TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer.

BACKGROUND: Patients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival, warranting the investigation of novel therapies. Preclinical studies implied that ruxolitinib (RUX), a JAK1/2 inhibitor, may be an effective therapy for TN-IBC. METHODS: We conducted a randomized phase II study with nested window-of-opportunity in TN-IBC. Treatment-naïve patients received a 7-day run-in of RUX alone or RUX plus paclitaxel (PAC). After the run-in, those who received RUX alone proceeded to neoadjuvant therapy with either RUX + PAC or PAC alone for 12 weeks; those who had received RUX + PAC continued treatment for 12 weeks. All patients subsequently received 4 cycles of doxorubicin plus cyclophosphamide prior to surgery. Research tumor biopsies were performed at baseline (pre-run-in) and after run-in therapy. Tumors were evaluated for phosphorylated STAT3 (pSTAT3) by immunostaining, and a subset was also analyzed by RNA-seq. The primary endpoint was the percent of pSTAT3-positive pre-run-in tumors that became pSTAT3-negative. Secondary endpoints included pathologic complete response (pCR). RESULTS: Overall, 23 patients were enrolled, of whom 21 completed preoperative therapy. Two patients achieved pCR (8.7%). pSTAT3 and IL-6/JAK/STAT3 signaling decreased in post-run-in biopsies of RUX-treated samples, while sustained treatment with RUX + PAC upregulated IL-6/JAK/STAT3 signaling compared to RUX alone. Both treatments decreased GZMB+ T cells implying immune suppression. RUX alone effectively inhibited JAK/STAT3 signaling but its combination with PAC led to incomplete inhibition. The immune suppressive effects of RUX alone and in combination may negate its growth inhibitory effects on cancer cells. CONCLUSION: In summary, the use of RUX in TN-IBC was associated with a decrease in pSTAT3 levels despite lack of clinical benefit. Cancer cell-specific-targeting of JAK2/STAT3 or combinations with immunotherapy may be required for further evaluation of JAK2/STAT3 signaling as a cancer therapeutic target. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , NCT02876302. Registered 23 August 2016.

Second primary non-breast cancers in young breast cancer survivors.

PURPOSE: We evaluated the incidence, timing, and risk factors for second primary non-breast cancers (SPNBC) among young breast cancer (BC) survivors. METHODS: This study included participants of the Young Women's BC Study (YWS) who were diagnosed with stage 0-III BC between 2006 and 2016 and age 40 or younger at diagnosis (N = 1,230). Patient characteristics, treatment information, and clinical events were collected via serial surveys. Tumor and treatment data were obtained from medical record review. Five- and 10-year risks of SPNBCs were estimated via the cumulative incidence function, considering death, metastasis, or second primary BC as competing events. Fine and Gray subdistribution hazard models estimated subdistribution hazard ratios (sHRs) and 95% confidence intervals (CI) for SPNBC risk based on risk factors including demographics, germline genetics, primary BC characteristics, and treatments. RESULTS: Among 1,230 women, over a median follow-up of 10.1 years, 47 patients (4%) developed an SPNBC. Types of malignancy included melanoma (n = 10), thyroid (n = 10), ovarian (n = 4), sarcoma (n = 4), uterine (n = 3), rectal (n = 3), bladder (n = 2), cervical (n = 2), head/neck (n = 2), lung (n = 2), lymphoma (n = 2), pancreatic (n = 2), and renal (n = 1). Five and 10-year cumulative incidence were 1.4% and 3.2%, respectively. Median time between primary BC and SPNBC was 7.3 years. No patient factors, primary tumor characteristics, or treatments were statistically significantly associated with SPNBC in univariable or multivariable models. CONCLUSION: In this population, five-year cumulative incidence was higher than that reported among healthy women under 50 years of age, highlighting the importance of long-term surveillance for new non-breast cancers in young adult BC survivors.

Clinical outcomes after 1 versus 2-3 lines of neoadjuvant therapy in stage III inflammatory breast cancer.

