Citations

Abstract Background: Locoregional recurrence (LRR) is a concern after neoadjuvant chemotherapy. Absolute risk of LRR and risk factors associated with LRR among women with node positive breast cancer treated with neoadjuvant chemotherapy on ACOSOG Z1071 were examined. Methods: ACOSOG Z1071 (Alliance for Clinical Trials in Oncology) enrolled cT1-3, N1-2 breast cancer patients treated with neoadjuvant chemotherapy from 2009-2011. All patients underwent axillary dissection. Data was analyzed for locoregional recurrence-free survival (LR-RFS) and multivariable analysis performed to identify factors impacting locoregional recurrence. Results: Of 756 women enrolled, 701 patients were eligible. Median follow-up was 4.0 years (range 0.03–6.2). 39 pts (5.6%) experienced LRR (32 LRR alone and 7 LRR concurrent with metastatic disease) and 96 patients (13.7%) died. LR-RFS was lowest in patients with triple negative tumors (TNBC) (87.6% at 3 years), followed by HER2-positive tumors (94.1%) compared with Hormone Receptor (HR) positive/HER2-negative tumors (96.9%). Residual in-breast disease was present in 57% of patients undergoing BCT and 73% of patients undergoing mastectomy (p<0.0001). LRR was higher in BCT compared to mastectomy (p=0.018), however when evaluated by subtype there was no significant difference in LRR by BCT vs mastectomy. There was no difference in LRR by clinical T stage at presentation or pathologic N stage, however LRR increased with higher pathologic T stage (p=0.006). Overall LRR was lower in patients who achieved a pathologic complete response (pCR) across all tumor subtypes (0% in HR positive/HER2-negative, 2.1% in TNBC, 4% in HER2-positive at 3 years) than in non-pCR patients (HR=0.37, p=0.04). By tumor subtype, pCR was associated with a lower LRR in patients with TNBC (HR=0.17, p=0.019), but was not significantly different by pCR in HER2-positive (HR=0.50, p=0.31) or HR-positive/HER2-negative tumors (HR=inestimable). In the multivariable model, factors associated with increased LRR risk were tumor subtype (TNBC and HER2-positive tumors, p<0.0001), lack of pCR in the breast (p=0.013), breast conservation surgery (p=0.018) and omission of adjuvant radiation therapy (p=0.010). Predictors of locoregional recurrence UnivariableMultivariableVariableHR (95% CI)p-valueHR (95% CI)p-valueClinical T stageT0-T2REF0.34REF0.087T3-T41.38 (0.72-2.65) 1.87 (0.91-3.84) Tumor BiologyHR+/Her2-REF0.002REF<0.0001Her2+1.49 (0.65-3.45) 2.11 (0.89-5.00) Triple negative3.59 (1.68-7.68) 5.53 (2.53-12.13) Path CR breastNoREF0.019REF0.013Yes0.35 (0.15-0.84) 0.27 (0.09-0.76) Path CR breastNoREF0.064REF0.81Yes0.51 (0.25-1.04) 0.67 (0.29-1.59) SurgeryBCTREF0.067REF0.018Mastectomy0.55 (0.29-1.04) 0.43 (0.22-0.87) RadiationYesREF0.033REF0.010No2.18 (1.06-4.48) 2.60 (1.26-5.39) Conclusion: In patients with node-positive breast cancer treated with neoadjuvant chemotherapy, early LRR is higher in TNBC and HER2-positive tumors. In TNBC patients pCR is associated with lower LRR than residual disease. In this contemporary cohort of node-positive, HER2-positive tumors treated with anti-HER2 therapy, patients achieving a pCR had low LRR rate. Adjuvant radiation appears to be important for locoregional control regardless of pCR. Citation Format: Boughey JC, Ballman KV, McCall LM, Mittendorf EA, Hunt KK. Predictors of locoregional recurrence after neoadjuvant chemotherapy and surgery for node positive breast cancer: Results from ACOSOG Z1071 (Alliance) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-01.

