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Development of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization. Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles, and NCI-MATCH arms. Compared with human tumors, PDXs typically have higher purity and fit to investigate dynamic driver events and molecular properties via multiple time points from same case PDXs. Here, we report on dynamic genomic landscapes and pharmacogenomic associations, including associations between activating oncogenic events and drugs, correlations between whole-genome duplications and subclone events, and the potential PDX models for NCI-MATCH trials. Lastly, we provide a web portal having comprehensive pan-cancer PDX genomic profiles and source code to facilitate identification of more druggable events and further insights into PDXs’ recapitulation of human tumors., Patient-derived xenograft models (PDX) have been extensively used to study the molecular and clinical features of cancers. Here the authors present a cohort of 536 PDX models from 25 cancers, as well as their genomic and evolutionary profiles and their suitability for clinical trials.

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.

Intratumoral heterogeneity, which is manifested in almost all of the hallmarks of cancer, including the significantly altered metabolic profiles of cancer cells, represents a challenge to effective cancer therapy. High-throughput measurements of the metabolism of individual cancer cells would allow direct visualization and quantification of intratumoral metabolic heterogeneity, yet the throughputs of current measurement techniques are limited to about 120 cells per hour. Here, we show that single-cell photoacoustic microscopy can reach throughputs of approximately 12,000 cells per hour by trapping single cells with blood in an oxygen-diffusion-limited high-density microwell array and by using photoacoustic imaging to measure the haemoglobin oxygen change (that is, the oxygen consumption rate) in the microwells. We demonstrate the capability of this label-free technique by performing high-throughput single-cell oxygen-consumption-rate measurements of cultured cells and by imaging intratumoral metabolic heterogeneity in specimens from patients with breast cancer. High-throughput single-cell photoacoustic microscopy of oxygen consumption rates should enable the faster characterization of intratumoral metabolic heterogeneity.

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.

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.

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.

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.

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

Assess the performance characteristics of axillary ultrasound (AUS) for accurate exclusion of clinically significant axillary lymph node (ALN) disease.Sentinel lymph node biopsy (SLNB) is currently the standard of care for staging the axilla in patients with clinical T1-T2, N0 breast cancer. AUS is a noninvasive alternative to SLNB for staging the axilla.Patients were identified using a prospectively maintained database. Sensitivity, specificity, and negative predictive value (NPV) were calculated by comparing AUS findings to pathology results. Multivariate analyses were performed to identify patient and/or tumor characteristics associated with false negative (FN) AUS. A blinded review of FN and matched true negative cases was performed by 2 independent medical oncologists to compare treatment recommendations and actual treatment received. Recurrence-free survival was described using Kaplan-Meier product limit methods.A total of 647 patients with clinical T1-T2, N0 breast cancer underwent AUS between January 2008 and March 2013. AUS had a sensitivity of 70%, NPV of 84%, and PPV of 56% for the detection of ALN disease. For detection of clinically significant disease (2.0 mm), AUS had a sensitivity of 76% and NPV of 89%. FN AUS did not significantly impact adjuvant medical decision making. Patients with FN AUS had recurrence-free survival equivalent to patients with pathologic N0 disease.AUS accurately excludes clinically significant ALN disease in patients with clinical T1-T2, N0 breast cancer. AUS may be an alternative to SLNB in these patients, where axillary surgery is no longer considered therapeutic, and predictors of tumor biology are increasingly used to make adjuvant therapy decisions.

Background Axillary surgery is not considered therapeutic in patients with clinical T1-T2 N0 breast cancer. The importance of axillary staging is eroding in an era in which tumor biology, as defined by biomarker and gene expression profile, is increasingly important in medical decision making. We hypothesized that axillary ultrasound (AUS) is a noninvasive alternative to sentinel lymph node biopsy (SLNB), and AUS could replace SLNB without compromising patient care. Study Design Patients with clinical T1-T2 N0 breast cancer and normal AUS were eligible for enrollment. Subjects were randomized to no further axillary staging (arm 1) vs SLNB (arm 2). Descriptive statistics were used to describe the results of the pilot phase of the randomized controlled trial. Results Sixty-eight subjects were enrolled in the pilot phase of the trial (34 subjects in arm 1, no further staging; 32 subjects in arm 2, SLNB; and 2 subjects voluntarily withdrew from the trial). The median age was 61 years (range 40 to 80 years) in arm 1 and 59 years (range 31 to 81 years) in arm 2, and there were no significant clinical or pathologic differences between the arms. Median follow-up was 17 months (range 1 to 32 months). The negative predictive value (NPV) of AUS for identification of clinically significant axillary disease (>2.0 mm) was 96.9%. No axillary recurrences have been observed in either arm. Conclusions Successful completion of the pilot phase of the randomized controlled trial confirms the feasibility of the study design, and provides prospective evidence supporting the ability of AUS to exclude clinically significant disease in the axilla. The results provide strong support for a phase 2 randomized controlled trial.