PURPOSE: Many stage III inflammatory breast cancer (IBC) patients experience a sufficient response to first-line (1L) neoadjuvant chemotherapy (NAC) to allow surgery, while some require additional NAC. We evaluated the pathologic complete response (pCR), breast cancer-free survival (BCFS) and overall survival (OS) among patients requiring 1 vs. 2-3 lines (L) of NAC prior to surgery. METHODS: Stage III IBC patients from 2 institutions who received 1L or 2-3L of NAC prior to surgery were identified. Hormone receptor and HER2 status, grade, and pCR were evaluated. BCFS and OS were evaluated by the Kaplan-Meier method. Multivariable Cox models were utilized to estimate the hazard ratio (HR). RESULTS: 808 eligible patients (1997-2020) were identified (median age 51 years, median follow-up 69 months). 733 (91%) had 1L and 75 (9%) had 2-3L of NAC. Grade III, triple-negative and HER2-positive disease were more prevalent in 2-3L patients. 178 (24%) 1L and 14 (19%) 2-3L patients had pCR. 376 1L patients and 41 2-3L patients had recurrences. The 5-year BCFS was worse for the 2-3L group (33 vs. 46%, HR = 1.37; 95% CI 0.99-1.91). However, in 192 patients with a pCR, BCFS was similar (76 vs. 83% in 1L vs. 2-3L, respectively). There were 308 deaths (276 among 1L and 32 among 2-3L patients). The 5-year OS in 1L vs. 2-3L was 60 vs. 53% (HR = 1.32, 95% CI 0.91-1.93). CONCLUSIONS: Among stage III IBC patients, pCR rates were similar, irrespective of the NAC lines number, and BCFS and OS were comparable with pCR after 1L and 2-3L.

Preoperative Risk Factors for Lymphedema in Inflammatory Breast Cancer.

BACKGROUND: Prophylactic lymphatic bypass or LYMPHA (LYmphatic Microsurgical Preventive Healing Approach) is increasingly offered to prevent lymphedema following breast cancer treatment, which develops in up to 47% of patients. Previous studies focused on intraoperative and postoperative lymphedema risk factors, which are often unknown preoperatively when the decision to perform LYMPHA is made. This study aims to identify preoperative lymphedema risk factors in the high-risk inflammatory breast cancer (IBC) population. METHODS: Retrospective review of our institution's IBC program database was conducted. The primary outcome was self-reported lymphedema development. Multivariable logistic regression analysis was performed to identify preoperative lymphedema risk factors, while controlling for number of lymph nodes removed during axillary lymph node dissection (ALND), number of positive lymph nodes, residual disease on pathology, and need for adjuvant chemotherapy. RESULTS: Of 356 patients with IBC, 134 (mean age: 51 years, range: 22-89 years) had complete data. All 134 patients underwent surgery and radiation. Forty-seven percent of all 356 patients (167/356) developed lymphedema. Obesity (body mass index > 30) (odds ratio [OR]: 2.7, confidence interval [CI]: 1.2-6.4, p = 0.02) and non-white race (OR: 4.5, CI: 1.2-23, p = 0.04) were preoperative lymphedema risk factors. CONCLUSION: Patients with IBC are high risk for developing lymphedema due to the need for ALND, radiation, and neoadjuvant chemotherapy. This study also identified non-white race and obesity as risk factors. Larger prospective studies should evaluate potential racial disparities in lymphedema development. Due to the high prevalence of lymphedema, LYMPHA should be considered for all patients with IBC.

Intraoperative Pathology Assessment May Lead to Overtreatment of the Axilla in Clinically Node-Negative Breast Cancer Patients Undergoing Upfront Mastectomy.

BACKGROUND: Randomized trials have established the safety of observation or axillary radiation (AxRT) as an alternative to axillary lymph node dissection (ALND) in patients with limited nodal disease who undergo upfront surgery. Variability remains in axillary management strategies in cN0 patients undergoing mastectomy found to have one to two positive sentinel lymph nodes (SLNs). We examined the impact of intraoperative pathology assessment in axillary management in a national cohort of AMAROS-eligible mastectomy patients. METHODS: The National Cancer Database was used to identify AMAROS-eligible cT1-2N0 breast cancer patients undergoing upfront mastectomy and SLN biopsy (SLNB) and found to have one to two positive SLNs, from 2018 to 2019. We constructed a variable defining intraoperative pathology as 'not performed/not acted on' if ALND was either not performed or performed at a later date than SLNB, or 'performed/acted on' if SLNB and ALND were completed on the same day. Adjusted multivariable analysis examined predictors of treatment with both ALND and AxRT. RESULTS: Overall, 8222 patients with cT1-2N0 disease underwent upfront mastectomy and had one to two positive SLNs. Intraoperative pathology was performed/acted on in 3057 (37.2%) patients. These patients were significantly more likely to have both ALND and AxRT than those without intraoperative pathology (41.0% vs. 4.9%; p < 0.001). On multivariate analysis, the strongest predictor of receiving both ALND and AxRT was use of intraoperative pathology (odds ratio 8.99, 95% confidence interval 7.70-10.5; p < 0.001). CONCLUSIONS: We advocate that consideration should be made for omission of routine intraoperative pathology in mastectomy patients likely to be recommended postmastectomy radiation to minimize axillary overtreatment with both ALND and AxRT in appropriate patients.

