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Background: Neoadjuvant immune checkpoint inhibition (ICI) in combination with chemotherapy is approved for patients with high-risk, early-stage triple-negative breast cancer (TNBC) based on improved outcomes in the KEYNOTE-522 trial. However, some patients have primary resistant disease and do not achieve a pathological complete response (pCR), while others experience significant toxicity. Tumor-associated macrophages (TAMs) are a potential resistance mechanism for ICIs and are dependent on colony-stimulating factor 1 receptor (CSF1R). Therefore, we examined the addition of cabiralizumab, a CSF1R inhibitor, to neoadjuvant paclitaxel, carboplatin, and nivolumab to assess the safety, tolerability, and changes in the tumor microenvironment (TME) in patients with early-stage TNBC. Methods: This is a phase Ib/II, single-institution, randomized controlled clinical trial (NCT04331067) in patients with newly diagnosed Stage II-III TNBC. The primary endpoints include: (1) to determine the safety of a 12-week neoadjuvant regimen of paclitaxel (80 mg/m2 IV q week) + carboplatin (AUC5 IV q3 weeks) + nivolumab (240 mg IV q2 weeks) with or without cabiralizumab (4 mg/kg IV q2 weeks) and (2) to evaluate the effect of cabiralizumab on TAMs and changes in tumor infiltrating lymphocytes (TILs) in the TME between baseline and an on-treatment biopsy after 4 weeks of therapy. Adjuvant treatment is per investigator’s choice. Secondary objectives include evaluation of pCR rate and recurrence-free survival. Paired tissue and bone marrow biopsies are collected for evaluation of the TME and disseminated tumor cells, respectively. The study was designed to enroll 50 patients, including a 12-patient safety lead-in cohort. Here, we report the planned interim analysis of the safety lead-in cohort. Results: Between December 2020 and May 2022, we enrolled 12 patients to the safety lead-in, including 6 patients in each arm. 5 of 12 patients (41.7%) enrolled are underrepresented minorities, including 4 Black patients and 1 Hispanic patient. 2 of 6 patients in the nivolumab arm experienced grade 3 severe toxicity, including 1 patient who developed sepsis and 1 who developed peripheral neuropathy. 3 of 6 patients in the nivolumab + cabiralizumab arm developed grade 3 severe toxicity including 2 patients who experienced myositis and 1 patient who developed periorbital edema. Of the first 10 patients enrolled, 5 had a pCR (2 pCR in cabiralizumab arm, 3 pCR in non-cabiralizumab arm) and 3 had non-pCR (1 RCB-1 and 1 RCB-3 in cabiralizumab arm, 1 RCB-1 in non-cabiralizumab arm). 2 patients came off study prior to surgery (1 due to toxicity and 1 due to missing study visits). Data from the final 2 patients still on treatment will be available at the time of presentation. Discussion: Full safety, pathologic, and clinical response data in the safety lead-in cohort for patients with early-stage TNBC receiving neoadjuvant chemotherapy + nivolumab with or without cabiralizumab, will be presented. Citation Format: Andrew A. Davis, Leonel Hernandez-Aya, Jingqin Luo, Mateusz Opyrchal, Foluso O. Ademuyiwa, Nusayba A. Bagegni, Katherine K. Clifton, Jill Anderson, Trish Hammerschmidt, Leslie Nehring, David DeNardo, Mark Watson, Rebecca Aft, Cynthia Ma, Katherine Weilbaecher. Phase Ib/II study to evaluate safety and tolerability of cabiralizumab in combination with nivolumab and neoadjuvant chemotherapy in patients with localized triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-06-07.

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. These NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of ductal carcinoma in situ and the workup and locoregional management of early stage invasive breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visitNCCN.org.

Background Patients (pts) with ER+ HER2+ breast cancer (BC) are less likely to achieve pathological complete response (pCR) after neoadjuvant chemotherapy with dual HER2 blockade than pts with ER- HER2+ BC. Endocrine therapy (ET) plus trastuzumab is effective in advanced ER+ HER2+ BC, but pCR rate is low in the neoadjuvant setting. Inhibition of CDK4/6 and HER2 results in synergistic reduction in cell proliferation in preclinical studies. We therefore combined ET with CDK4/6 inhibition and trastuzumab in ER+ HER2+ BC as a chemotherapy-sparing regimen. Methods We evaluated the efficacy of palbociclib, letrozole, trastuzumab (PLT) in the neoadjuvant setting for pts with stages II or III ER+ HER2+ BC. Primary endpoint was pCR after 16 weeks of therapy. We assumed null of 15% pCR and pCR ≥ 30% warrants further investigation. To achieve 80% power at 1-sided 0.05 significance, 48 pts were to be enrolled. Evaluable population included pts who completed Cycle (C) 1 unless discontinued due to treatment-emergent adverse events (TEAEs) prior to completing C1. All who received one dose on study were considered evaluable for toxicity. Biopsies were collected at baseline (BL), C1 day 15 (C1D15), and surgery for RNA sequencing and central Ki67 assessment, for PAM50 subtype distribution, complete cell cycle arrest (CCCA: Ki67 ≤2.7%) at C1D15 and surgery, and treatment induced signaling changes. Results Accrual stopped early due to futility. 26 pts accrued were evaluable for efficacy and toxicity. pCR (residual cancer burden- [RCB] 0) was 7.7% (95% CI 0.9 - 25.1%) and RCB 0/I was 38.5% (95% CI 20.2 - 59.4%). TEAEs (n= 337) were seen in all pts (71.5% grade [G] 1, 19.3% G2, 8.6% G3, 0.6% G4); the most common were leukopenia (7.7%), neutropenia (7.1%), anemia (5.9%). G3/4 TEAEs occurred in 19 pts (73.1%). Among the 19, incidence of G3/4 neutropenia was 50%, hypertension 26.9%, leucopenia 7.7%. TEAEs (hypertension, ventricular tachycardia, pulmonary edema) leading to treatment discontinuation were reported in 1 pt. Two pts had at least one SAE. No treatment-related deaths occurred. Pt reported outcomes using NCI PRO-CTCAE revealed no differences in appetite, nausea, respiratory symptoms, edema, palpitations, rashes and dry skin, or concentration from BL to end of C4. Pts had worsening hair loss from BL to end of C4. Ki67 analysis indicated CCCA in 78% at C1D15, compared to 18% at surgery after only P had been discontinued approximately 4 weeks prior to surgery. RNA sequencing was performed on available biopsies collected at BL (N=16), C1D15 (N=5), and surgery (N=2) from 16 pts. Among 16 BL samples, PAM50 subtyping identified 5 (31.3%) basal-like, 2 (12.5%) HER2-E, 6 (37.5%) Lum B, and 3 (18.8%) normal. Subtype switching to Lum A at C1D15 (N=3, 1 each with HER2-E, Lum B, and normal at BL) or normal (N=2, 1 basal and 1 HER2-E at BL) was observed. 161 genes were differentially expressed (FDR p Citation Format: Foluso O Ademuyiwa, Donald Northfelt, Tracey O'Connor, Ellis Levine, Jingqin Luo, Yu Tao, Jeremy Hoog, Marie Laury, Tracy Summa, Trish Hammerschmidt, Zhanfang Guo, Ashley Frith, Katherine Weilbaecher, Mateusz Opyrchal, Rebecca Aft, Katherine Clifton, Rama Suresh, Nusayba Bagegni, Ian S Hagemann, Cynthia X Ma. Phase 2 study of neoadjuvant palbociclib, letrozole, and trastuzumab in patients with ER+ HER2+ breast cancer (PALTAN) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-01.

Patients with ER+/HER2+ breast cancer (BC) are less likely to achieve pathological complete response (pCR) after chemotherapy with dual HER2 blockade than ER−/HER2+ BC. Endocrine therapy plus trastuzumab is effective in advanced ER+/HER2+ BC. Inhibition of CDK4/6 and HER2 results in synergistic cell proliferation reduction. We combined palbociclib, letrozole, and trastuzumab (PLT) as a chemotherapy-sparing regimen. We evaluated neoadjuvant PLT in early ER+/HER2+ BC. Primary endpoint was pCR after 16 weeks. Research biopsies were performed for whole exome and RNA sequencing, PAM50 subtyping, and Ki67 assessment for complete cell cycle arrest (CCCA: Ki67 ≤ 2.7%). After 26 patients, accrual stopped due to futility. pCR (residual cancer burden—RCB 0) was 7.7%, RCB 0/I was 38.5%. Grade (G) 3/4 treatment-emergent adverse events occurred in 19. Among these, G3/4 neutropenia was 50%, hypertension 26.9%, and leucopenia 7.7%. Analysis indicated CCCA in 85% at C1 day 15 (C1D15), compared to 27% at surgery after palbociclib was discontinued. Baseline PAM50 subtyping identified 31.2% HER2-E, 43.8% Luminal B, and 25% Luminal A. 161 genes were differentially expressed comparing C1D15 to baseline. MKI67, TK1, CCNB1, AURKB, and PLK1 were among the genes downregulated, consistent with CCCA at C1D15. Molecular Signatures Database gene-sets analyses demonstrated downregulated processes involved in proliferation, ER and mTORC1 signaling, and DNA damage repair at C1D15, consistent with the study drug’s mechanisms of action. Neoadjuvant PLT showed a pCR of 7.7% and an RCB 0/I rate of 38.5%. RNA sequencing and Ki67 data indicated potent anti-proliferative effects of study treatments. ClinicalTrials.gov- NCT02907918.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor–positive, HER2-negative breast cancer.

