent for SURMOUNT, a sub-study of the I-SPY 2 Trial (NCT01042379), had bone marrow collected after NAC at the time of surgery. EPCAM+CD45- cells in 4 mLs of bone marrow aspirate were enumerated using immunomagnetic enrichment/flow cytometry (IE/FC). Patients with > 4.16 EPCAM+CD45- cells per mL of bone marrow were classified as DTC-positive. Tumor response was assessed using the residual cancer burden (RCB), a standardized approach to quantitate the extent of residual invasive cancer present in the breast and the axillary lymph nodes after NAC. Association of DTC-positivity with clinicopathologic variables and survival was examined. RESULTS: A total of 73 patients were enrolled, 51 of whom had successful EPCAM+CD45- cell enumeration. Twenty-four of 51 (47.1%) were DTC-positive. The DTC-positivity rate was similar across receptor subtypes, but DTC-positive patients were significantly younger (p = 0.0239) and had larger pretreatment tumors compared to DTC-negative patients (p = 0.0319). Twenty of 51 (39.2%) achieved a pathologic complete response (pCR). While DTC-positivity was not associated with achieving pCR, it was significantly associated with higher RCB class (RCB-II/III, 62.5% vs. RCB-0/I; 33.3%; Chi-squared p = 0.0373). No significant correlation was observed between DTC-positivity and distant recurrence-free survival (p = 0.38, median follow-up = 3.2 years). CONCLUSION: DTC-positivity at surgery after NAC was higher in younger patients, those with larger tumors, and those with residual disease at surgery.

Localizing Positive Axillary Lymph Nodes in Breast Cancer Patients Post Neoadjuvant Therapy.

INTRODUCTION: Multiple trials demonstrated the feasibility of sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy. Those trials reported > 10% false-negative rate; however, a subset analysis of the Z1071 trial demonstrated that removing the clipped positive lymph node (LN) during SLNB reduces the false-negative rate to 6.8% post neoadjuvant chemotherapy. This study examines the factors that might contribute to the ability to identify the clipped nodes post neoadjuvant therapy (NAT). MATERIALS AND METHODS: Breast cancer patients with biopsy-proven metastatic axillary LN who underwent NAT, converted to N0, had preoperative localization, and then SLNB between 2018 and 2020 at a single institution were identified. A retrospective chart review was performed. Demographic and preoperative variables were compared between localization and nonlocalization groups. RESULTS: Eighty patients who met inclusion criteria were included. A total of 39 patients were localized after NAT completion (49%). Only half of the patients with ultrasound-detectable marker clips were able to be localized. Minimal LN abnormality was seen in imaging after NAT completion in 39 patients and is significantly associated with localization; 26 (67%) were localized (Odds Ratio 4.31, P = 0.002, 95% Confidence Interval 1.69-10.98). CONCLUSIONS: Our study suggests that radiologically abnormal LNs on preoperative imaging after NAT completion are more likely to be localized. Nodes that ultimately normalize by imaging criteria remain a significant challenge to localize, and thus localization before starting NAT is suggested. A better technology is needed for LN localization after prolonged NAT for best accuracy and avoids repeated procedures.

Wearable, noninvasive, pulsed shortwave (radiofrequency) therapy for analgesia and opioid sparing following outpatient surgery: A proof-of-concept case series.

BACKGROUND: It is often difficult to concurrently provide adequate analgesia while minimizing opioid requirements following ambulatory surgery. Nonthermal, pulsed shortwave (radiofrequency) fields are a noninvasive treatment used as an adjunct analgesic and wound healing therapy. The devices may be placed by nursing staff in less than a minute, are relatively inexpensive and readily available, theoretically provide analgesia for nearly any anatomic location, and have no systemic side effects-patients cannot detect any sensations from the devices-or significant risks. Here we present a case series to demonstrate the use of pulsed, electromagnetic field devices for outpatient herniorrhaphy and breast surgery. CASE REPORT: Following moderately painful ambulatory umbilical (n = 3) and inguinal (n = 2) hernia repair as well as bilateral breast surgery (n = 2), patients had taped over their surgical incision(s) 1 or 2 noninvasive, wearable, disposable, pulsed shortwave therapy devices (RecoveryRx, BioElectronics Corporation, Frederick, Maryland) which functioned continuously for 30 days. Average resting pain scores measured on the 0-10 numeric rating scale were a median of 0 during the entire treatment period. Six patients avoided opioid use entirely, while the remaining individual required only 5 mg of oxycodone during the first postoperative day. CONCLUSIONS: These cases demonstrate that the ambulatory use of pulsed shortwave devices is feasible and may be an effective analgesic, possibly obviating opioid requirements following outpatient herniorrhaphy and breast surgery. Considering the lack of any side effects, adverse events, and misuse/dependence/diversion potential, further study with a randomized, controlled trial appears warranted.