Incidence, characteristics, and management of central nervous system metastases in patients with inflammatory breast cancer.

BACKGROUND: Patients with inflammatory breast cancer (IBC) have a high risk of central nervous system metastasis (mCNS). The purpose of this study was to quantify the incidence of and identify risk factors for mCNS in patients with IBC. METHODS: The authors retrospectively reviewed patients diagnosed with IBC between 1997 and 2019. mCNS-free survival time was defined as the date from the diagnosis of IBC to the date of diagnosis of mCNS or the date of death, whichever occurred first. A competing risks hazard model was used to evaluate risk factors for mCNS. RESULTS: A total of 531 patients were identified; 372 patients with stage III and 159 patients with de novo stage IV disease. During the study, there were a total of 124 patients who had mCNS. The 1-, 2-, and 5-year incidence of mCNS was 5%, 9%, and 18% in stage III patients (median follow-up: 5.6 years) and 17%, 30%, and 42% in stage IV patients (1.8 years). Multivariate analysis identified triple-negative tumor subtype as a significant risk factor for mCNS for stage III patients. For patients diagnosed with metastatic disease, visceral metastasis as first metastatic site, triple-negative subtype, and younger age at diagnosis of metastases were risk factors for mCNS. CONCLUSIONS: Patients with IBC, particularly those with triple-negative IBC, visceral metastasis, and those at a younger age at diagnosis of metastatic disease, are at significant risk of developing mCNS. Further investigation into prevention of mCNS and whether early detection of mCNS is associated with improved IBC patient outcomes is warranted.

Optimizing Axillary Management in Clinical T1-2N0 Mastectomy Patients with Positive Sentinel Lymph Nodes.

BACKGROUND: Following publication of the AMAROS trial, we sought to optimize axillary lymph node dissection (ALND) or postmastectomy radiation therapy (PMRT) + axillary radiation (AxRT) utilization in cT1-2N0 patients with 1-2 positive sentinel lymph nodes (SLNs) after mastectomy. METHODS: In November 2015, our multidisciplinary group implemented a protocol to omit intraoperative SLN evaluation for mastectomy patients with cT1-2N0 breast cancer likely to be recommended PMRT if found to have 1-2 positive SLNs (age ≤ 60 years and/or high-risk features defined as estrogen receptor-negative and/or positive for lymphovascular invasion). We prospectively evaluated axillary management, short-term complications, and oncologic outcomes in patients with 1-2 positive SLNs. RESULTS: From November 2015 to December 2018, 479 of 560 (85%) cT1-2N0 breast cancers treated with mastectomy were potential candidates for PMRT. Intraoperative SLN evaluation was omitted in 344 (72%), thus following the protocol. Overall, 121 cases had 1-2 positive SLNs: 17 (14%) were managed with observation, 5 (4%) PMRT alone, 59 (49%) PMRT + AxRT, 16 (13%) ALND alone, and 24 (20%) ALND + PMRT. Protocol compliance resulted in less ALND (8% vs. 24%) and less ALND + PMRT (9% vs. 41%, p < 0.01). At median follow-up of 24 months, there was one regional and four distant recurrences, with no regional recurrences or differences in disease-free survival in patients treated with ALND versus PMRT + AxRT (100% vs. 98%, p = 0.67). Similarly, there were no differences in complication rates (p = 0.18). CONCLUSIONS: Omitting intraoperative SLN evaluation in cT1-2N0 mastectomy patients who would be candidates for PMRT if found to have positive nodes decreased rates of ALND and minimized use of ALND + PMRT without compromising outcomes.

Time-Driven Activity-Based Costing in Breast Cancer Care Delivery.