Background: TSECs were developed to treat menopausal symptoms after progesterone containing hormone replacement therapy was found to significantly increase the risk of invasive breast cancer (IBC). The first of this class of agents combines conjugated estrogens (CE), a collection of steroidal estrogens that collectively have both estrogen receptor (ERα) agonistic and antagonistic activity, and bazedoxifene (BZA), a third generation selective estrogen receptor modulator that does not stimulate the mammary gland or endometrium. The FDA approved CE/BZA for treatment of menopausal symptoms and osteoporosis after five randomized placebo controlled trials demonstrated the safety, efficacy and tolerability of CE/BZA in healthy postmenopausal women. Since then, a substantial body of evidence has emerged suggesting that CE/BZA may have additional therapeutic benefits in women. It is widely accepted that progression to IBC occurs through both epithelial and stromal mechanisms. Recent in vitro and in vivo data provide support that CE/BZA prevents progression to IBC through its effects on both epithelium and stroma. In epithelial cells, CE/BZA antagonizes estrogen-induced proliferation and expression of markers of ERα activity and also degrades ERα protein. In the stroma, CE/BZA increases expression of the scavenger receptor CD36 and consequently, reduces expression of extracellular matrix proteins (ECM) and pro-inflammatory cytokines that have been shown to contribute to the development of pro-tumorigenic microenvironment. Based on these preliminary data, we hypothesized that CE/BZA will have an anti-tumorigenic effect in the breast. Our ultimate objective is to provide postmenopausal women diagnosed with DCIS a novel and safe therapeutic option to prevent progression to IBC. Specific Aims: Aim 1: To assess epithelial contributions by determining if a short intervention of CE/BZA will have antagonistic activity in breast epithelium of postmenopausal women with ER + DCIS. Aim 2: To assess stromal contributions by determining if a short intervention of CE/BZA will alter expression of stromal markers of progression in breast tissue of postmenopausal women with ER + DCIS. Aim 3: To determine if a short intervention of CE/BZA is well tolerated and safe in postmenopausal women with ER + DCIS. Trial Design: We are currently conducting a multicenter randomized placebo controlled window of opportunity trial with CE/BZA in post-menopausal women with DCIS, a non-obligate precursor to IBC. The duration of intervention is 28 ± 7 days prior to surgical resection to enable comparison of CE/BZA on the breast using the diagnostic core biopsy and surgical sample. To date 33/166 women have enrolled in the trial. Eligibility Criteria: Post-menopausal women between 18-79 years of age diagnosed with ER (+) DCIS (>1cm on imaging) undergoing surgery are eligible. Women must not be on current hormonal therapy, have a current or past diagnosis of IBC, other ER sensitive tumors or have recurrent DCIS. Statistics: Results will be compared between diagnostic biopsy and surgical resection specimens and contrasted between the CE/BZA intervention group and placebo group using Fisher’s exact test for categorical variables and independent sample t-tests, or rank sum tests for continuous data. For RNAseq data, transcripts that have >1.5-fold expression change (at 20% FDR) between control and experimental samples will be used for downstream analysis, such as to plot heat maps, pathway and gene ontology analysis. Summary: At the conclusion of this study, we will have the first direct evidence of the potential benefits of CE/BZA therapy on DCIS lesions in the human breast, along with an initial assessment of symptoms and pharmacogenomics that will inform the design of future studies. Citation Format: Swati A. Kulkarni, Geoffrey Greene, Thea Tlsty, Luis Blanco, Judy Garber, Al George, Fred Rademaker, Seema A Khan, Nora Hansen, Kevin Bethke, Rebecca Aft, Julia Tchou. A large-scale multicenter phase II study evaluating the protective effect of a tissue selective estrogen complex (TSEC) in women with newly diagnosed ductal carcinoma in situ (DCIS) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-09-02.

Purpose Disseminated tumor cells (DTCs) in the BM of breast cancer patients predict early disease relapse, but the molecular heterogeneity of these cells is less well characterized. Expression of a 46-gene panel was used to detect DTCs and classify patient BM samples to determine whether a composite set of biomarkers could better predict metastatic relapse. Methods Using a high-throughput qRT-PCR assay platform, BM specimens collected from 70 breast cancer patients prior to neoadjuvant therapy were analyzed for the expression of 46 gene transcripts. Gene expression was scored positive (detectable) relative to a reference pool of 16 healthy female control BM specimens. To validate findings from a subset of 28 triple-negative breast cancer (TNBC) patients in the initial 70 patient cohort, an independent set of pre-therapeutic BM specimens from 16 TNBC patients was analyzed. Results Expression of each of the 46 gene transcripts was highly variable between patients. Individual gene expression was detected in 0–84% of BM specimens analyzed and all but two patient BM specimens expressed at least one transcript. Among a subset of 28 patients with TNBC, positivity of one or more of eight transcripts correlated with time to distant relapse (p = 0.03). In an independent set of 16 triple-negative patient BM samples, detection of five of these same eight gene transcripts also correlated with time to distant relapse (p = 0.03) with a positive predictive value of 89%. Conclusions We identified a set of gene transcripts whose detection in the BM of TNBC patients, prior to any treatment intervention, predicts time to first distant relapse, thus identifying a TNBC patient population which requires additional treatment intervention. Because these genes are presumably expressed in populations of DTCs and many encode proteins that are known therapeutic targets (e.g., ERBB2), these results also suggest a potential approach for targeted DTC therapy to mitigate distant metastases in TNBC. Electronic supplementary material The online version of this article (10.1007/s10549-019-05405-7) contains supplementary material, which is available to authorized users.

Background Consensus guidelines published in 2016 recommended a 2 mm free margin as the standard for negative margins in patients undergoing breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS). The goal of the guideline recommendation was standardization of re-excision practices. Aims To evaluate the impact of this consensus guideline on our institutional practices. Methods We identified all patients at our institution with pure DCIS who were initially treated with BCS from September 2014 to August 2018 using a prospectively-maintained institutional database. A retrospective chart review was performed to determine margin status and re-excision rates during the 2 years before and the 2 years after the guideline was published in order to determine the effect on our re-excision rates. Close margins were defined as Results In the 2 years before the consensus guideline was published, 184 patients with DCIS underwent BCS. Twenty-six patients had positive margins and 24 underwent re-excision, including three who had completion mastectomy. Of the remaining 159 patients, 76 had ≥2 mm (negative) margins. The remaining 82 patients had close margins and 48 of these patients (58.5%) underwent re-excision, including one who had a completion mastectomy. Excluding the patients with positive margins, our re-excision rate was 30.4% prior to the guideline. In the 2 years after the consensus guideline was published, 192 patients with DCIS underwent initial BCS. Twenty-four patients had positive margins and 22 underwent re-excision, including three who had completion mastectomy. Of the remaining 168 patients, 95 patients had ≥2 mm (negative) margins. The remaining 73 patients had close margins and 45 of those patients (61.6%) underwent re-excision, including six who had completion mastectomy. Excluding the patients with positive margins, our re-excision rate was 26.8% after the guideline. Conclusions Our institution's re-excision rate did not change significantly during the 2 years before and after the publication of the consensus guideline on adequate margins for patients undergoing BCT for DCIS. Our overall re-excision rate decreased slightly. However, of the patients who had close margins, a larger proportion underwent re-excision after the guideline was published. The guideline publication appears to have affected our institutional practices slightly, but not dramatically as many of our surgeons' practices were comparable to the guideline recommendations prior to 2016. We continue to use clinical judgment based on patient and tumor characteristics in deciding which patients will benefit from margin re-excision.

Purpose: Presence of disseminated tumour cells (DTCs) in the bone marrow (BM) has been described as a surrogate of residual disease in patients with early breast cancer (EBC). PADDY (Pooled Analysis of DTC Detection in Early Breast Cancer) is a large international analysis of pooled data that aimed to assess the prognostic impact of DTCs in patients with EBC. Experimental design: Individual patient data were collected from 11 centres. Patients with EBC and available follow-up data in whom BM sampling was performed at the time of primary diagnosis before receiving any anticancer treatment were eligible. DTCs were identified by antibody staining against epithelial cytokeratins. Multivariate Cox regression was used to compare the survival of DTC-positive versus DTC-negative patients. Results: In total, 10,307 patients were included. Of these, 2814 (27.3%) were DTC-positive. DTC detection was associated with higher tumour grade, larger tumour size, nodal positivity, oestrogen receptor and progesterone receptor negativity, and HER2 positivity (all p < 0.001). Multivariate analyses showed that DTC detection was an independent prognostic marker for overall survival, disease-free survival and distant disease-free survival with hazard ratios (HR) and 95% confidence intervals (CI) of 1.23 (95% CI: 1.06-1.43, p = 0.006), 1.30 (95% CI: 1.12 e1.52, p < 0.001) and 1.30 (95% CI: 1.08-1.56, p = 0.006), respectively. There was no association between locoregional relapse-free survival and DTC detection (HR 1.21; 95% CI 0.68-2.16; p = 0.512). Conclusions: DTCs in the BM represent an independent prognostic marker in patients with EBC. The heterogeneous metastasis-initiating potential of DTCs is consistent with the concept of cancer dormancy. (C) 2021 Elsevier Ltd. All rights reserved.

Simple Summary The objective of this study is to identify potential proteomic biomarkers in triple negative breast cancer (TNBC) that associate with response to PI3K inhibitors which are in clinical trials. We tested a panel of TNBC patient-derived xenograft (PDX) models for their tumor growth response to a pan-PI3K inhibitor, BKM120. Proteomic analyses by reverse phase protein array (RPPA) of 182 markers were performed on baseline and post short-term treatment PDX samples, to correlate with tumor growth response. We identified several baseline and treatment induced proteomic biomarkers in association with resistance. These results provide important insights for the development of PI3K inhibitors in TNBC. Abstract PI3K pathway activation is frequently observed in triple negative breast cancer (TNBC). However, single agent PI3K inhibitors have shown limited anti-tumor activity. To investigate biomarkers of response and resistance mechanisms, we tested 17 TNBC patient-derived xenograft (PDX) models representing diverse genomic backgrounds and varying degrees of PI3K pathway signaling activities for their tumor growth response to the pan-PI3K inhibitor, BKM120. Baseline and post-treatment PDX tumors were subjected to reverse phase protein array (RPPA) to identify protein markers associated with tumor growth response. While BKM120 consistently reduced PI3K pathway activity, as demonstrated by reduced levels of phosphorylated AKT, percentage tumor growth inhibition (%TGI) ranged from 35% in the least sensitive to 84% in the most sensitive model. Several biomarkers showed significant association with resistance, including elevated baseline levels of growth factor receptors (EGFR, pHER3 Y1197), PI3Kp85 regulatory subunit, anti-apoptotic protein BclXL, EMT (Vimentin, MMP9, IntegrinaV), NFKB pathway (IkappaB, RANKL), and intracellular signaling molecules including Caveolin, CBP, and KLF4, as well as treatment-induced increases in the levels of phosphorylated forms of Aurora kinases. Interestingly, increased AKT phosphorylation or PTEN loss at baseline were not significantly correlated to %TGI. These results provide important insights into biomarker development for PI3K inhibitors in TNBC.