Characterization of the diffusion signal of breast tissues using multi-exponential models.

PURPOSE: Restriction spectrum imaging (RSI) decomposes the diffusion-weighted MRI signal into separate components of known apparent diffusion coefficients (ADCs). The number of diffusion components and optimal ADCs for RSI are organ-specific and determined empirically. The purpose of this work was to determine the RSI model for breast tissues. METHODS: The diffusion-weighted MRI signal was described using a linear combination of multiple exponential components. A set of ADC values was estimated to fit voxels in cancer and control ROIs. Later, the signal contributions of each diffusion component were estimated using these fixed ADC values. Relative-fitting residuals and Bayesian information criterion were assessed. Contrast-to-noise ratio between cancer and fibroglandular tissue in RSI-derived signal contribution maps was compared to DCE imaging. RESULTS: A total of 74 women with breast cancer were scanned at 3.0 Tesla MRI. The fitting residuals of conventional ADC and Bayesian information criterion suggest that a 3-component model improves the characterization of the diffusion signal over a biexponential model. Estimated ADCs of triexponential model were D1,3 = 0, D2,3 = 1.5 × 10-3 , and D3,3 = 10.8 × 10-3 mm2 /s. The RSI-derived signal contributions of the slower diffusion components were larger in tumors than in fibroglandular tissues. Further, the contrast-to-noise and specificity at 80% sensitivity of DCE and a subset of RSI-derived maps were equivalent. CONCLUSION: Breast diffusion-weighted MRI signal was best described using a triexponential model. Tumor conspicuity in breast RSI model is comparable to that of DCE without the use of exogenous contrast. These data may be used as differential features between healthy and malignant breast tissues.

Preoperative Ultrasound-guided Percutaneous Cryoneurolysis for the Treatment of Pain after Mastectomy: A Randomized, Participant- and Observer-masked, Sham-controlled Study.

BACKGROUND: Ultrasound-guided percutaneous cryoneurolysis is an analgesic technique in which a percutaneous probe is used to reversibly ablate a peripheral nerve(s) using exceptionally low temperature, and has yet to be evaluated with randomized, controlled trials. Pain after mastectomy can be difficult to treat, and the authors hypothesized that the severity of surgically related pain would be lower on postoperative day 2 with the addition of cryoanalgesia compared with patients receiving solely standard-of-care treatment. METHODS: Preoperatively, participants at one enrolling center received a single injection of ropivacaine, 0.5%, paravertebral nerve block at T3 or T4, and perineural catheter. Participants subsequently underwent an active or sham ultrasound-guided percutaneous cryoneurolysis procedure of the ipsilateral T2 to T5 intercostal nerves in a randomized, patient- and observer-masked fashion. Participants all received a continuous paravertebral block with ropivacaine, 0.2%, until the early morning of discharge (usually postoperative day 2). The primary endpoint was the average pain level measured using a 0 to 10 numeric rating scale the afternoon of postoperative day 2. Participants were followed for 1 yr. RESULTS: On postoperative day 2, participants who had received active cryoneurolysis (n = 31) had a median [interquartile range] pain score of 0 [0 to 1.4] versus 3.0 [2.0 to 5.0] in patients given sham (n = 29): difference -2.5 (97.5% CI, -3.5 to -1.5), P < 0.001. There was evidence of superior analgesia through month 12. During the first 3 weeks, cryoneurolysis lowered cumulative opioid use by 98%, with the active group using 1.5 [0 to 14] mg of oxycodone compared with 72 [20 to 120] mg in the sham group (P < 0.001). No oral analgesics were required by any patient between months 1 and 12. After 1 yr chronic pain had developed in 1 (3%) active compared with 5 (17%) sham participants (P < 0.001). CONCLUSIONS: Percutaneous cryoneurolysis markedly improved analgesia without systemic side effects or complications after mastectomy.