BACKGROUND: Accurate measurement of healthcare costs is required to assess and improve the value of oncology care. OBJECTIVES: We aimed to determine the cost of breast cancer care provision across collaborating health care organizations. METHODS: We used time-driven activity-based costing (TDABC) to calculate the complete cost of breast cancer care-initial treatment planning, chemotherapy, radiation therapy, surgical resection and reconstruction, and ancillary services (e.g., psychosocial oncology, physical therapy)-across multiple hospital sites. Data were collected between December 2019 and February 2020. TDABC steps involved (1) developing process maps for care delivery pathways; (2) determine capacity cost rates for staff, medical equipment, and hospital space; (3) measure the time required for each process step, both manually through clinic observation and using data from the Real-Time Location System (RTLS); and (4) calculate the total cost of care delivery. RESULTS: Surgical care costs ranged from $1431 for a lumpectomy to $12,129 for a mastectomy with prepectoral implant reconstruction. Radiation therapy was costed at $1224 for initial simulation and patient education, and $200 for each additional treatment. Base costs for chemotherapy delivery were $382 per visit, with additional costs driven by chemotherapy agent(s) administered. Personnel expenses were the greatest contributor to the cost of surgical care, except in mastectomy with implant reconstruction, where device costs equated to up to 60% of the cost of surgery. CONCLUSION: The cost of complete breast cancer care depended on (1) treatment protocols; (2) patient choice of reconstruction; and (3) the need for ancillary services (e.g., physical therapy). Understanding the actual costs and cost drivers of breast cancer care delivery may better inform resource utilization to lower the cost and improve the quality of care.

Utilization and predictors of postmastectomy radiation receipt in an Oncology Center in Zimbabwe.

PURPOSE: Few sub-Saharan African studies have ascertained utilization for postmastectomy radiation (PMRT) for breast cancer, the second most common cancer among African women. We estimated PMRT utilization and identified predictors of PMRT receipt in Zimbabwe. METHODS: Retrospective patient cohort included non-metastatic breast cancer patients treated from 2014 to 2019. PMRT eligibility was assigned per NCCN guidelines. Patients receiving chemotherapy for non-metastatic disease were also included. The primary endpoint was receipt of PMRT, defined as chest wall with/without regional nodal radiation. Predictors of receiving PMRT were identified using logistic regression. Model performance was evaluated using the c statistic and Hosmer-Lemeshow test for goodness-of-fit. RESULTS: 201 women with localized disease and median follow-up of 11.4 months (IQR 3.3-17.9) were analyzed. PMRT was indicated in 177 women and utilized in 59(33.3%). Insurance coverage, clinical nodal involvement, higher grade, positive margins, and hormone therapy receipt were associated with higher odds of PMRT receipt. In adjusted models, no hormone therapy (aOR 0.12, 95% CI 0.043, 0.35) and missing grade (aOR 0.07, 95% CI 0.01, 0.38) were associated with lower odds of PMRT receipt. The resulting c statistic was 0.84, with Hosmer-Lemeshow p-value of 0.93 indicating good model fit. CONCLUSION: PMRT was utilized in 33% of those meeting NCCN criteria. Missing grade and no endocrine therapy receipt were associated with reduced likelihood of PMRT utilization. In addition to practice adjustments such as increasing hypofractionation and increasing patient access to standard oncologic testing at diagnosis could increase postmastectomy utilization.

Discrepancy between FDG-PET/CT and contrast-enhanced CT in the staging of patients with inflammatory breast cancer: implications for treatment planning.

PURPOSE: Optimizing treatment strategies for patients with inflammatory breast cancer (IBC) relies on accurate initial staging. This study compared contrast-enhanced computed tomography (ce-CT) and FDG-PET/CT for initial staging of IBC to determine the frequency of discordance between the two imaging modalities and potential impact on management. METHODS: 81 patients with IBC underwent FDG-PET/CT and ce-CT prior to starting treatment. FDG-PET/CT and ce-CT scans were independently reviewed for locoregional and distant metastases and findings recorded by anatomic site as negative, equivocal, or positive for breast cancer involvement. Each paired ce-CT and FDG-PET/CT case was classified as concordant or discordant for findings. Discordant findings were subclassified as (a) related to the presence or absence of distant metastases; (b) affecting the locoregional radiation therapy plan; or (c) due to incidental findings not related to IBC. RESULTS: There were 47 discordant findings between ce-CT and FDG-PET/CT in 41 of 81 patients (50.6%). Thirty (63.8%) were related to the presence or absence of distant metastases; most commonly disease detection on FDG-PET/CT but not ce-CT (n = 12). FDG-PET/CT suggested alterations of the locoregional radiation therapy plan designed by CT alone in 15 patients. FDG-PET/CT correctly characterized 5 of 7 findings equivocal for metastatic IBC on ce-CT. CONCLUSIONS: This study demonstrates differences between ce-CT and FDG-PET/CT for initial staging of IBC and how these differences potentially affect patient management. Preliminary data suggest that FDG-PET/CT may be the imaging modality of choice for initial staging of IBC. Prospective trials testing initial staging with FDG-PET/CT versus important clinical end-points in IBC are warranted.