The role of zoledronic acid (ZOL), a bone-targeted bisphosphonate, in the treatment of patients with breast cancer remains an active area of study. Here, we report the long-term outcomes of a randomized placebo-controlled phase II clinical trial in which ZOL treatment was added to neoadjuvant chemotherapy in women with locally advanced breast cancer. 120 women with clinical stage II–III (≥ T2 and/or ≥ N1) newly diagnosed breast cancer were randomized to receive either 4 mg intravenous ZOL every 3 weeks for 1 year (17 total doses) beginning with the first dose of neoadjuvant chemotherapy, or chemotherapy alone. Clinical endpoints included time to recurrence (TTR), time to bone recurrence (TTBR), time to non-bone recurrence (TTNBR), breast cancer survival (BCS) and overall survival (OS). With a median follow-up interval of 14.4 years, there were no significant differences in any of the clinical endpoints studied between the control and ZOL groups in the overall study population. However, ER+/HER2− patients younger than age 45 who were treated with ZOL had significantly worse TTR and TTNBR with a trend towards worse TTBR, BCS and OS (TTR: P = 0.024, HR 6.05 [1.26–29.1]; TTNBR: P = 0.026, HR 6.94 [1.26–38.1]; TTBR: P = 0.054, HR 6.01 [0.97–37.1]; BCS: P = 0.138, HR 4.43 [0.62–31.7]; OS: P = 0.138, HR 4.43 [0.62–31.7]). These differences were not seen in older ER+/HER2− patients or triple-negative patients of any age. Addition of ZOL to neoadjuvant therapy did not significantly affect clinical outcomes in the overall study population but was associated with increased extra-skeletal recurrence and a trend towards worse survival in ER+/HER2− patients younger than age 45. These findings suggest caution when using zoledronic acid in young, premenopausal women with locally advanced breast cancer and warrant further investigation. Clinical Trial Registration Number NCT00242203, Date of Registration: 10/17/2005

Disseminated tumors cells (DTCs) present in the bone marrow (BM) are believed to be the progenitors of distant metastatic spread, a major cause of mortality in breast cancer patients. To better understand the behavior and therapeutic vulnerabilities of these rare cell populations, unbiased methods for selective cell enrichment are required. In this study, we have evaluated a microfluidic-based filtration system (ParsortixR, Angle PLC), previously demonstrated for use in circulating tumor cell (CTC) capture, to capture BM DTCs. Performance using BM samples was also compared directly to enrichment of CTCs in the peripheral blood (PB) from both metastatic and non-metastatic breast cancer patients. Although the non-specific capture of BM immune cells was significant, the device could routinely achieve significant cytoreduction of BM and PB WBCs and at least 1,000-fold enrichment of DTCs, based on labeled tumor cell spike-in experiments. Detection of previously characterized DTC-associated gene expression biomarkers was greatly enhanced by the enrichment method, as demonstrated by droplet digital PCR assay. Cells eluted from the device were viable and suitable for single cell RNA sequencing experiments. DTCs in enriched BM samples comprised up to 5% of the total cell population, allowing for effective single cell and population-based transcriptional profiling of these rare cells. Use of the Parsortix instrument will be an effective approach to enrich for rare BM DTCs in order to better understand their diverse molecular phenotypes and develop approaches to eradicate these cells to prevent distant disease development in breast cancer patients.

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor–positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.

Background Women of lower socioeconomic status (SES) with early‐stage breast cancer are more likely to report poorer physician‐patient communication, lower satisfaction with surgery, lower involvement in decision making, and higher decision regret compared to women of higher SES. The objective of this study was to understand how to support women across socioeconomic strata in making breast cancer surgery choices. Methods We conducted a 3‐arm (Option Grid, Picture Option Grid, and usual care), multisite, randomized controlled superiority trial with surgeon‐level randomization. The Option Grid (text only) and Picture Option Grid (pictures plus text) conversation aids were evidence‐based summaries of available breast cancer surgery options on paper. Decision quality (primary outcome), treatment choice, treatment intention, shared decision making (SDM), anxiety, quality of life, decision regret, and coordination of care were measured from T0 (pre‐consultation) to T5 (1‐year after surgery. Results Sixteen surgeons saw 571 of 622 consented patients. Patients in the Picture Option Grid arm (n = 248) had higher knowledge (immediately after the visit [T2] and 1 week after surgery or within 2 weeks of the first postoperative visit [T3]), an improved decision process (T2 and T3), lower decision regret (T3), and more SDM (observed and self‐reported) compared to usual care (n = 257). Patients in the Option Grid arm (n = 66) had higher decision process scores (T2 and T3), better coordination of care (12 weeks after surgery or within 2 weeks of the second postoperative visit [T4]), and more observed SDM (during the surgical visit [T1]) compared to usual care arm. Subgroup analyses suggested that the Picture Option Grid had more impact among women of lower SES and health literacy. Neither intervention affected concordance, treatment choice, or anxiety. Conclusions Paper‐based conversation aids improved key outcomes over usual care. The Picture Option Grid had more impact among disadvantaged patients. Lay Summary The objective of this study was to understand how to help women with lower incomes or less formal education to make breast cancer surgery choices.Compared with usual care, a conversation aid with pictures and text led to higher knowledge. It improved the decision process and shared decision making (SDM) and lowered decision regret. A text‐only conversation aid led to an improved decision process, more coordinated care, and higher SDM compared to usual care. The conversation aid with pictures was more helpful for women with lower income or less formal education.Conversation aids with pictures and text helped women make better breast cancer surgery choices., A paper‐based pictorial conversation aid (pictures plus text) is beneficial to all patients with early‐stage breast cancer and particularly to disadvantaged patients. Between‐surgeon variation suggests that the maximal impact of such interventions requires standardized physician training combined with these interventions.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on the clinical presentation and workup of suspected bladder cancer, treatment of non-muscle-invasive urothelial bladder cancer, and treatment of metastatic urothelial bladder cancer because important updates have recently been made to these sections. Some important updates include recommendations for optimal treatment of non-muscle-invasive bladder cancer in the event of a bacillus Calmette-Guerin (BCG) shortage and details about biomarker testing for advanced or metastatic disease. The systemic therapy recommendations for second-line or subsequent therapies have also been revised. Treatment and management of muscle-invasive, nonmetastatic disease is covered in the complete version of the NCCN Guidelines for Bladder Cancer available at NCCN.org. Additional topics covered in the complete version include treatment of nonurothelial histologies and recommendations for nonbladder urinary tract cancers such as upper tract urothelial carcinoma, urothelial carcinoma of the prostate, and primary carcinoma of the urethra.

Neoadjuvant endocrine therapy (NET) can be effective at downstaging patients with estrogen receptor-positive tumors and identifying those tumors that are endocrine sensitive and resistant. The optimal prognostic markers for stratification are under investigation. Use of NET will allow the identification of patients with estrogen receptor-positive tumors who might benefit from additional treatment and allow better understanding of endocrine resistance.

Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor–positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer. Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2− breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17. Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery. Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER+ breast cancer and should not be studied further in the target patient population. Clin Cancer Res; 23(22); 6823–32. ©2017 AACR.

Background HER2 (ERBB2) gene amplification and its corresponding overexpression are present in 15–30% of invasive breast cancers. While HER2-targeted agents are effective treatments, resistance remains a major cause of death. The American College of Surgeons Oncology Group Z1041 trial (NCT00513292) was designed to compare the pathologic complete response (pCR) rate of distinct regimens of neoadjuvant chemotherapy and trastuzumab, but ultimately identified no difference. Patients and methods In supplement to tissues from 37 Z1041 cases, 11 similarly treated cases were obtained from a single institution study (NCT00353483). We have extracted genomic DNA from both pre-treatment tumor biopsies and blood of these 48 cases, and performed whole genome (WGS) and exome sequencing. Coincident with these efforts, we have generated RNA-seq profiles from 42 of the tumor biopsies. Among patients in this cohort, 24 (50%) achieved a pCR. Results We have characterized the genomic landscape of HER2-positive breast cancer and investigated associations between genomic features and pCR. Cases assigned to the HER2-enriched subtype by RNA-seq analysis were more likely to achieve a pCR compared to the luminal, basal-like, or normal-like subtypes (19/27 versus 3/15; P=0.0032). Mutational events led to the generation of putatively active neoantigens, but were overall not associated with pCR. ERBB2 and GRB7 were the genes most commonly observed in fusion events, and genomic copy number analysis of the ERBB2 locus indicated that cases with either no observable or low-level ERBB2 amplification were less likely to achieve a pCR (7/8 versus 17/40; P=0.048). Moreover, among cases that achieved a pCR, tumors consistently expressed immune signatures that may contribute to therapeutic response. Conclusion The identification of these features suggests that it may be possible to predict, at the time of diagnosis, those HER2-positive breast cancer patients who will not respond to treatment with chemotherapy and trastuzumab. ClinicalTrials.gov identifiers NCT00513292, NCT00353483

Introduction As early breast cancer might relapse even after complete removal of breast and lymphnodes, the disease must persist in secondary sites. The detection of disseminated tumor cells (DTC) in the bone marrow (BM) has been described as a surrogate of residual disease. Various trials showed an impaired prognosis of DTC positive early breast cancer (EBC) patients. The PADDY (Pooled Analysis of DTC Detection in Early Breast Cancer) study is a large international pooled analysis that aimed to assess the prognostic impact of DTC detection in patients with EBC. Methods A pre-specified protocol was followed, and centers known to practice BM sampling for DTC detection were contacted for individual patient data. Patients with EBC, with available follow-up data and BM sampling before any anti-cancer treatment were eligible. BM aspirates were collected at the time of primary surgery. DTC were identified by antibody (A45-B/B3, AE1/AE3, 2E11 and E29) staining against cytokeratin. The DTC status was compared to other prognostic factors using the chi-squared test. Univariate log-rank test and multivariate cox regression were used to compare survival of DTC positive versus DTC negative patients. Results Individual data from 10,320 patients (11 centers from Europe and USA) were included with a median follow-up of 91 months. Of all patients, 2,823 (27.4 %) were DTC positive. DTC detection was associated with higher tumor grade, higher T stage, nodal positivity, ER and PR negativity, and HER2 positivity (all p Conclusions Detection of DTC in the bone marrow is an independent prognostic marker in patients with non-metastatic breast cancer. Further studies should investigate the impact of DTC on metastatic cancer progression and their role for clinical decision making. Citation Format: Hartkopf AD, Brucker SY, Taran F-A, Harbeck N, von Au A, Naume B, Pierga J-Y, Hoffmann O, Beckmann MW, Rydén L, Fehm T, Aft R, Montserrat S, Walter V, Rack B, Schuetz F, Borgen E, Ta M-H, Bittner A-K, Fasching P, Fernö M, Krawczyk N, Weilbaecher K, Margelí M, Hahn M, Jueckstock J, Domschke C, Bidard F-C, Kasimir-Bauer S, Schoenfisch B, Kurt AG, Wallwiener M, Gebauer G, Wallwiener D, Janni W, Pantel K. International pooled analysis of the prognostic impact of disseminated tumor cells from the bone marrow in early breast cancer: Results from the PADDY study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS5-07.