Abstract Background: Negative margins are important in decreasing risk of local recurrence after breast conservation surgery. Further, positive margins on final pathology require a second operation, burdening patients and increasing costs. We identified factors predicting positive margins at lumpectomy prompting intraoperative re-excision in a large referral center. Methods With IRB approval we reviewed all breast cancer lumpectomy cases from January 2012 to December 2013. Associations between rates of positive margin (defined as tumor at ink) and patient and tumor factors were assessed using chi square tests and univariate and adjusted multivariable logistic regression, overall and stratified by DCIS or invasive cancer. Results 385 patients (105 DCIS and 280 invasive disease) were identified. Overall positive margin rate at lumpectomy requiring intraoperative re-excision was 62.3% and was higher in DCIS than in invasive disease (78.1% vs 56.4%, OR=2.78, p=0.001). Positive margin rates did not vary by surgeon, patient age, ER, PR or HER2 status of the tumor. On univariate analysis higher tumor grade was associated with a higher margin positive rate (grade 3 vs grade 1, OR=1.71, p=0.049). Within the 105 DCIS cases, no factors had statistically significantly different odds of positive margins on univariate or multivariable analysis. Within the 280 cases of invasive breast cancer, factors independently associated with lower odds of margin positivity were neoadjuvant chemotherapy (OR 0.30, p=0.037, relative to no neoadjuvant therapy) and seed localized excision (OR 0.24, p=0.03, relative to no localization). Multivariable Logistic Regression* Modeling DCISInvasive DiseaseVariableOdds RatioP-valueOdds RatioP-valueAge 50+ vs Age <502.860.111.590.23Grade 2 vs Grade 10.940.921.500.21Grade 3 vs Grade 13.250.121.580.37Estrogen Receptor Positive vs Negative3.950.221.640.42Progesterone Receptor Positive vs Negative0.840.871.110.84Her2 Positive vs Negative 1.270.68Stage T2 vs T1 2.540.45Stage T3 vs T1 2.180.69Ki67 <15% vs 15%+ 0.570.09Neoadjuvant Chemotherapy vs None 0.300.04Seed Localization vs No Localization 0.240.03Wire Localization vs No Localization 0.330.13Intraoperative Ultrasound vs No Localization 0.670.53*adjusted for individual surgeons (all p >0.05) Conclusion DCIS was associated with higher rate of positive margins at lumpectomy than invasive breast cancer. Within invasive disease, neoadjuvant chemotherapy and seed localization were associated with lower rates of margin positivity. Strategies to decrease positive margins would be best employed in cases of lumpectomy for DCIS and for invasive disease treated without neoadjuvant chemotherapy. Seed localization may be one strategy to lower positive margin rates. Citation Format: Boughey JC, Keeney MG, Glasgow AE, Keeney GL, Habermann EB. Tumor and procedural factors associated with positive margins at lumpectomy in women undergoing breast conservation surgery [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-11-08.

Abstract Purpose/Objectives: The optimal clinical target volume (CTV) for internal mammary node irradiation (IMNI) is uncertain in an era of increasingly conformal volume-based treatment planning for breast cancer. We mapped the location of gross internal mammary lymph node (IMN) metastases in order to identify areas at highest risk for harboring occult disease. Methods and Materials: Patients with axial imaging of IMN disease, including fluorodeoxyglucose F-18 (FDG18) positron emission tomography (PET-CT) and magnetic resonance imaging (MRI), were identified from a breast cancer registry. The IMN location was transferred by a radiation oncologist and breast radiologist onto the corresponding anatomic position on representative axial CT images of a patient in the treatment position. Distribution of lymph nodes, and their location was compared with consensus group guidelines of IMN target delineation. Results: Sixty-seven patients with 130 IMN metastases were mapped. The location was in the first three intercostal spaces in 102 of 130 (78%) nodal metastases. Eighteen of 130 (14%) IMN were located caudal to the third intercostal space, while 10 of 130 (8%) IMN were located cranial to the first intercostal space, including 3 patients with isolated IMN metastases at that location in the absence of distant disease. Of the 102 nodal metastases within the first three intercostal spaces, 54 (53%) were located within the RTOG consensus volume. Relative to the internal mammary (IM) vessels, 19 (19%) nodal metastases were located medially with a mean distance of 2.2 mm (SD 2.9 mm), while 29 (28%) were located laterally with a mean distance of 3.6 mm (SD 2.5 mm). Ninety and ninety-five percent of lymph nodes within the first three intercostal spaces would have been encompassed within a 4 mm and 6 mm medial and lateral expansion on the IM vessels, respectively. Conclusions: For women with indications for elective IMNI, a 4 mm medial and lateral expansion on the IM vessels within the first 3 intercostal spaces may be appropriate. In women with known IMN involvement, cranial extension to the confluence of the IM vein with the brachiocephalic vein +/- caudal extension to the 4th or 5th interspace with a 6 mm medial and lateral expansion may be considered, provided that normal tissue constraints are met. Citation Format: Jethwa KR, Kahila MM, Hunt KN, Brown LC, Corbin KS, Park SS, Yan ES, Boughey JC, Mutter RW. Delineation of internal mammary nodal target volumes in breast cancer radiotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-10-09.