Characteristics associated with inflammatory breast cancer (IBC): An epidemiologic study from a dedicated IBC program.

There are scant data identifying epidemiologic characteristics among individuals diagnosed with inflammatory breast cancer (IBC), which is considered the most aggressive subtype of breast cancer. The purpose of this study was to evaluate the epidemiologic features among patients seen at a dedicated IBC program, to elucidate the potential causes of this disease and guide prevention strategies. We reviewed retrospective data from 447 patients enrolled in an IRB-approved IBC registry through Dana-Farber Cancer Institute from 1997 to 2016. The data examined included the following: demographics, medical, reproductive and family history, duration of symptoms prior to the diagnosis of IBC, pathologic characteristics, and clinical outcome. JMP statistical software was used to compile the data. Descriptive statistics were used to evaluate the data. The majority of patients (66.0%) were overweight or obese (body mass index [BMI] ≥25) at the time of diagnosis. Fifty patients (11.1%) had "secondary" IBC, defined as developing IBC after a previous history of non-IBC breast cancer in an ipsilateral breast. Of those patients with secondary IBC, 60% were also overweight or obese at the time of IBC diagnosis. Approximately 58% of IBC patients had a family history of breast or ovarian cancer, including first- and second-degree relatives. This analysis suggested a high frequency of familial breast/ovarian cancer among IBC patients which supports further evaluating genetic risks. This may have implications for screening and prevention strategies as well as insight into additional contributing risk factors. The prevalence of a high BMI among both pre- and postmenopausal women with IBC, including those diagnosed with secondary IBC, warrants focusing on strategies targeting the obesity crisis as a potential means of reducing the risk of developing this disease.

Patterns of breast reconstruction in patients diagnosed with inflammatory breast cancer: The Dana-Farber Cancer Institute's Inflammatory Breast Cancer Program experience.

Inflammatory breast cancer (IBC) exhibits dermal lymphatic involvement at presentation, and thus, the standard surgical approach is a nonskin-sparing modified radical mastectomy (MRM) without breast reconstruction (BR). In this study, we evaluated immediate and delayed BR receipt and its outcomes in IBC. Using an IRB-approved database, we retrospectively evaluated stage III IBC patients who received trimodality therapy (preoperative systemic therapy, followed by MRM and postmastectomy chest wall/regional nodal radiation). Patients with an insufficient response to preoperative systemic therapy and/or who required preoperative radiotherapy were excluded. BR receipt, timing, and morbidity were evaluated. Among 240 stage III IBC patients diagnosed between 1997 and 2016, 40 (17%) underwent BR. Thirteen (33%) had immediate, and 27 (67%) had delayed BR. Four patients had complications (1 [8%] immediate BR and 3 [11%] delayed BR); only 1 BR (delayed) was unsuccessful. From the MRM date, the median time to recurrence was 35 months (<1-212) and median overall survival was 87 months (<1-212). In this cohort of stage III IBC patients, only 11% pursued delayed BR following trimodality therapy, possibly attributable to the observed high recurrence rates hindering BR. Further studies addressing BR outcomes in IBC are needed for better counseling patients regarding their reconstructive options.

Long-term outcomes of breast-conserving therapy for women with ductal carcinoma in situ.