3535 Background: Peripheral blood allows for a simple non-invasive method for isolating various cancer associated circulating stromal cells (CStCs) which may predict for cancer presence. Cancer Associated Macrophage-Like cells (CAMLs), a specific CStC, are phagocytic myeloid cells that derive from an immunological response to cancer and emanate from primary tumors. Using a filtration platform we screened the peripheral blood of untreated newly diagnosed cancer patients (n = 308) for CAMLs. In parallel, we screened patients with newly diagnosed non-malignant diseases, i.e. lupus, benign cysts, etc. (n = 39), and healthy control samples (n = 76). We found that CAMLs are highly prevalent (87%) in the blood of cancer patients, but uncommon in non-malignant conditions (20%) & absent in healthy individuals (0%). Methods: Anonymized peripheral blood were taken from 308 cancer patients after confirmation of invasive malignancy [stage I (n = 76), stage II (n = 73), stage III (n = 72), stage IV (n = 65) and unstaged non-metastatic (n = 22)] with pathologically confirmed lung (n = 65), pancreas (n = 53), breast (n = 52), prostate (n = 40), esophageal (n = 30), renal cell (n = 18), hepatocellular (n = 15), neuroblastoma (n = 10), melanoma (n = 8), and other (n = 17). Further, anonymized blood was taken from patients with untreated non-malignant conditions including benign breast masses (n = 19), lupus (n = 11), liver cirrhosis (n = 5), benign prostatic hyperplasia (BPH) (n = 3), and viral infection (n = 1); or from healthy control volunteers (n = 76). CAMLs were isolated from whole peripheral blood by the CellSieve™ microfiltration technique and defined as enlarged, multinuclear cells with cytokeratin and/or CD45/CD14 positive. Results: CAMLs were found in 87% of all cancer patients regardless of stage, ~5.4 CAMLs/7.5mL blood. Specifically, CAMLs were found in 80% of Stage I, 90% Stage II, 89% Stage III, and 97% Stage IV patients. No CAMLs were found in any healthy controls, but were found in 26% of benign breast masses, 18% of lupus, 0% of BPH and 0% of cirrhosis. In total, CAML sensitivity in cancer vs healthy was 87% (CI95% 82-90%), specificity = 100% (CI95% 95-100%), PPV = 100% (CI95% 100%), NPV = 67% (CI95% 58-71%). CAML sensitivity in cancer vs benign was 87% (CI95% 82-90%), specificity = 80% (CI95% 64-91%), PPV = 97% (CI95% 95-98%), NPV = 43% (CI95% 35-51%). Conclusions: CAMLs, a Circulating Stromal Cell subtype, is a sensitive blood based biomarker found in all stages of cancer that is rare in non-malignant conditions and absent in healthy individuals.

Background Activating mutations in PIK3CA occur in approximately 40% ER+BC. MK-2206 (M), a pan-AKT inhibitor, induced apoptosis of ER+ BC under estrogen deprivation in preclinical studies. We conducted this neoadjuvant trial to determine the pathologic complete response (pCR) rate of M plus anastrozole (A) for PIK3CA mutant (Mut) ER+ BC. Methods This single arm open label study of M+A used a 2-stage Simon phase II design (stage 1, n=16; stage 2, n=13, alpha=0.10, power=0.90) to test whether pCR rate Eligible patients (pts) with clinical stage II or III ER+HER2- BC were pre-registered and proceeded to a research tumor biopsy for PIK3CA sequencing, followed by treatment with daily A monotherapy for 28 days (cycle 0). Pts with PIK3CA Mut BC were subsequently registered, underwent a second biopsy, and started M (150mg PO weekly) with daily A on cycle 1 day 1 (C1D1) for a maximum of four 28-day cycles followed by surgery. Goserelin was added for premenopausal pts. A tumor biopsy on C1D17, 17 days post the start of M, was performed. Those with C1D17 Ki67 >10% discontinued study treatment. pCR was defined as no invasive cancer in the breast and the lymph nodes. Tumor specimens collected at all timepoints are being analyzed for markers of proliferation, apoptosis, and PI3K pathway activity, gene expression microarray, intrinsic subtypes, and next generation sequencing of 83 genes. Results Of the 51 pts pre-registered, 35 pts did not register due to no PIK3CA mutation (n=22), inadequate specimen for testing (n=6), physician/pt decision (n=7). The remaining 16 pts (median age: 58, range: 40-77 years) received combination therapy. Three pts did not complete 4 cycles due to C1D17 Ki67 >10% (n=2) and intolerability (grade (Gr) 4 transaminase elevation in C1, n=1). Other severe toxicities possibly related to M included Gr 3 rash (25%) and pruritus (12.5%). Of the 13 pts completed study therapy and underwent surgery, all had residual disease in the breast and 7 also had positive nodes. Table 1 summarized changes in Ki67 during treatment. ComparisonsnAbsolute changes in Ki67 median (range)Wilcoxon signed rank p-valueC1D1 relative to pre-registration11-17.0% (-49.8 to 4.1%)0.0020C1D17 relative to pre-registration14-16.4% (-51.4 to 4.1%)0.0004C1D17 relative to C1D112-1.5% (-18.6 to 15.8%)0.9697C1D1, biopsy post 28 days of A alone; C1D17 biopsy post 17 days on combination therapy Although Ki67 levels post A monotherapy (C1D1) or M+A (C1D17) were significantly lower than that of pre-registration samples, Ki67 did not differ between C1D17 and C1D1 samples. Other correlative studies are ongoing and results will be presented. Conclusion Despite the small sample size, biomarker analysis on serial biopsy specimens demonstrated that M+A is unlikely to be more effective than A alone in PIK3CA Mut ER+ BC. This trial demonstrated the feasibility of genomic sequencing for pt selection and the value of a small, well-designed proof-of-principle neoadjuvant trial for the evaluation of targeted agents. Citation Format: Ma CX, Suman VJ, Goetz M, Northfelt D, Burkard M, Ademuyiwa F, Naughton M, Margenthaler J, Aft R, Gray R, Tavaarwerk A, Wilke L, Haddad T, Moynihan T, Loprinzi C, Hieken T, Hoog J, Guo Z, Han J, Vij K, Mardis E, Sanati S, Al-Kateb H, Doyle L, Erlichman C, Ellis MJ. A phase II neoadjuvant trial of MK-2206, an AKT inhibitor, in combination with anastrozole for clinical stage 2 or 3 PIK3CA mutant estrogen receptor positive HER2 negative (ER+HER2-) breast cancer (BC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-13-04.

Younger age diagnosis of breast cancer is a predictor of adverse outcome. Here, we evaluate prognostic factors in young women with locally advanced breast cancer (LABC). We present a retrospective review of 104 patients younger than 40 years with LABC treated with surgery, radiotherapy (RT), and chemotherapy from 2003 to 2014. Patient‐, tumor‐, and treatment‐related factors important for overall survival (OS), local/regional recurrence (LRR), distant metastasis (DM), and recurrence‐free survival (RFS) were evaluated. Mean age at diagnosis was 34 years (23–39 years) with a median follow‐up of 47 months (8–138 months). Breast‐conserving surgery was performed in 27%. Axillary lymph node dissection was performed in 85%. Sixty percent of patients received neoadjuvant chemotherapy with 19% achieving pathologic complete response (pCR), and 61% downstaged. Lymph node positivity was present in 91% and lymphovascular space invasion (LVSI) in 35%. Thirty‐two percent of patients had triple negative tumors (TN, ER‐/PR‐/HER2 nonamplified). Four‐year OS and RFS was 84% and 71%, respectively. Factors associated with worse OS on multivariate analysis include TN status, LVSI, and number of positive lymph nodes. LVSI was also associated with DM and LRR, as well as worse RFS. Downstaging was associated with improved 4 year RFS in patients receiving neoadjuvant chemotherapy (74% vs. 38%, P = 0.002). With high risks of recurrence and inferior OS compared to older women, breast cancer in young women can be difficult to treat. Among additional factors, presence of LVSI and lack of downstaging portends a particularly worse prognosis.

The SDF-1 receptor CXCR4 has been associated with early metastasis and poorer prognosis in breast cancers, especially the most aggressive triple-negative subtype. In line with previous reports, we found that tumoral CXCR4 expression in patients with locally advanced breast cancer was associated with increased metastases and rapid tumor progression. Moreover, high CXCR4 expression identified a group of bone marrow–disseminated tumor cells (DTC)-negative patients at high risk for metastasis and death. The protein epitope mimetic (PEM) POL5551, a novel CXCR4 antagonist, inhibited binding of SDF-1 to CXCR4, had no direct effects on tumor cell viability, but reduced migration of breast cancer cells in vitro. In two orthotopic models of triple-negative breast cancer, POL5551 had little inhibitory effect on primary tumor growth, but significantly reduced distant metastasis. When combined with eribulin, a chemotherapeutic microtubule inhibitor, POL5551 additively reduced metastasis and prolonged survival in mice after resection of the primary tumor compared with single-agent eribulin. Hypothesizing that POL5551 may mobilize tumor cells from their microenvironment and sensitize them to chemotherapy, we used a “chemotherapy framing” dosing strategy. When administered shortly before and after eribulin treatment, three doses of POL5551 with eribulin reduced bone and liver tumor burden more effectively than chemotherapy alone. These data suggest that sequenced administration of CXCR4 antagonists with cytotoxic chemotherapy synergize to reduce distant metastases. Mol Cancer Ther; 14(11); 2473–85. ©2015 AACR.