Abstract Background: DNA methylation is a promising prognostic and predictive biomarker of response to treatment in advanced breast cancer (Fackler MJ. Can Res 2014). We evaluated whether baseline and change in tissue and serum methylation would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer treated with PST. Methods: TBCRC008 was a multicenter placebo-controlled trial that investigated pCR (no invasive cancer in breast/axilla) following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel with or without the histone deacetylase (HDAC) inhibitor vorinostat in 62 patients with HER2-negative breast cancer. We performed an exploratory planned biomarker study correlating baseline and change (D15) in tumor tissue and serum methylation with pCR. Methylation was measured using cumulative methylation index (CMI) in quantitative multiplexed methylation-specific polymerase chain reaction (QM-MSP) assays; cMethDNA assay for serum (Fackler MJ. Can Res 2014) and QM-MSP for tissue (Fackler MJ. Can Res 2004). The analysis population included all patients with available methylation and pCR data. Association between CMI level (log transformed baseline, D15, change) and pCR was evaluated using univariate as well as multivariable logistic regression models controlling for treatment arm and estrogen receptor (ER) status. Additional subgroup analyses assessed association of CMI level with pCR stratified by ER status and treatment arms, respectively. Spearman's correlation coefficient was performed to evaluate the correlation between tissue and serum CMI. Results: pCR data were available for 61 of 62 patients. One patient with unknown response was treated as a non-responder. The pCR rate was similar in both arms (vorinostat 25.8%, placebo 29%). Both tissue and serum CMI data were available in 55 (baseline), 50 (D15) and 46 (change) patients. Elevated serum methylation based on a predefined threshold (6.9 units) was identified in 23/59 (39%) patients. In univariate analysis, one log unit increase in tissue CMI levels at D15 was associated with a 40% lower chance of obtaining a pCR (odds ratio, OR=0.60, 95% CI 0.37-0.97; p=0.037). The multivariable analysis did not show a statistically significant association of tissue or serum CMI with pCR, although a similar trend in magnitude towards association with pCR was observed for D15 and change in tumor tissue CMI (OR 0.67 and 0.57, p=0.129 and 0.147 respectively). Subgroup analyses suggested a significant association between tissue CMI levels at D15 and pCR in the group treated with vorinostat [tissue OR: 0.44 (0.20, 0.93), p=0.03; serum OR 0.37 (0.13, 1.07), p=0.07] but not in the placebo group. No significant correlation was observed between tissue and serum CMI. Conclusion: This is the first study to evaluate the predictive role of tissue and serum methylation (CMI) in patients with early breast cancer treated with PST ± an HDAC inhibitor. Methylation was detected more frequently in tissue than serum. Tissue CMI levels at D15 may predict poor response to this regimen. Further evaluation of the predictive role of methylation in early breast cancer is warranted. Citation Format: Connolly RM, Fackler MJ, Zhang Z, Zhou XC, Goetz MP, Boughey JC, Walsh B, Carpenter J, Storniolo AM, Watkins S, Barielson E, Sukumar S, Stearns V. Tumor and serum DNA methylation in women receiving preoperative chemotherapy (PST) with or without vorinostat in primary operable HER2-negative breast cancer in TBCRC008 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-15.