PURPOSE: Improved imaging, surgical techniques, and pathologic evaluation likely have decreased local recurrence rates for patients with ductal carcinoma in situ (DCIS). We present long-term outcomes of a large single-institution series after breast-conserving surgery (BCS) and adjuvant radiation therapy (RT). METHODS: We retrospectively reviewed the records of 245 women treated for DCIS with BCS and RT between 2001 and 2007. Competing risk analysis was used to calculate local recurrence (LR) as a first event with the development of a second non-breast malignancy, contralateral breast cancer, and death as competing first events. RESULTS: At a median follow-up of 10.6 years, 4 patients had a LR (2 DCIS, 2 invasive) as a first event with a cumulative LR incidence of 0.0% and 1.5% at 5 and 10 years, respectively. Most patients had > 2 mm margins (90%), specimen radiographs (93%), and received a tumor bed boost (99%). The majority (60%) of patients with hormone receptor-positive disease received adjuvant endocrine therapy. Ten-year cumulative incidence of contralateral breast cancer (CBC) was 7.9%, second non-breast malignancy was 4.5%, and death unrelated to breast cancer was 3.5%. Family history, age at diagnosis, and receipt of endocrine therapy were not significantly associated with the development of CBC (all P > 0.05). CONCLUSIONS: With mature follow-up, our rates of local recurrence following breast-conserving therapy for DCIS remain very low (1.5% at 10 years). The incidence of CBC was higher than the LR incidence. Predisposing factors for the development of CBC are worthy of investigation.

Local-regional recurrence in women with small node-negative, HER2-positive breast cancer: results from a prospective multi-institutional study (the APT trial).

PURPOSE: Women with HER2-positive breast cancer treated prior to effective anti-HER2 therapy have higher rates of local-regional recurrence (LRR) than those with HER2-negative disease. Effective systemic therapy, however, has been shown to decrease LRR. This study examines LRR in women with HER2-positive breast cancer treated on a single-arm prospective multicenter trial of adjuvant trastuzumab (H) and paclitaxel (T). METHODS: Patients with HER2-positive tumors ≤ 3.0 cm with negative axillary nodes or micrometastatic disease were eligible. Systemic therapy included weekly T and H for 12 weeks followed by continuation of H to complete 1 year. Radiation therapy (RT) was required following breast-conserving surgery (BCS), but dose and fields were not specified. Disease-free survival (DFS) and LRR-free survival were calculated using the Kaplan-Meier method. RESULTS: Of the 410 patients enrolled from September 2007 to September 2010, 406 initiated protocol therapy and formed the basis of this analysis. A total of 272 (67%) had hormone receptor-positive tumors. Of 162 patients undergoing mastectomy, local therapy records were unavailable for two. None of the 160 for whom records were available received RT. Among 244 BCS patients, detailed RT records were available for 217 (89%). With a median follow-up of 6.5 years, 7-year DFS was 93.3% (95% CI 90.4-96.2), and LRR-free survival was 98.6% (95% CI 97.4-99.8). CONCLUSION: LRR in this select group of early-stage patients with HER2-positive disease receiving effective anti-HER2 therapy is extremely low. If confirmed in additional studies, future investigational efforts should focus on de-escalating local therapy.

Patterns of Axillary Management in Stages 2 and 3 Hormone Receptor-Positive Breast Cancer by Initial Treatment Approach.

BACKGROUND: Data regarding axillary management after neoadjuvant endocrine therapy (NET) are lacking. This study examined axillary management of hormone receptor-positive (HR+) patients based on initial treatment with NET, neoadjuvant chemotherapy (NAC), or upfront surgery. METHODS: Patients with stage 2 or 3 HR+/HER2- breast cancer treated between 2012 and 2015 were identified in the National Cancer Database. The study examined axillary surgery [sentinel lymph node biopsy (SLNB), SLNB followed by axillary lymph node dissection (ALND), or upfront ALND] by initial treatment stratified by cN0/N1 using pairwise comparisons and multivariable logistic regression. RESULTS: Of 92,204 eligible patients, 2138 (2.3%) received NET, 11,014 (12%) received NAC, and 79,052 (85.7%) received surgery. Among 60,998 cN0 patients, attempted SLNB was more likely for surgery patients (86.2%, 47,159/54,684) and NET patients (85.8%, 1342/1564) than for NAC patients (79.9%, 3793/4750) (both p < 0.001). Among 31,206 cN1 patients, attempted SLNB was more likely for the surgery patients (46.0%, 11,201/24,368) than for the NET patients (41.8%, 240/574; p = 0.05) or the NAC patients (39.8%, 2491/6264; p < 0.0001). The differences between surgery and NET did not persist in the adjusted analyses. Among both the cN0 patients (n = 13,856) and the cN1 patients (n = 8688) with pN1 disease shown by SLNB, the NET patients were treated with ALND less frequently than those receiving NAC or surgery (p < 0.0001 for all comparisons). In the multivariate analysis, for the patients with pN1 disease shown by SLNB, NET use was associated with increased odds of undergoing SLNB alone [cN0 patients: odds ratio (OR), 1.31, 95% confidence interval (CI), 1.04-1.64; cN1 patients: OR 1.45; 95% CI 1.00-2.10]. CONCLUSIONS: For stages 2 and 3 HR+/HER2- patients, SLNB use after NET was similar to that for upfront surgery. Among those with pN1 disease, the NET patients were less likely to undergo ALND. Additional outcomes data are needed to guide axillary management after NET.