Purpose Studies have shown that there is a negative prognostic impact of young age at diagnosis on clinical outcome in women with breast cancer (BC). We sought to determine if there is a differential effect of race in this high-risk population of women and examined mortality trends according to race and diagnosis age. Methods Using the Surveillance, Epidemiology, and End Results (SEER) program 1990-2009, women diagnosed with invasive BC under the age 50 were identified. Clinicopathologic characteristics, overall survival, and BC specific survival rates were compared between racial groups. After adjustments for stage, ER, PR, histology, age, diagnosis year, tumor size, nodal status, and grade, multivariate logistic regression analyses determined the risk-adjusted likelihood of survival for whites and blacks. Annual hazard rates (HR) of BC deaths after diagnosis according to race and calendar period, and adjusted relative hazards of death for white and black women stratified by age at diagnosis were computed. Results Overall, 162,976 women were identified, including 126,573 whites (77.7%), 20,405 blacks (12.5%), and 15,998 of other races (9.8%). At a median follow-up of 85 months, five year disease specific survival rates were 90.1% for whites, and 79.3% for blacks. During the study period, the annual HR for death in whites decreased by 26% at 5 years after diagnosis, in contrast to the rates in blacks women decreasing by only 19%. With 1990 as referent, adjusted relative hazards for death in 2005 for white and black women Conclusion Among young women diagnosed with BC, blacks have a worse outcome than whites. Mortality declines in both racial groups have been observed over time, although more rapid gains have occurred in whites. Emphasis should be placed on improving outcomes for young BC patients. Citation Format: Foluso O Ademuyiwa, Feng Gao, Lin Hao, Daniel Morgensztern, Rebecca L Aft, Cynthia X Ma. United States breast cancer mortality trends in young women according to race [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-14-04.

Background: The addition of bisphosphonates to adjuvant systemic therapy reduces bone metastases and improves survival in postmenopausal patients with early breast cancer. We have conducted four randomised trials of neoadjuvant chemotherapy (CT) +/- zoledronic (ZA) in stage II/III breast cancer to investigate the potential for enhancing pathological response within the breast and axilla. We report here a meta-analysis of these studies to enable more reliable evaluation of treatment effects and investigate activity in pre-defined subgroups of interest. Methods: Individual patient data from four prospective randomized clinical trials reporting the effect of the addition of ZA on pathological response after neoadjuvant CT were pooled. Primary outcomes were pathological complete response in the breast (pCRb) and in the breast and lymph nodes (pCR). A fixed effects Mantel-Haenszel meta-analysis was performed using odds ratios (OR) from multivariate analyses in each study correcting for T-status and ER-status after testing for heterogeneity. Predefined subgroup analyses were performed for postmenopausal women and patients with triple-negative breast cancer. Results: pCRb and pCR data were available in 736 and 553 women respectively. A summary of results is shown in the table below. In the total study population, ZA addition to neoadjuvant CT did not increase pCRb/pCR rates (12.9% for CT only vs. 16.0% with CT+ ZA; OR 1.34, 95% C.I. 0.86-2.08). However, in postmenopausal women, the addition of ZA resulted in a doubling of the pCRb rate (8.5% for CT only vs. 17.0% with CT+ ZA; OR 2.72, 95% C.I. 1.15-6.42) and pCR rate (7.8% for CT only vs. 13.6% with CT+ ZA; OR 2.48, 95% C.I. 0.80-7.69). There was significant interaction between menopausal status and ZA benefit (P for interaction=0.047). In patients with triple-negative breast cancer a trend was observed favouring CT+ZA. Pathological responseCTCT + ZAOdd's Ratio95% C.I.pCRb/totalPercentagepCRb/totalPercentagepCR in breastTotal population48/37312.958/36316.01.340.86-2.08Postmenopausal patients11/1308.524/14117.02.721.15-6.42*Pre/perimenopausal patients34/23214.733/21415.41.030.59-1.79Triple-negative breast cancer13/7018.621/6731.31.990.85-4.66pCR/totalPercentagepCR/totalPercentagepCR in breast and lymph nodesTotal population28/27910.033/27412.01.310.73-2.34Postmenopausal patients7/907.814/10313.62.480.80-7.69Pre/perimenopausal patients19/17810.718/16311.01.000.49-2.08Triple-negative breast cancer9/5217.315/5129.41.800.63-5.21Overview of pCRb and pCR in both treatment arms in the total population and predefined subgroups Conclusion: This meta-analysis shows that no overall benefit from the addition of ZA to neoadjuvant CT. However, as has been seen in the adjuvant setting, the addition of ZA to CT in postmenopausal women with early breast cancer appears to specifically increase the effects of CT with increases in pCRb and pCR. Further translational research is warranted to explore the mechanism of these observations and the potential treatment interaction with menopause. Citation Format: Judith R Kroep, Ayoub Charehbili, Rob E Coleman, Rebecca L Aft, Yoshie Hasegawa, Gerrit-Jan Liefers, Matthew C Winter, Katherine N Weilbaecher, Kohei Akazawa, Samantha Hinsley, Hein Putter, Hans WR Nortier, Norio Kohno. Effects of neoadjuvant chemotherapy with or without zoledronic acid on pathological response: A meta-analysis of randomised trials [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-11-04.

Purpose Radial scar’s stellate appearance may mimic carcinoma mammographically and histologically. Management of radial scar (RS) found on breast core needle biopsies (CNB) ranges from excision to clinical observation due to the variation in reported upgrades to malignancy at surgical excision. We examined the upgrade rate in patients with RS detected on CNB at our institution and reviewed the current literature. Methods A retrospective study was conducted of all cases with RS diagnosed on CNB between December 2006 and March 2017 at our institution. Inclusion criteria were patients with “pure” RS and RS associated with high-risk lesions (HRL). Upgrade was defined as invasive or non-invasive cancer in the excisional biopsy. Results 157 cases were identified with RS on CNB, and 122 cases met inclusion criteria. Of these 122 cases, 91 (75%) had pure RS on CNB while 31 (25%) had associated atypia or HRL. 81 (66%) of patients proceeded to excisional biopsy and 41 (34%) did not. Two patients (1.6% of total) were found to have a low-grade invasive ductal carcinoma (0.6 and 0.8 cm) upon surgical excision. None of the remaining 120 patients developed an ipsilateral breast cancer with a mean of 32.3-month follow-up. Conclusions We found a very low upgrade rate to breast cancer when RS was found on CNB with or without associated HRL. Our results are consistent with other reported series. Our data do not support surgical excision for RS but rather close clinical follow-up for patients with RS on CNB. Electronic supplementary material The online version of this article (10.1007/s10549-018-4741-y) contains supplementary material, which is available to authorized users.

Purpose: Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor–positive (ER+) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. Experimental Design: Eligible patients with clinical stage II/III ER+/HER2− breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1–21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 > 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%). Results: Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%, P < 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and PIK3CA status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression. Conclusions: Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect. Clin Cancer Res; 23(15); 4055–65. ©2017 AACR.

Randomized trials have clearly established breast conservation therapy (BCT) as appropriate treatment for early-stage invasive breast cancer. Current evidence shows that positive margins confer a greater than twofold risk of ipsilateral breast tumor recurrence. Thus, patients who have positive margins after BCT warrant re-excision. With regard to negative margins, however, the optimal negative margin width remains unclear. This article reviews the recent guidelines set forth by the Society of Surgical Oncology and the American Society of Radiation Oncology regarding the margin width in stage I and II invasive breast cancer. We also discuss the controversies related to implementation of these guidelines.

Purpose There is a negative prognostic impact of young age at diagnosis on outcome in breast cancer (BC). We sought to determine if there is a differential effect of race and examined mortality trends according to race and age.

Background: The American College of Surgeons Oncology Group Z0011 prospective randomized trial demonstrated no local control or survival advantage with more extensive axillary surgery, even in the setting of known axillary disease. These results convincingly showed that axillary surgery provides little, if any, therapeutic benefit. Given that axillary surgery is not associated with local control or survival benefit, the current role of sentinel lymph node (SLNB) is limited to staging the axilla (in other words, SLNB provides staging information but is not therapeutic). Objectives: In this randomized, controlled non-inferiority trial we aim to determine the utility of axillary ultrasound (AUS) as a pre-operative staging modality for patients with clinically node-negative invasive breast cancer with the hope that it will be a minimally invasive replacement for SLNB. 1. Primary Objective: To assess whether axillary recurrence rates for patients randomized to Arm 1 (no SLNB) is equivalent to axillary recurrence rates for patients randomized to Arm 2 (SLNB). 2. Secondary Objective: To assess disease-free survival in Arm 1 vs. Arm 2. 3. Tertiary Objective: To assess overall survival in Arm 1 vs. Arm 2. Study Design: A randomized non-inferiority trial comparing no further axillary staging versus SLNB in women with clinical T1-T2, N0 M0 breast cancer and negative AUS. Following a negative AUS, four hundred sixty women will be randomized in a 1:1 fashion to no further axillary staging or SLNB. Subjects will be monitored for local-regional and distant recurrence per NCCN guidelines. We have recruited 28 study participants. Eligibility Criteria: To be eligible the patient must be 18-y.o. or older; female; have tissue-diagnosis of invasive breast cancer; cT1-2N0M0 cancer; negative AUS; ECOG Statistical Methods: Power analysis: A power analysis was performed to determine the accrual goal. The power analysis is based on axillary recurrence, our primary endpoint. We expect an axillary recurrence rate of 1% in patients undergoing SLNB. By assuming a noninferiority limit of 2% difference, our sample size will allow us 80% power at 1-sided 0.1 significance level to assure such a noninferiority. Data analysis: Longer-term formal data analysis for the study will be performed following the intent-to-treat (ITT) principle. Demographic and clinical characteristics of the sample, as well as efficacy, complication rates and loss to follow-up will be summarized using descriptive statistics. The balance of demographic and baseline clinical characteristics between two arms will be compared using t-test, Mann-Whitney rank-sum test, or Chi-square test as appropriate. The differences in OS and DFS between treatment arms will be compared using log-rank test. Citation Format: Natalia S Tucker, William E Gillanders, Timothy Eberlein, Rebecca Aft, Julie Margenthaler, Feng Gao, Catherine Appleton, Imran Zoberi, Ademuyiwa Foluso, Amy Cyr. A prospective, randomized trial of sentinel lymph node biopsy versus no additional staging in patients with T1-T2 invasive breast cancer and negative axillary ultrasound [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-5-01.