3 Background: Atypical ductal hyperplasia (ADH) is a high-risk breast lesion usually diagnosed with core needle biopsy. Although upgraded to cancer at surgical excision in ~15 to 25% of cases, routine excision is questioned due to cost and overtreatment. We evaluated clinical, imaging, and histologic features associated with cancer upgrade and developed a multivariate model to predict risk of upgrade. Methods: With IRB approval a single institution retrospective review was performed of patients who underwent surgical excision of ADH diagnosed by core biopsy from 06/2005 to 06/2013. Review was performed of electronic records, breast imagin,g and biopsy slides. Multiple imputations were used for missing data. Association of cancer upgrade with various features was assessed with logistic regression. Results: 409 biopsies with ADH on core biopsy, with later surgical excision, were included. The overall upgrade rate was (16.1%, 95% CI:12.9-20.0%); 10 patients had invasive cancer at excision and 56 DCIS only. Features on core biopsy most strongly associated with upgrade were imaging estimated percent of lesion removed (upgrade 9% for 90% removed, 14% for 50 to 75%, and 27% for < 50% removed), individual cell necrosis (upgrade 34% with necrosis vs. 9.5% without), and # foci of ADH (22% for >1 focus vs 8% for 1 focus). A multivariate predictive model (see Table) showed an average C-statistic of 0.77. Women with no necrosis and either 1 focus with ≥ 50% removal or >1 focus with 90% removal (36% of the sample) have low risk of upgrade (5.0%, 95% CI:1.3-8.7%). Conclusions: ADH on core biopsy with low risk of upgrade to cancer is defined by percent of imaging lesion removed, # of foci of ADH, and lack of individual cell necrosis. If findings are validated, women whose biopsies meet low-risk criteria might be considered for chemoprevention and surveillance rather than surgical excision.[Table: see text]

98 Background: Concomitant with widespread adoption of axillary ultrasound (AUS) with ultrasound-guided needle biopsy (USNB) of suspicious lymph nodes (LN) for preoperative nodal staging of breast cancer patients, utilization of breast MRI, which includes axillary imaging, has increased. Little is known about the added value of MRI imaging of the axilla in this context. We undertook this study to assess the role of breast MRI in preoperative axillary nodal staging. Methods: We studied 988 consecutive invasive breast cancers in patients undergoing primary operation including axillary surgery, without neoadjuvant therapy, from 2010-2011. Results: 505 patients (51%) underwent MRI of which 168 (33%) demonstrated suspicious findings in the axilla. Abnormal axillary MRI findings included cortical thickening, edema, enhancement, hilar effacement, and/or altered shape and size. 114 patients had findings concordant with AUS. 54 patients had suspicious LNs on MRI either without a preceding AUS (33 cases) or after an initially negative AUS (21 cases). Second look AUS was performed in 29 of these cases and was abnormal in 3 (10%) in whom USNB confirmed metastatic adenopathy. Of the 54 cases with MRI-detected suspicious LNs 20 (37%) were node positive at operation with a pN stage of N0 (63%), N0i+ (5%), N1mic (4%), N1 (20%), N2 (6%), N3 (2%); extranodal extension was seen in 7 of 20 node-positive patients (35%). Conclusions: Second look AUS, when performed secondary to suspicious axillary MRI findings, identified LN metastasis preoperatively in 10% of patients. When MRI is done to evaluate the breast in newly diagnosed breast cancer patients, axillary findings can enhance the accuracy of preoperative nodal staging. We recommend second look AUS when MRI demonstrates suspicious axillary LN findings. [Table: see text]