Large and diffuse ductal carcinoma in situ: potentially lethal subtypes of "preinvasive" disease.

PURPOSE: Trials for DCIS have not explored whether outcomes for patients with large disease burden requiring mastectomy are comparable to those of patients with lumpectomy-amenable disease. We aim to identify whether patients with DCIS larger than 5 cm and diffuse-type DCIS differ in breast cancer mortality (BCM) from patients with disease less than 5 cm. METHODS: Patients diagnosed with DCIS in the SEER program were assessed to identify factors prognostic of breast-cancer-specific survival using competing risks regression. RESULTS: 44,849 patients met criteria for the cumulative incidence estimate. On competing risks cumulative incidence approximation, the 10-year estimate for BCM for each group was 1.3%, 1.3%, 2.3%, and 5.1%, respectively, and the difference among groups was significant (p = 0.017). On competing risks regression of patients with known covariates, both diffuse-type disease and disease larger than 5 cm (hazard ratio [HR] = 6.2 and 1.7, p = 0.013 and p = 0.042, respectively) were associated with increased risk of BCM. After matching, DCIS > 5 cm and diffuse disease were associated with increased BCM relative to disease < 5 cm (HR = 1.69, p = 0.04). Among patients undergoing mastectomy for disease larger than 5 cm or diffuse disease, the 10-year cumulative incidence for BCM was 0.5% among patients undergoing bilateral mastectomy and 2.4% for patients undergoing unilateral mastectomy. CONCLUSION: Patients with large and diffuse DCIS represent uncommon but poorly studied DCIS subgroups with worse prognoses than patients with disease smaller than 5 cm. Further studies are needed to elucidate the appropriate treatment for these patients.

Ductal carcinoma in situ in patients younger than 30 years: differences in adjuvant endocrine therapy and outcomes.

PURPOSE: To use the National Cancer Database to assess treatment patterns in very young women with ductal carcinoma in situ (DCIS) given their propensity for higher risk features and increased risk of recurrence. METHODS: We used the NCDB to identify female patients who underwent surgery for a first cancer diagnosis of DCIS within three different age groups: ≤30, 31-50, and >50. Demographic information, tumor characteristics, and initial treatment patterns were characterized and compared. Univariable and multivariable logistic regression of individuals with hormone-receptor-positive disease who underwent breast-conserving surgery (BCS) was conducted to assess for group differences in adjuvant endocrine therapy utilization. Survival analysis was conducted via Kaplan-Meier method and Cox regression. RESULTS: We identified 236,832 patients meeting inclusion criteria. Individuals in the youngest group were more likely to be a minority, had better Charlson-Deyo scores, lived further from their treatment facility, and were less often insured. This group also had more unfavorable tumor features and were more likely to undergo bilateral mastectomy. In subgroup analysis of patients with hormone-receptor-positive disease who underwent BCS, the youngest group was significantly less likely to have received endocrine therapy. There was also a trend toward worse overall survival in the youngest group. CONCLUSION: We report differences in demographics, tumor characteristics, and treatment of very young women with DCIS. Given the known reduction in recurrence with use of adjuvant endocrine therapy, there may be room for increasing therapy rates or otherwise altering guidelines for treatment of young women with hormone-receptor-positive DCIS who undergo BCS.

Controversial Areas in Axillary Staging: Are We Following the Guidelines?

BACKGROUND: Sentinel lymph node biopsy (SLNB) has been the standard of care for clinically node-negative women with invasive breast cancer (IBC); however, there is less agreement on whether to perform SLNB when the risk of metastasis is low or when it does not affect survival or locoregional control. METHODS: An Institutional Review Board-approved survey was sent to members of the American Society of Breast Surgeons asking in which scenarios surgeons would recommend SLNB. Descriptive statistics and multivariable analysis were performed using SPSS software. RESULTS: There was a 23% response rate; 68% identified as breast surgical oncologists, 6% as surgical oncologists, 24% as general surgeons, and 2% as other. The majority practiced in a community setting (71%) versus an academic setting (29%). In a healthy female with clinical T1N0 hormone receptor-positive (HR+) IBC, 83% favored SLNB if the patient was 75 years of age, versus 35% if the patient was 85 years of age. Academic surgeons were less likely to perform axillary staging in a healthy 75-year-old (odds ratio [OR] 0.51 [0.32-0.80], p = 0.004) or a healthy 85-year-old (OR 0.48 [0.31-0.74], p = 0.001). For DCIS, 32% endorsed SLNB in women undergoing lumpectomy, with breast surgical oncologists and academic surgeons being less likely to endorse this procedure (OR 0.54 [0.36-0.82], p = 0.028; and OR 0.53 [0.34-0.83], p = 0.005, respectively). CONCLUSIONS: Despite studies showing that omitting SLNB in older patients with HR+ IBC does not impact regional control or survival, most surgeons are still opting for axillary staging. In addition, one in three are performing SLNB for lumpectomies for DCIS. Breast surgical oncologists and academic surgeons were more likely to be practicing based on recent data and guidelines. Practice patterns are changing but there is still room for improvement.