Background: 20% of invasive breast cancers are triple negative (TN). Chemotherapy improves the outcome for a subset of these patients. Recurrence rates of 40-50% have been reported in those patients who do not achieve a complete pathological response to neoadjuvant therapy. Currently, there are no targeted therapies to TN cancers. Data suggest that micrometastases or disseminated tumor cells (DTCs) that persist despite chemotherapy are enriched with cells that have stem cell-like features. The Hedgehog (Hh) signaling pathway, which is involved in modulating epithelial-mesenchymal transition and maintenance of breast cancer stem cells, is an attractive therapeutic target for patients with TN tumors. In preclinical models, we have shown that Hh inhibition reduced breast cancer growth and metastasis. Trial Design: This is a placebo-controlled, double blinded, randomized phase II trial in early stage TN breast cancer patients with detectable DTCs in their bone marrow (BM) at the completion of all therapy. LDE225 is administered at 400 mg orally daily for a 28 day cycle for 20 cycles. After 6 cycles, BM will be collected for analysis. Specific Aims: The primary endpoint is the elimination of DTCs after 6 cycles of LDE225. Additional endpoints include: 2-year disease-free survival (DFS) and overall survival (OS), effect on BM Ptch1 gene expression, toxicity profile of LDE225, DFS and OS in patients with no DTCs at screening versus DTC-positive patients in the placebo arm. Eligibility: Patients with ER-/Her2- stage I-III invasive breast cancers who have completed all therapy and have detectable DTCs, as defined by a molecular based assay for DTCs performed in a CLIA-licensed facility are eligible. Statistical Methods: Based on preliminary data, 60% of patients in the LDE225 arm are expected to be Ptch1 positive, and 50% of these patients are expected eliminate DTCs after 6 cycles of treatment. The expected clearance rate in the remaining 40% of the LDE225 arm is 5% with an overall clearance rate of 32%. In the placebo arm, the expected clearance rate is 5% regardless of Ptch1 status. A sample of 68 patients, 34 in each treatment arm, will have power ∼ 0.8 at a 0.05 significance level, after adjusting for one interim analysis, to detect a difference in DTC clearance rate of 32% in the LDE225 arm versus 5% in the placebo arm. Assuming that 40% of patients screened have detectable DTCs, approximately 170 patients will be screened to identify 68 with detectable DTCs. Enrollment will be suspended for 3 months after the first 6 patients have been randomized to LDE225 therapy to allow time to document toxicity and adverse events. One interim analysis will be conducted after 50% of the patients have completed 6 months on study. The proportion of patients who are DTC-positive at 6 months will be estimated. The power of the study power to achieve its primary goal will be calculated conditional on results obtained to that point. The significance level of the final analysis will be adjusted to 0.048 in order to maintain an overall 0.05 significance level. Accrual: Accrual is anticipated to begin August 2013. Target = 34 per arm. NCT01757327. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-12.

Purpose To report the incidence and potential predictors of fat necrosis in women with early stage breast cancer treated with adjuvant high-dose-rate (HDR) multicatheter interstitial brachytherapy. Methods and Materials Between 2003 and 2010, 238 treated breasts in 236 women were treated with accelerated partial breast irradiation using HDR interstitial brachytherapy. Selection criteria included patients with Tis–T2 tumors measuring ≤3 cm, without nodal involvement, who underwent breast-conserving surgery. Ninety-nine percent of treatments were to a total dose of 34 Gy. The presence and severity of fat necrosis were prospectively recorded during followup. Cosmesis was qualitatively scored in all patients. Cosmesis was quantitatively measured via the percentage breast retraction assessment in 151 cases. Results Median followup was 56 months. The crude rate of fat necrosis was 17.6%. The rate of symptomatic fat necrosis was 10.1%. In univariate analysis, acute breast infection and anthracycline-based chemotherapy, number of catheters, volume encompassed by the prescription isodose, volume encompassed by the 150% isodose (V150), volume encompassed by the 200% isodose, and integrated reference air kerma were significantly associated with fat necrosis. There was significant collinearity between the brachytherapy-related factors; of these, V150 was most predictive. In multivariate analysis, only V150 was significantly associated with fat necrosis. At 3 years, patients with fat necrosis were more likely to have a fair or poor cosmetic outcome and a larger percentage breast retraction assessment. Conclusions Mammary fat necrosis is a common adverse event after breast-conserving surgery and HDR interstitial brachytherapy. Fat necrosis is associated with worse qualitative and quantitative cosmetic outcomes. Minimizing exposure volumes, such as V150, may decrease the incidence of fat necrosis and improve cosmesis.

Purpose Molecular characterization of disseminated tumor cells (DTCs) in the bone marrow (BM) of breast cancer (BC) patients has been hindered by their rarity. To enrich for these cells using an antigen-independent methodology, we have evaluated a size-based microfiltration device in combination with several downstream biomarker assays. Methods BM aspirates were collected from healthy volunteers or BC patients. Healthy BM was mixed with a specified number of BC cells to calculate recovery and fold enrichment by microfiltration. Specimens were pre-filtered using a 70 μm mesh sieve and the effluent filtered through CellSieve microfilters. Captured cells were analyzed by immunocytochemistry (ICC), FISH for HER-2/neu gene amplification status, and RNA in situ hybridization (RISH). Cells eluted from the filter were used for RNA isolation and subsequent qRT-PCR analysis for DTC biomarker gene expression. Results Filtering an average of 14×106 nucleated BM cells yielded approximately 17-21×103 residual BM cells. In the BC cell spiking experiments, an average of 87% (range 84-92%) of tumor cells were recovered with approximately 170- to 400-fold enrichment. Captured BC cells from patients co-stained for cytokeratin and EpCAM, but not CD45 by ICC. RNA yields from 4 ml of patient BM after filtration averaged 135ng per 10 million BM cells filtered with an average RNA Integrity Number (RIN) of 5.3. DTC-associated gene expression was detected by both qRT-PCR and RISH in filtered spiked or BC patient specimens but, not in control filtered normal BM. Conclusions We have tested a microfiltration technique for enrichment of BM DTCs. DTC capture efficiency was shown to range from 84.3% to 92.1% with up to 400-fold enrichment using model BC cell lines. In patients, recovered DTCs can be identified and distinguished from normal BM cells using multiple antibody-, DNA-, and RNA-based biomarker assays.

Margin status is a significant risk factor for local recurrence. We sought to examine whether the method of tumor localization predicted the margin status and the need for re-excision for both nonpalpable and palpable breast cancer.We identified 358 consecutive breast cancer patients who were treated with breast-conserving therapy (BCT) from 1999 to 2006. Data included patient and tumor characteristics, method of localization (needle versus palpation), and pathologic outcomes. Descriptive statistics were used for data summary and data were compared using χ(2).Of 358 patients undergoing BCT, 234 (65%) underwent needle localization for a nonpalpable tumor and 124 (35%) underwent a palpation-guided procedure. Patients undergoing palpation-guided procedures were younger and had larger tumors at a more advanced pathologic stage of disease than those undergoing needle localization procedures (P0.05 for each). Patient race, tumor grade, presence of lymphovascular invasion, biomarker profile, and nodal status were not significantly different between the two groups (P0.05). Overall, 137 patients (38%) had one or more positive margins: 90 of 234 (38%) who had a needle localization procedure and 47 of 124 (38%) who had a palpation-guided procedure (P0.05). The number of margins affected did not differ significantly between the two groups.Although patients with palpable breast cancer had larger tumors than those with nonpalpable breast cancer, the incidence and number of positive margins was similar to those who had needle localization for nonpalpable tumors. Improved methods of localization are needed to reduce the rate of positive margins and the need for re-excision.

Background We investigated factors associated with positive margins following mastectomy and the impact on outcomes. Methods We identified 240 patients with stage I–III invasive breast cancer who underwent mastectomy from 1999 to 2009. Data included patient and tumor characteristics, pathologic margin assessment, and outcomes. Margin positivity was defined as the presence of in situ or invasive malignancy at any margin. Descriptive statistics were used for data summary and were compared using χ2. Results Of the 240 patients, 132 (55%) had a simple mastectomy with sentinel lymph node biopsy and 108 (45%) had a modified radical mastectomy. Overall, 21 patients (9%) had positive margins, including 12 (57%) with one positive margin, 3 (14%) with two positive margins, and 6 (29%) with three or more positive margins. The most commonly affected margin was the deep margin (48% of patients). Eight of the 21 patients (38%) received adjuvant chest wall irradiation. There were no differences between patients who had a positive margin and those who did not with respect to patient age, race, percentage of in situ component, tumor size, tumor grade, lymphovascular invasion, or immunostain profile (P > 0.05 for all). None of the patients with positive margins experienced a local recurrence. Conclusions Positive margins following mastectomy occurred in nearly 10% of our patients. No specific patient or tumor characteristics predicted a risk for having a positive margin. Despite the finding that only approximately 40% of patients received adjuvant radiation in the setting of a positive margin, no local recurrences have been observed.

Background: Despite neoadjuvant/adjuvant chemotherapy, women with resectable stage II/III breast cancer (BC) have high risk of recurrent disease. Recent data suggest that zoledronic acid (ZOL) therapy concurrent with adjuvant treatments may improve cancer-related outcomes in patients with BC. Methods: Disease-free survival (DFS; secondary end point) and overall survival (OS; tertiary end point) were evaluated in 119 women with stage II/III BC randomised to intravenous ZOL 4 mg every 3 weeks for 1 year or no ZOL (control) starting with the first chemotherapy cycle. Results: At 61.9 months' median follow-up, there was no significant difference in recurrence or survival between study arms. However, time to recurrence or death (DFS) was significantly different between subgroups defined by oestrogen receptor (ER) status (interaction P=0.010 for DFS and 0.025 for OS). Hazard ratios (HRs) for disease recurrence and death were significantly less among patients with ER-negative (ER−) tumours who received ZOL vs no ZOL (DFS: HR=0.361, 95% confidence interval (CI) 0.148, 0.880; OS: HR=0.375, 95% CI 0.143, 0.985). Conclusion: ZOL administered with chemotherapy may improve DFS and OS in a subset of BC patients with ER− tumours. This study was not powered to compare subgroups of patients; thus, these findings should be considered hypothesis generating.