49 Background: Predicting nodal positivity can guide surgical planning in breast cancer. Memorial Sloan-Kettering Cancer Center (MSKCC) and MD Anderson Cancer Center (MDACC) have established nomograms to predict sentinel node positivity. We propose that addition of distance of tumor from the nipple (DFN) can improve their performance. Methods: With IRB approval clinical T1/T2 tumors with pre-biopsy ultrasound were reviewed. MSKCC and MDACC nomogram predictions and the AUC-ROC were calculated. The addition of DFN was examined using multiple logistic regression and comparison of AUC-ROC values. Results: 401 breast cancers with clinical T1 (85%) or T2 (15%) tumors in 395 patients were included; of which 79/401 (19.7%) were node positive. Tumors were significantly closer to the nipple in those with positive nodes. 17/33 (51.5%) tumors within 2 cm of the nipple were node-positive versus 62/368 (16.8%) tumors > 2 cm from the nipple (p<0.0001). The MSKCC and MDACC nomograms each demonstrated good discrimination between node positive and negative patients with AUC-ROC values of 0.71 (95% CI: 0.64-0.77) and 0.74 (95% CI: 0.68-0.81), respectively. When added to the MSKCC nomogram, DFN ≤2 cm contributed significantly (OR 4.78, p=0.0001) to prediction of node positivity and improved the AUC-ROC to 0.73 (95% CI: 0.67-0.80). Similarly, DFN ≤2 cm was significant (OR 4.73, p=0.0002) when added to the MDACC nomogram and improved the AUC to 0.76 (95% CI: 0.70-0.82). Within nomogram probability categories, the proportion with positive nodes was consistently higher with DFN ≤2 cm. Conclusions: Tumor distance from nipple is associated with nodal positivity. When added to nomograms it improves prediction of node positivity. DFN should be considered when considering likelihood of nodal positivity for treatment planning. [Table: see text]

60 Background: Indications for nipple-sparing mastectomy (NSM) with immediate reconstruction have expanded. For cancer patients, NSM is thought best-suited for early stage patients, with nodal involvement initially viewed as a relative contraindication. We undertook this study to evaluate the use and early outcomes of NSM in node-positive (LN+) breast cancer. Methods: We identified 240 cancers in 226 patients (14 bilateral) scheduled for NSM and operated on at our institution 1/2009-6/2014. Data on intraoperative conversion from NSM, recurrence and follow-up was abstracted from the medical record. Chi-square and long-rank tests were used for statistical analysis. P-values < 0.05 were considered significant. Results: Of 240 cancers, 182 were LN- and 58 were LN+. More LN+ patients had T2/T3 tumors (27/58, 47%) than LN- patients (31/182, 17%), p < 0.0001, but ER and HER2 status was similar. Of 58 LN+ cases, 19 (33%) were cN1 confirmed by positive LN cytology and 39 (67%) were cN0 but LN+ at operation. 10 patients LN+ at diagnosis received neoadjuvant therapy (NT) followed by operation (at which 6 were pLN+ and 4 rendered ypN0); 39 cN0 (4 NT, 35 primary surgery) and 9 cN1 primary surgery patients were pLN+ at operation with a median of 1 LN+. NSM was successful in 13/14 LN+ NT patients (93%) and 39/44 LN+ primary surgery patients (89%), p = 0.64. Six LN+ patients (10%) were converted to skin-sparing mastectomy (SSM) at initial operation based on frozen section pathology (n = 5) or at a second operation (n = 1) vs 13/182 LN- patients (7%), p = 0.44. Among cancer patients treated with NSM, 7 locoregional recurrences (5 in LN+, 2 in LN- patients) occurred at 25 mos median follow-up. 3-year locoregional disease-free estimates were 87% (95% CI 75-100%) for LN+ vs 99% (95% CI 97-100%) for LN- patients, p = 0.007. One nipple-areolar recurrence occurred, in a LN- patient. 3-year breast cancer-specific survival was 97% (95% CI 92-100%) in LN+ vs 99% (95% CI 98-100%) in LN- patients, p = 0.40. Conclusions: Conversion from planned NSM to SSM did not differ significantly between LN+ and LN- patients. Short-term oncologic outcomes were satisfactory. These data suggest that NSM may be appropriate for carefully selected LN+ breast cancer patients.