Prognostic Significance of Residual Axillary Nodal Micrometastases and Isolated Tumor Cells After Neoadjuvant Chemotherapy for Breast Cancer.

BACKGROUND: The prognostic significance of low-volume residual nodal disease following neoadjuvant chemotherapy (NAC) is unknown. METHODS: Women with cT1-4N0-1 breast cancer treated with NAC were identified from Dana-Farber/Brigham and Women's Cancer Center (DFBWCC) and the National Cancer Database (NCDB). Disease-free survival (DFS) and overall survival (OS) estimates according to pathologic nodal status were calculated using the Kaplan-Meier method, with Cox proportional hazards regression used to assess the effect of clinical variables on survival outcomes. RESULTS: Among 967 DFBWCC patients, 27 (2.8%) had residual isolated tumor cells (ITCs) and 61 (6.3%) had micrometastases. Five-year DFS was significantly worse in those with residual ITCs (73.5%) and micrometastases (74.7%) relative to those who were ypN0 following NAC (88.4%, p < 0.001). On adjusted analysis, those with residual ITCs (hazard ratio [HR] 2.4, 95% confidence interval [CI] 1.20-3.81) and micrometastases (HR 2.14, 95% CI 1.20-3.81) had increased risk of recurrence relative to ypN0 patients. Among 35,536 NCDB patients, 543 (1.5%) had ITCs and 1132 (3.2%) had micrometastases. Five-year OS estimates were significantly worse with increasing residual nodal burden: ypN0, 88.9%; ypN0[i+], 82.8%; ypN1mi, 79.5%; ypN1, 77.6% (p < 0.001). Compared with patients with ypN0 disease, NCDB patients with ITCs and micrometastases had 1.9- and 2.2-fold risk of death (p < 0.001). On subgroup analysis, the effect of low-volume residual disease on mortality was most pronounced in patients with triple-negative and human epidermal growth factor receptor 2 (HER2)-positive disease. CONCLUSIONS: Low-volume residual nodal disease following NAC is associated with poorer DFS and OS relative to those who are node negative.

Multidisciplinary Management of the Axilla in Patients with cT1-T2 N0 Breast Cancer Undergoing Primary Mastectomy: Results from a Prospective Single-Institution Series.

BACKGROUND: The after mapping of the axilla: radiotherapy or surgery (AMAROS) trial concluded that for patients with cT1-2 N0 breast cancer and one or two positive sentinel lymph nodes (SLNs), axillary radiotherapy (AxRT) provides equivalent locoregional control and a lower incidence of lymphedema compared with axillary lymph node dissection (ALND). The study prospectively assessed how often ALND could be replaced by AxRT in a consecutive cohort of patients undergoing mastectomy for cT1-2 N0 breast cancer. METHODS: In November 2015, our multidisciplinary group agreed to omit routine intraoperative SLN evaluation for cT1-2 N0 patients undergoing upfront mastectomy and potentially eligible for postmastectomy radiation therapy (PMRT), including those 60 years of age or younger and those older than 60 years with high-risk features. Patients with one or two positive SLNs on final pathology were reviewed to determine whether PMRT including the full axilla was an appropriate alternative to ALND. RESULTS: From November 2015 to December 2016, 154 patients met the study criteria, and 114 (74%) formed the final study cohort. Intraoperative SLN evaluation was omitted for 76 patients (67%). Of these patients, 20 (26%) had one or two positive SLNs, and 14 of these patients received PMRT + AxRT as an alternative to ALND. Three patients returned for ALND, and three patients were observed. On univariate analysis, tumor size, LVI, number of positive lymph nodes, and receipt of chemotherapy were associated with receipt of PMRT. CONCLUSIONS: For the majority of patients with one or two positive SLNs, ALND was avoided in favor of PMRT + AxRT. With appropriate multidisciplinary strategies, intraoperative evaluation of the SLN and immediate ALND can be avoided for patients meeting the AMAROS criteria and eligible for PMRT.