Little is known about quality-of-life (QOL) differences over time between incident ductal carcinoma in situ (DCIS) and early-stage invasive breast cancer (EIBC) cases as compared with same-aged women without breast cancer (controls). We prospectively recruited and interviewed 1,096 women [16.8 % DCIS, 33.3 % EIBC (25.7 % Stage I; and 7.6 % Stage IIA), 49.9 % controls; mean age 58; 23.7 % non-white] at mean 6.7 weeks (T1), and 6.2 (T2), 12.3 (T3), and 24.4 months (T4) after surgery (patients) or screening mammogram (controls). We tested two hypotheses: (1) DCIS patients would report lower levels of QOL compared with controls but would report similar QOL compared with EIBC patients at baseline; and (2) DCIS patients’ QOL would improve during 2-year follow-up and approach levels similar to that of controls faster than EIBC patients. We tested hypothesis 1 using separate general linear regression models for each of the eight subscales on the RAND 36-item Health Survey, controlling for variables associated with at least one subscale at T1. Both DCIS and EIBC patients reported lower QOL at T1 than controls on all subscales (each P < 0.05). We tested hypothesis 2 using generalized estimating equations to examine change in each QOL subscale over time across the three diagnostic groups adjusting for covariates. By T3, physical functioning, role limitations due to physical problems, energy/fatigue, and general health each differed significantly by diagnostic group at P < 0.05, because of larger differences between EIBC patients and controls; but DCIS patients no longer differed significantly from controls on any of the QOL subscales. At T4, EIBC patients still reported worse physical functioning (P = 0.0001) and general health (P = 0.0017) than controls, possibly because of lingering treatment effects. DCIS patients’ QOL was similar to that of controls two years after diagnosis, but some aspects of EIBC patients’ QOL remained lower.

Epithelial–mesenchymal transition (EMT) is a normal developmental program that is considered to also play an important role in cancer metastasis. Ultimate inducers of EMT are transcriptional repressors that individually can induce experimental EMT, yet in many cells, particularly cancer cells, multiple inducers are expressed simultaneously. Why, and if, and how they interact to regulate EMT is unanswered. Using RNA interference technology to affect protein knockdown and avoid potential overexpression artifact coupled with transient TGFβ treatment to better mimic in vivo conditions we show, in both nontumorigenic and tumorigenic epithelial cancer cells, that Snail1 is uniquely required for EMT initiation, whereas Twist1 is required to maintain late EMT. Twist1, present in resting epithelial cells, is dispensable for EMT initiation. Mechanistically, in response to transient TGFβ treatment, transient Snail1 expression represses Twist1 transcription directly, which is subsequently upregulated, as Snail1 levels decrease, to sustain E-cadherin downregulation and growth arrest of EMT. Persistent Twist1 expression is associated with a p38 and extracellular signal–regulated kinase signal feedback loop that sustains growth-inhibitory signals characteristic of quiescent micrometastatic tumors. This Snail1–Twist1 temporal and spatial cooperation was also observed in vivo during human breast cancer progression to metastasis. Twist1 level, but not Snail1 level, and Twist1:Snail1 ratio in disseminated micrometastatic bone marrow tumor cells was found to correlate with survival and treatment resistance and is highly predictive of metastatic or recurrent disease. Mol Cancer Res; 9(12); 1644–57. ©2011 AACR.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is known to be chemosensitive. In patients with TNBC, we sought to compare survival outcomes between patients receiving neoadjuvant chemotherapy, with and without complete pathologic response (pCR), and those receiving adjuvant chemotherapy.We performed a retrospective chart review and identified 385 patients with stage I-III TNBC who were treated with neoadjuvant or adjuvant chemotherapy between 2000 and 2008. Patients were divided according to receipt of neoadjuvant chemotherapy with pCR, neoadjuvant chemotherapy without pCR, and adjuvant chemotherapy. Data were compared using Fisher's exact test and analysis of variance (ANOVA). Kaplan-Meier curves were generated.Of 385 patients, 151 (39%) received neoadjuvant chemotherapy and 234 (61%) received adjuvant chemotherapy. Twenty-six (17%) of those patients receiving neoadjuvant chemotherapy had pCR. After controlling for covariates associated with survival in unadjusted tests, patients undergoing neoadjuvant chemotherapy with residual tumor had significantly worse survival compared with patients receiving adjuvant therapy [hazard ratio (HR) = 0.51, P = 0.007] and a trend towards worse survival compared with patients receiving neoadjuvant therapy with pCR (HR = 0.19, P = 0.10).Although previous clinical trials have not demonstrated a survival difference between patients receiving neoadjuvant versus adjuvant chemotherapy for breast cancer, our study suggests an overall survival benefit in patients with pCR following neoadjuvant chemotherapy compared with patients receiving adjuvant therapy. It is clear that a prospective study needs to be carried out to better elucidate the timing of chemotherapy in patients with TNBC.

Background: We conducted a randomized Phase II study examining the effect zoledronic acid (ZA) on disseminated tumor cells (DTC) in women undergoing neoadjuvant chemotherapy (Lancet Oncology11:421). We now report on the effect of ZA administered concurrently with neoadjuvant/adjuvant chemotherapy on disease-free survival and overall survival in this patient population. Methods: Between March 2003-2006, 120 women with newly diagnosed clinical stage II/III breast cancer were randomized to either ZA 4 mg IV every 3 weeks for 1 year starting with the first cycle of chemotherapy or no bisphosphonate. 4 cycles of epirubicin (75 mg/m2)/docetaxel (75 mg/m2) were given prior to surgery and 2 cycles in the adjuvant setting. Eligible patients received adjuvant endocrine therapy and trastuzumab. Disease-free survival was defined as the time from trial registration to first detectable recurrence. Overall survival was defined as the time from trial registration to date of breast-cancer related death. Data was analyzed using Kaplan-Meier and Cox proportional hazard models. Results: Of 120 patients randomized 119 patients were evaluable. Treatment arms were balanced for grade, menopausal status, and tumor biomarkers. Tumors of 55 (46.2%) women were estrogen-receptor (ER) positive/Her2-negative, 40 (33.6%) were ER-negative/Her2-negative and 24 (20.2%) were Her2-positive.With a median follow up of 61.9 (4.93-85.43) months, there was no significant difference in recurrence or survival between the ZA and no ZA groups (p=0.88, p=.92 respectively). Subgroup analysis demonstrated that time to recurrence and death was significantly different between patient groups based on ER-status and ZA treatment (p=.013 for recurrence, p=.013 for survival). Months Time to recurrence and hazard of death was similar in three of the subgroups, ER-positive/Her2-negative/control, ER-positive/Her2-negative/ZA, and ER-negative/Her2-negative/ZA (p>.05 for recurrence and p>.05 for survival. ER-negative/Her2- negative patients in the no ZA treatment arm experienced a significantly decreased time to recurrence and survival compared to ER-positive patients (p=.0039, p=.0074, respectively). The hazard ratio of death for ER-negative/Her2-negative patients was reduced from 8.36 to 3.15 with ZA treatment. The estimated 5yr survival for ER-positive/Her2-negative/control, ER-positive/Her2-negative/ZA, ER-negative/Her2-negative/control, ER-negative/Her2-negative/ZA were 96.6%, 80.0%, 63.2% and 81.0% respectively. Discussion: ZA administered with chemotherapy conferred a disease-free survival and overall survival benefit to a subset of breast cancer patients with ER-negative/Her2-negative tumors. Longer follow-up may be required to determine if there is a benefit in other tumor subgroups. Larger studies are warranted to examine the effects of ZA in patients at high risk of developing metastatic disease. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-04.

Background: Noninfectious wound complications, including tissue necrosis and dehiscence, may complicate healing of the breast surgical incision after mastectomy. Breast cancer patients may be at increased risk of noninfectious wound complications due to adjuvant chemo-and radiotherapy. Objective: To identify independent risk factors for noninfectious wound complications (necrosis and/or dehiscence), including the impact of neo-and adjuvant chemotherapy, and previous and adjuvant radiotherapy after mastectomy alone or with immediate breast reconstruction. Methods: We performed a prospective cohort study of all mastectomy patients with invasive or in situ breast cancer at a tertiary care academic medical center from 8/2005 — 7/2008. Data were collected from the original surgical admission and all hospital readmissions and surgery and oncology clinic visits within 1 year of surgery. Follow-up data included documented signs and symptoms of wound complications, microbiology cultures, additional surgical procedures, and chemo-and radiation therapy dates. Extended Cox proportional hazards models were used to determine independent risk factors for wound complications, controlling for underlying comorbidities, previous chest irradiation and neoadjuvant chemotherapy, and with adjuvant radiotherapy and chemotherapy included as time-dependent covariates. Results: 777 women had a mastectomy (408 (52.5%) mastectomy only, 325 (41.8%) mastectomy plus implant, and 44 (5.7%) mastectomy plus autologous tissue reconstruction). 173/777 women (22.3%) received neoadjuvant chemotherapy. 105 women had breast wound complications within 180 days after surgery (13.5%). Repeat surgery (incision and drainage, debridement, and/or implant removal) was required in 40/105 (38.1%) women with wound complication. 13/105 (12.4%) women had subsequent infection after wound complication, while 9/105 (8.6%) had infection diagnosed before the wound complication. Independent risk factors for noninfectious wound complication within 180 days after surgery included autologous tissue reconstruction (hazard ratio (HR) 5.6, 95% CI: 2.9-10.5), implant reconstruction (HR 4.3, 95% CI: 2.8-6.8), smoking (HR 3.3, 95% CI: 2.2-4.9), higher ASA class (HR 1.7 (95% CI: 1.0-2.9), and morbid obesity (BMI > 35, HR 2.6, 95% CI: 1.7-4.0). Preadmission anticoagulant therapy was marginally associated with increased risk of necrosis/dehiscence (HR 1.8, 95% CI: 0.9-3.7). Diabetes (p = .365), neoadjuvant chemotherapy (p = .254), adjuvant chemotherapy (p = .222), previous radiotherapy (p = .195), and adjuvant radiotherapy (p = .106) were not associated with increased risk of necrosis/dehiscence within 180 days of surgery after accounting for other risk factors for wound complication. Discussion: Immediate breast reconstruction, smoking, and morbid obesity were associated with increased risk of tissue necrosis/dehiscence within 180 days after mastectomy. Neo-and adjuvant chemotherapy and adjuvant radiotherapy were not associated with increased risk of noninfectious wound complications after controlling for underlying comorbidities and other risk factors. These results emphasize the important of smoking cessation in women undergoing mastectomy, particularly with immediate breast reconstruction. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-14-07.