247 Background: There are no prospective and few large retrospective studies of male breast cancer (MBC). This study’s aim was to describe our institutional experience with MBC and evaluate the ability of the AJCC staging system to stratify survival. Methods: All MBC cases were identified from our institution’s cancer registry from 1984-2008. Data collected included tumor characteristics, lymph node status, treatment, age, and survival. Results: During the study period 166 MBC cases were identified. Median age at diagnosis was 62 years (range 27-87). Most common presentation was a palpable breast mass (77%). Stage at diagnosis was stage 0 (6%), stage 1 (27%), stage 2 (36%), stage 3 (17%), stage 4 (5%), and unknown (9%). Procedure performed was mastectomy in 148 patients (89%), lumpectomy in 10 patients (6%) and unknown in 8 patients (5%). Median tumor size was 2.0 cm (range 0.2-11.0 cm). Most common histology was invasive ductal carcinoma (91%). Estrogen and progesterone receptor status assessed at diagnosis was positive in 93% and 86% of cases tested respectively. HER2/neu status was positive in 6 of 47 cases tested (13%). Nodal staging was performed by axillary dissection (AD) (70%), sentinel node biopsy (SN) alone (11%), SN and AD (11%) and no axillary staging (8%); 43% were node positive, 47% node negative and 10% unknown. Adjuvant chemotherapy was given to 40 patients (24%), adjuvant hormonal therapy to 42 patients (25%) and adjuvant radiation therapy was used in 33 cases (20%). With a median follow-up of 5.5 years, 86 patients (52%) have died: 44 due to breast cancer, 23 due to causes unrelated to breast cancer, and in 19 the cause of death is unknown. Median overall survival was 9.3 years. Median cancer-specific survival was 16.0 years. For patients initially diagnosed at stage 2, 3, and 4 median cancer-specific survival was 12.9, 7.2, and 0.8 years respectively. Median cancer-specific survival was significantly different for stages 2 vs. 3 (p = 0.03) and 3 vs. 4 (p = 0.0006). Conclusions: MBC most commonly presents as a palpable mass, is hormone responsive, and is most commonly treated with mastectomy. The TNM system appropriately stratifies men with MBC by duration of survival.

240 Background: Contralateral prophylactic mastectomy (CPM) is increasingly chosen by patients with breast cancer. Satisfaction after CPM is high. However, decreased satisfaction has been associated with reoperation after reconstruction. This study’s aim was to examine the adverse aspects patients attribute to reconstruction and the subsequent effect on psychosocial consequences and satisfaction with CPM. Methods: 487 unilateral breast cancer patients with a family history of breast cancer who underwent CPM between 1960 and 1993 were mailed a questionnaire evaluating QOL and satisfaction with CPM. Results: Of 269 respondents, 210 (78%) underwent reconstruction and 59 (22%) did not. Mean age at CPM was 46 and 50 years respectively (p=0.01). Mean follow-up was 20.2 years. Reconstruction was immediate in 96%, 98% with implants and 2% with tissue flap. Reconstruction was associated with lower satisfaction with CPM (p=0.03), but still only 7% (vs 2% in those without reconstruction) said they were dissatisfied. Most (83%) of those with reconstruction said they would choose reconstruction again while 7% were unsure and 10% said they would not. In those who did not undergo reconstruction, 18% said they would choose reconstruction if able to make the choice again while 5% were unsure and 77% said they still would not. 95 patients (45%) of those that underwent reconstruction required one or more reoperations for complications. Those with reoperation reported poorer responses for satisfaction with CPM (p=0.04), choice to have CPM again (p=0.008), and choice to have reconstruction again (p=0.004) when compared to patients with reconstruction and no reoperation. Those with and without reconstruction did not differ significantly with respect to femininity, sexual relationships or emotional stability, but those without reconstruction reported significantly poorer effects related to self esteem (p=0.04) and body appearance (p=0.002). Conclusions: In patients who undergo CPM, many years after surgery satisfaction with CPM is higher in those choosing not to have reconstruction than those with reconstruction although it was high in both groups. Reoperation is common after reconstruction and is associated with lower satisfaction.