Correction of Artifacts Induced by B0 Inhomogeneities in Breast MRI Using Reduced-Field-of-View Echo-Planar Imaging and Enhanced Reversed Polarity Gradient Method.

BACKGROUND: Diffusion-weighted (DW) echo-planar imaging (EPI) is prone to geometric distortions due to B0 inhomogeneities. Both prospective and retrospective approaches have been developed to decrease and correct such distortions. PURPOSE: The purpose of this work was to evaluate the performance of reduced-field-of-view (FOV) acquisition and retrospective distortion correction methods in decreasing distortion artifacts for breast imaging. Coverage of the axilla in reduced-FOV DW magnetic resonance imaging (MRI) and residual distortion were also assessed. STUDY TYPE: Retrospective. POPULATION/PHANTOM: Breast phantom and 169 women (52.4 ± 13.4 years old) undergoing clinical breast MRI. FIELD STRENGTH/SEQUENCE: A 3.0 T/ full- and reduced-FOV DW gradient-echo EPI sequence. ASSESSMENT: Performance of reversed polarity gradient (RPG) and FSL topup in correcting breast full- and reduced-FOV EPI data was evaluated using the mutual information (MI) metric between EPI and anatomical images. Two independent breast radiologists determined if coverage on both EPI data sets was adequate to evaluate axillary nodes and identified residual nipple distortion artifacts. STATISTICAL TESTS: Two-way repeated-measures analyses of variance and post hoc tests were used to identify differences between EPI modality and distortion correction method. Generalized linear mixed effects models were used to evaluate differences in axillary coverage and residual nipple distortion. RESULTS: In a breast phantom, residual distortions were 0.16 ± 0.07 cm and 0.22 ± 0.13 cm in reduced- and full-FOV EPI with both methods, respectively. In patients, MI significantly increased after distortion correction of full-FOV (11 ± 5% and 18 ± 9%, RPG and topup) and reduced-FOV (8 ± 4% both) EPI data. Axillary nodes were observed in 99% and 69% of the cases in full- and reduced-FOV EPI images. Residual distortion was observed in 93% and 0% of the cases in full- and reduced-FOV images. DATA CONCLUSION: Minimal distortion was achieved with RPG applied to reduced-FOV EPI data. RPG improved distortions for full-FOV images but with more modest improvements and limited correction near the nipple. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 1.

Cutaneous intralymphatic anaplastic lymphoma kinase-negative anaplastic large-cell lymphoma arising in a patient with multiple rounds of breast implants.

Primary cutaneous anaplastic large-cell lymphoma and breast implant-associated ALCL (BIA-ALCL) are rare subtypes of anaplastic lymphoma kinase (ALK)-negative ALCLs originating from skin and breast implants, respectively. Herein, we report a unique case of cutaneous ALK-negative ALCL occurring in the skin of left medial breast from a patient with multiple rounds of bilateral breast implants and a history of breast carcinoma. The lymphoma cells are entirely confined to the lymphatic channels in the dermis, and the patient has no other areas of skin abnormality, no lymphadenopathy, peri-implant fluid accumulation, or masses from the bilateral capsules of implants. The differential diagnosis and its relationship with breast implants are further explored.

The Impact of Surgeons on the Likelihood of Mastectomy in Breast Cancer.