Objective The study aim was to investigate the methods of breast cancer diagnosis and treatment for women at advanced ages. Methods We identified 134 patients ≥80 years old treated for breast cancer. Data included patient and tumor characteristics, treatment, and outcomes. Results Of 134 women ≥80 years old, 146 breast cancers were diagnosed. Sixty-five (45%) were detected by mammography. Surgical therapy included partial mastectomy in 50% and mastectomy in 50%. Although 12 (9%) women had no axillary staging, 22 (16%) underwent axillary lymph node dissection for node-negative disease. Of 73 patients undergoing partial mastectomy, 34 (47%) received adjuvant radiation. Of 113 cancers with known estrogen receptor (ER) status, 83% were ER positive; 95% received endocrine therapy. Fourteen (10%) received adjuvant chemotherapy. Eleven (8%) were Her-2neu-amplified; one patient received adjuvant trastuzumab. At follow-up, 87 (65%) patients were alive without evidence of disease, while 6 (4%) died of breast cancer. Conclusions Breast cancer in women ≥80 years is more likely to be early-stage with favorable tumor biology. While most women eligible for anti-estrogen therapy received it, adjuvant radiation, chemotherapy, and/or trastuzumab were utilized infrequently. Despite these variations, older women with breast cancer are unlikely to suffer breast cancer-related mortality. J. Surg. Oncol. 2011; 103:201–206. © 2010 Wiley-Liss, Inc.

We read with interest the article by Collins et al. [1] about body image (BI) and breast cancer surgery. The authors should be commended for their efforts to describe the impact of surgical treatments and surgical side-effects severity on breast cancer patients’ BI over time. As a plastic and breast cancer surgeons, it has been our opinion that each of these surgical treatments has the potential to impact a patient’s quality of life (QL) across several domains and BI is one of these important related aspects. We believe that understanding these domains will help to improve the informed consent process and assist general and plastic surgeons and patients alike with treatment decision. Recently, there has been a resurgence of interest in the effects of surgical treatment on breast cancer patients’ BI, and this paper again illustrates the value of these questions. Contrary as we observed in previous studies, the current study with longitudinal cohort designs allow for repeated measures of individual patients over time. Although many of the present data described are valuable and interesting, the clinical relevance to be drawn from this data deserves clarification. As the authors point out, several studies have reported better BI, however, other studies have found no significant differences by surgery type. In the present study, the authors concluded that although BI problems were quite low, problems were significantly higher among patients who received mastectomy with reconstruction than patients with conservation breast surgery/mastectomy alone. As the authors well observed, it is possible that patients who received mastectomy with reconstruction had more problems with their BI prior to surgical treatment and chose to undergo immediate reconstruction with the hopes of improving this aspect. We totally agree with this aspect and it has been our experience that patients who choose immediate reconstruction may differ from patients who do not, in terms of their preoperative BI and QL. One might surmise that if patient who choose immediate reconstruction start out with poorer BI/QL prior to cancer surgery, then equivalent postoperative evolution may reflect improvements from baseline after reconstruction. Otherwise, if patient who choose immediate reconstruction have better baseline BI/QL, then equivalent postoperative evolution would suggest that reconstruction causes some impairment. Without knowing the preoperative characteristics in all groups, however, it is difficult to know the real effects of immediate breast reconstruction and postoperative outcome [2]. Another important point is related to the appropriateness of decisions. It has been our impression that the present study did not take into account whether or not a patient’s decision to undergo immediate reconstruction was an A. M. Munhoz Department of Plastic Surgery, Hospital Sirio-Libanes, Sao Paulo, Brazil

Summary Background Treatment with bisphosphonates decreases bone loss and can increase disease-free survival in patients with breast cancer. The aim of our study was to assess the effect of zoledronic acid on clearance of disseminated tumour cells (DTCs) from the bone marrow in women undergoing neoadjuvant chemotherapy for breast cancer. Methods Patients were recruited for this open-label, phase 2 randomised trial between March 17, 2003, and May 19, 2006, at a single centre. Eligible patients had clinical stage II–III (≥T2 and/or ≥N1) newly diagnosed breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, and normal cardiac, renal, and liver function. 120 women were randomly assigned, using allocation concealment, to receive 4 mg zoledronic acid intravenously every 3 weeks (n=60), or no zoledronic acid (n=60), for 1 year concomitant with four cycles of neoadjuvant epirubicin (75 mg/m 2 ) plus docetaxel (75 mg/m 2 ) and two cycles of adjuvant epirubicin plus docetaxel. The primary endpoint was the number of patients with detectable DTCs at 3 months. Final analysis was done 1 year after the last patient was enrolled. Analyses were done for all patients with available data at 3 months. This study is registered with ClinicalTrials.gov, number NCT00242203. Findings Of the 120 patients initially enrolled, one withdrew after signing consent and one patient's baseline bone marrow was not available. Both of these patients were in the control group. At 3 months, 109 bone-marrow samples were available for analysis. In the zoledronic acid group, bone marrow was not collected from one patient because of disease progression, one patient was taken off study because of severe diarrhoea, and two patients had not consented at the time of surgery. In the control group, bone marrow was not collected from two patients because of disease progression, one patient withdrew consent, and three patients were not consented at the time of surgery. At baseline, DTCs were detected in 26 of 60 patients in the zoledronic acid group and 28 of 58 patients in the control group. At 3 months, 17 of 56 patients receiving zoledronic acid versus 25 of 53 patients who did not receive zoledronic acid had detectable DTCs (p=0·054). The most common grade 3–4 toxicities were infection (five of 60 patients in the zoledronic acid group and six of 59 in the control group) and thrombosis (five of 60 in the zoledronic acid and two of 59 in the control group). There was one documented case of osteonecrosis in the zoledronic acid group. Interpretation Zoledronic acid administered with chemotherapy resulted in a decreased proportion of patients with DTCs detected in the bone marrow at the time of surgery. Our study supports the hypothesis that the antimetastatic effects of zoledronic acid may be through effects on DTCs. Funding Novartis Pharmaceuticals and Pfizer Inc.

We examined racial disparities (White, African American, and other race) in health status (self-rated health, lower-body functional limitations, psychological distress, and body mass index [BMI]) and behaviors (smoking, alcohol use, and physical activity) of long-term cancer survivors (or=5 years) when compared to non-cancer controls.Using 2005-2007 National Health Interview Survey data, we computed adjusted prevalence estimates of health status and behaviors for all six groups, controlling for sociodemographic factors, medical-care access, or presence of other chronic conditions.The sample included 2,762 (3.6%) survivors and 73,059 controls. Adjusted prevalence estimates for each race were higher for long-term survivors than controls in terms of having fair-poor self-rated health,or=1 limitation, psychological distress, and higher BMI but were similar between survivors and controls in terms of physical activity, smoking, and alcohol use. Adjusted prevalence estimates for having fair-poor self-rated health were higher for African American survivors than white survivors, lower for psychological distress, physical activity and alcohol use, and similar for smoking and BMI.With the exception of smoking and limitations, racial differences existed among survivors for all health-status and behavioral measures. Clinicians may play a key role in helping to reduce disparities.

Neoadjuvant chemotherapy reduces tumor size before surgery in women with breast cancer. The aim of this study was to assess the ability of mammography and ultrasound to predict residual tumor size following neoadjuvant chemotherapy.In a retrospective review of consecutive breast cancer patients treated with neoadjuvant chemotherapy, residual tumor size estimated by diagnostic imaging was compared with residual tumor size determined by surgical pathology.One hundred ninety-two patients with 196 primary breast cancers were studied. Of 104 tumors evaluated by both imaging modalities, ultrasound was able to size 91.3%, and mammography was able to size only 51.9% (chi(2)P.001). Ultrasound also was more accurate than mammography in estimating residual tumor size (62 of 104 [59.6%] vs 33 of 104 [31.7%], P.001). There was little difference in the ability of mammography and ultrasound to predict pathologic complete response (receiver operating characteristic, 0.741 vs 0.784).Breast ultrasound was more accurate than mammography in predicting residual tumor size following neoadjuvant chemotherapy. The likelihood of a complete pathologic response was 80% when both imaging modalities demonstrated no residual disease.

Background: A goal of Healthy People 2010 was to reduce health disparities. We determined the extent of reductions in geographic disparities in five breast cancer screening indicators.Methods: We examined the extent of reductions in geographic disparities in five breast cancer screening indicators using data about women ages 40 years and older from 200 counties in the 1988 to 2005 Surveillance, Epidemiology, and End Results Program database. County-level trends in five breast cancer indicators (in situ, stage I, lymph node–positive, locally advanced, and mortality) were summarized using the estimated annual percentage change. Observed county rates were smoothed using hierarchical Bayesian spatiotemporal methods to calculate measures of absolute and relative geographic disparity and their changes over time.Results: For in situ breast cancer, absolute disparity increased 93.7% during 1988 to 2005. Relative disparity declined 61.5% during the entire study period. Absolute and relative disparity for stage I breast cancer declined 18.5% and 41.4%, respectively. Absolute disparity for lymph node–positive breast cancer declined 37.9% during the study period, whereas relative disparity declined 17.6%. Absolute disparity for locally advanced breast cancer declined 66.5%, whereas relative disparity declined 17.8% during the study period. Absolute disparity in breast cancer mortality declined 60.5%, whereas relative disparity declined 19.8%.Conclusions: Absolute and relative geographic disparities narrowed over time for all breast cancer indicators except for in situ breast cancer.Impact: Progress has been made toward reducing geographic disparities in breast cancer outcomes, particularly in advanced-stage breast cancer incidence and mortality rates, although disparities remain. Cancer Epidemiol Biomarkers Prev; 19(4); 1122–31. ©2010 AACR.

Background and Objectives The goal of the current study was to determine whether MRI impacts multidisciplinary treatment planning and if it leads to increased mastectomy rates. Methods A retrospective review was conducted of 441 patients treated for breast cancer between January 2005 and May 2008 who underwent breast MRI. Data included number of additional findings and their imaging and pathologic work-up. This was analyzed to determine impact of MRI on treatment planning. Results Of 441 patients, 45% had ≥1 additional finding on MRI. Of 410 patients with complete records, 29% had changes in the treatment plan, including 36 patients who were initially considered for breast conservation but proceeded directly to mastectomy based on MRI findings of suspected multicentricity. Twenty-three of those patients did not have a biopsy of the MRI lesion, with 87% having unicentric disease on final pathology. Overall, the mastectomy rate was 44%, which was significantly increased compared to patients not undergoing MRI (32%, P

The effect of caregiving roles on risk of elevated depressed mood over 12 months was examined in early-stage (0–IIA) breast cancer patients and same-aged women without breast cancer. Women were interviewed 4–6 weeks, 6 months, and 12 months following definitive surgical treatment (patients) or routine screening mammogram (controls). The Center for Epidemiologic Studies-Depression Scale was administered at each interview and dichotomized for analysis (