OBJECTIVE: This study evaluates the impact of individual surgeons and institutions on the use of mastectomy or breast conserving surgery (BCS) among elderly women with breast cancer. SUMMARY OF BACKGROUND DATA: Current literature characterizes patient clinical and demographic factors that increase likelihood of mastectomy use. However, the impact of the individual provider or institution is not well understood, and could provide key insights to biases in the decision-making process. METHODS: A retrospective cohort study of 29,358 women 65 years or older derived from the SEER-Medicare linked database with localized breast cancer diagnosed from 2000 to 2009. Multilevel, multivariable logistic models were employed, with odds ratios (ORs) used to describe the impact of demographic or clinical covariates, and the median OR (MOR) used to describe the relative impact of the surgeon and institution. RESULTS: Six thousand five hundred ninety-four women (22.4%) underwent mastectomy. Unadjusted rates of mastectomy ranged from 0% in the bottom quintile of surgeons to 58.0% in the top quintile. On multivariable analysis, the individual surgeon (MOR 1.97) had a greater impact on mastectomy than did the institution (MOR 1.71) or all other clinical and demographic variables except tumor size (OR 3.06) and nodal status (OR 2.95). Surgeons with more years in practice, or those with a lower case volume were more likely to perform mastectomy (P < 0.05). CONCLUSION: The individual surgeon influences the likelihood of mastectomy for the treatment of localized breast cancer. Further research should focus on physician-related biases that influence this decision to ensure patient autonomy.

Adaptive Randomization of Neratinib in Early Breast Cancer.

BACKGROUND: The heterogeneity of breast cancer makes identifying effective therapies challenging. The I-SPY 2 trial, a multicenter, adaptive phase 2 trial of neoadjuvant therapy for high-risk clinical stage II or III breast cancer, evaluated multiple new agents added to standard chemotherapy to assess the effects on rates of pathological complete response (i.e., absence of residual cancer in the breast or lymph nodes at the time of surgery). METHODS: We used adaptive randomization to compare standard neoadjuvant chemotherapy plus the tyrosine kinase inhibitor neratinib with control. Eligible women were categorized according to eight biomarker subtypes on the basis of human epidermal growth factor receptor 2 (HER2) status, hormone-receptor status, and risk according to a 70-gene profile. Neratinib was evaluated against control with regard to 10 biomarker signatures (prospectively defined combinations of subtypes). The primary end point was pathological complete response. Volume changes on serial magnetic resonance imaging were used to assess the likelihood of such a response in each patient. Adaptive assignment to experimental groups within each disease subtype was based on Bayesian probabilities of the superiority of the treatment over control. Enrollment in the experimental group was stopped when the 85% Bayesian predictive probability of success in a confirmatory phase 3 trial of neoadjuvant therapy reached a prespecified threshold for any biomarker signature ("graduation"). Enrollment was stopped for futility if the probability fell to below 10% for every biomarker signature. RESULTS: Neratinib reached the prespecified efficacy threshold with regard to the HER2-positive, hormone-receptor-negative signature. Among patients with HER2-positive, hormone-receptor-negative cancer, the mean estimated rate of pathological complete response was 56% (95% Bayesian probability interval [PI], 37 to 73%) among 115 patients in the neratinib group, as compared with 33% among 78 controls (95% PI, 11 to 54%). The final predictive probability of success in phase 3 testing was 79%. CONCLUSIONS: Neratinib added to standard therapy was highly likely to result in higher rates of pathological complete response than standard chemotherapy with trastuzumab among patients with HER2-positive, hormone-receptor-negative breast cancer. (Funded by QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

Adaptive Randomization of Veliparib-Carboplatin Treatment in Breast Cancer.

BACKGROUND: The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin. METHODS: In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well. RESULTS: With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib-carboplatin was greater than that of the control. CONCLUSIONS: The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).

Outcomes of "one-day" vs "two-day" injection protocols using Tc-99m tilmanocept for sentinel lymph node biopsy in breast cancer.

No prior studies have compared Tc-99m tilmanocept (TcTM) one-day and two-day injection protocols for sentinel lymph node (SLN) biopsy in breast cancer (BC). We retrospectively identified patients with clinically node-negative BC undergoing SLN biopsy at our institution. Patients received a single, intradermal peritumoral injection of TcTM on day of surgery or day prior to surgery in addition to an intraoperative injection of isosulfan blue dye. Univariable and multivariable Poisson regression count models were constructed to assess the effects of injection timing, radiologist, patient and surgeon characteristics on the number of removed SLNs. A total of 617 patients underwent SLN biopsy with TcTM and blue dye. Sixty-seven (10.9%) patients were injected with the two-day protocol. Patients in the one-day protocol had a mean of 3.0 (standard deviation (SD) 1.9) SLNs removed compared with 2.7 (SD 1.4) SLNs in the two-day protocol, P-value = .13. On multivariable analysis, patient age and operating surgeon significantly affected the number of removed SLNs; however, the injection timing and the nuclear radiologist did not influence the number of removed SLNs. The performance of Tc-99m tilmanocept did not differ significantly between one-day and two-day injection protocols. These results are similar to other radiotracers used for SLN biopsy in BC.

Intrapersonal Variation in Goal Setting and Achievement in Health Coaching: Cross-Sectional Retrospective Analysis.

BACKGROUND: Chronic conditions in the United States are among the most costly and preventable of all health problems. Research suggests health coaching is an effective strategy for reducing health risks including decreases in weight, blood pressure, lipids, and blood glucose. Much less is known about how and when coaching works. OBJECTIVE: The aim of this study was to conduct an analysis of intrapersonal variations in participants' progression in health coaching, examining gender and age-related differences. METHODS: This was a cross-sectional, retrospective analysis of 35,333 health coaching participants between 2012 and 2016. Differences in number of goals and activities set and completed, and number of interactions were assessed using negative binomial models. Differences in goal type were assessed using logistic regression for gender and using the Welch test for age to account for unequal variances. RESULTS: Participants choosing online coaching were more likely to be younger and female (P<.001). Gender and age differences were found for the types of goals set by participants. Regarding program activity, women set and completed 12% more action steps than men (P<.001), averaging 21% more interactions than men (P<.001); no gender differences were found in number of goals completed (P=.12), although the percentage of males and females completing goals was significantly different at 60 and 120 days postenrollment (P<.001). Results indicated significant age-related differences in all aspects of program activity: number of interactions, goals set and completed, action steps set and completed (all P values <.01), as well as significant differences in percentage of individuals completing initial goals within 30 days, with older individuals completing more than younger individuals did (all P values <.001). CONCLUSIONS: This study found significant intrapersonal variation in how people participate in and progress through a coaching program. Age-related variations were found in all aspects of coaching activity, from modality preference and initial choice of goal type (eg, weight management, tobacco cessation) to goal completion, whereas gender-related differences were demonstrated for all program activities except number of goals set and completed. These findings indicate that to maximize behavior change, coaches need to personalize the coaching experience to the individual.

Process of Care in Breast Reconstruction and the Impact of a Dual-Trained Surgeon.

BACKGROUND: For postmastectomy reconstruction, the most common model in the United States is a two-team approach, consisting of breast and plastic surgeon. In other countries, a single-surgeon approach trained in both plastic and oncologic surgery is well described. We hypothesized that a dual-trained breast and plastic surgeon would decrease the postoperative care burden for the patient without compromising outcomes and serve as a model for team-centered breast reconstruction care. METHODS: A retrospective review was performed of patients undergoing mastectomy with immediate expander reconstruction from January 2013 to October 2014. Patient data up to 1 year postoperatively was recorded. Patients were stratified by treatment to "single-surgeon" or "two-surgeon" team. Demographic and operative data were recorded. Google Maps was used to calculate travel distance. A standard of mean cost of travel per mile and mean hourly wage for San Diego County was used. The primary outcome was the total number of postoperative clinic visits. In addition, factors predictive of postoperative clinic visits were evaluated. RESULTS: During the study period, 147 patients were included in analysis (69, single-surgeon; 78, two-surgeon). The mean cost of travel per mile was US $59.2 cents and mean hourly wage for San Diego County was US $25.49. For the 1-year follow-up period, patients with the single surgeon had a mean (SD) of 9.3 (3.72) postoperative visits compared with 15.6 (3.96) for patients in the two-surgeon team (P < 0.0001).There were no statistical differences between groups in the rate of complications. In the final model, treatment team, bilateral mastectomies, and complications (operative and nonoperative) were significant predictors of the total number of postoperative visits. Patients in the two-surgeon team spent an additional 11.13 hours and 216 miles commuting and in clinic. In total, the additional 6.3 clinic visits for patients in the two-surgeon team resulted in an average of US $695.33 additional dollars spent on travel and lost wages. CONCLUSIONS: Single-surgeon patients required fewer postoperative visits. Fewer postoperative clinic visits may have significant socioeconomic and psychological benefits to patients. Given these results, we believe that streamlining care into an integrated multidisciplinary model would be beneficial.