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.

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.

Most cancer treatment strategies target cell proliferation, angiogenesis, migration, and intravasation of tumor cells in an attempt to limit tumor growth and metastasis. An in vitro platform to assess tumor progression and drug sensitivity could provide avenues to enhance our understanding of tumor metastasis as well as precision medicine. We present a microfluidic platform that mimics biological mass transport near the arterial end of a capillary in the tumor microenvironment. A central feature is a quiescent perfused 3D microvascular network created prior to loading tumor cells or patient-derived tumor organoids in an adjacent compartment. The physiological delivery of nutrients and/or drugs to the tumor then occurs through the vascular network. We demonstrate the culture, growth, and treatment of tumor cell lines and patient-derived breast cancer organoids. The platform provides the opportunity to simultaneously and dynamically observe hallmark features of tumor progression including cell proliferation, angiogenesis, cell migration, and tumor cell intravasation. Additionally, primary breast tumor organoids are viable in the device for several weeks and induce robust sprouting angiogenesis. Finally, we demonstrate the feasibility of our platform for drug discovery and personalized medicine by analyzing the response to chemo- and anti-angiogenic therapy. Precision medicine-based cancer treatments can only be realized if individual tumors can be rapidly assessed for therapeutic sensitivity in a clinically relevant timeframe (≲14 days). Our platform indicates that this goal can be achieved and provides compelling opportunities to advance precision medicine for cancer.

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.

In 2016, an estimated ~250,000 new cases of invasive and non-invasive breast cancer were diagnosed in US women. About 60–75% of these cases were treated with breast conserving surgery (BCS) as the initial therapy. To reduce the local recurrence rate, the goal of BCS is to excise the tumor with a rim of normal surrounding tissue, so that no cancer cells remain at the cut margin, while preserving as much normal breast tissue as possible. Therefore, patients with remaining cancer cells at the cut margin commonly require a second surgical procedure to obtain clear margins. Different approaches have been used to decrease the positive margin rate to avoid re-excision. However, these techniques are variously ineffective in reducing the re-operative rate, difficult to master by surgeons, or time-consuming for large specimens. Thus, 20-60% of patients undergoing BCS still require second surgeries due to positive surgical margins. The ideal tool for margin assessment would provide the same information as histological analysis, without the need for processing specimens. To achieve this goal, we have developed and refined label-free photoacoustic microscopy (PAM) for breast specimens. Exploiting the intrinsic optical contrast of tissue, ultraviolet (UV) laser illumination can highlight cell nuclei, thus providing the same contrast as hematoxylin labeling used in conventional histology and measuring features related to the histological landscape without the need for labels. We demonstrate that our UV-PAM system can provide label-free, high-resolution, and histology-like imaging of fixed, unprocessed breast tissue.

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.

Background Disseminated tumor cells (DTCs) found in the bone marrow (BM) of patients with breast cancer portend a poor prognosis and are thought to be intermediaries in the metastatic process. To assess the clinical relevance of a mouse model for identifying possible prognostic and predictive biomarkers of these cells, we have employed patient-derived xenografts (PDX) for propagating and molecularly profiling human DTCs. Methods Previously developed mouse xenografts from five breast cancer patients were further passaged by implantation into NOD/SCID mouse mammary fat pads. BM was collected from long bones at early, serial passages and analyzed for human-specific gene expression by qRT-PCR as a surrogate biomarker for the detection of DTCs. Microarray-based gene expression analyses were performed to compare expression profiles between primary xenografts, solid metastasis, and populations of BM DTCs. Differential patterns of gene expression were then compared to previously generated microarray data from primary human BM aspirates from patients with breast cancer and healthy volunteers. Results Human-specific gene expression of SNAI1, GSC, FOXC2, KRT19, and STAM2, presumably originating from DTCs, was detected in the BM of all xenograft mice that also developed metastatic tumors. Human-specific gene expression was undetectable in the BM of those xenograft lines with no evidence of distant metastases and in non-transplanted control mice. Comparative gene expression analysis of BM DTCs versus the primary tumor of one mouse line identified multiple gene transcripts associated with epithelial-mesenchymal transition, aggressive clinical phenotype, and metastatic disease development. Sixteen of the PDX BM associated genes also demonstrated a statistically significant difference in expression in the BM of healthy volunteers versus the BM of breast cancer patients with distant metastatic disease. Conclusion Unique and reproducible patterns of differential gene expression can be identified that presumably originate from BM DTCs in mouse PDX lines. Several of these identified genes are also detected in the BM of patients with breast cancer who develop early metastases, which suggests that they may be clinically relevant biomarkers. The PDX model may also provide a clinically relevant system for analyzing and targeting these intermediaries of metastases. Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0927-1) contains supplementary material, which is available to authorized users.

A photoacoustic microscope system provides label-free multilayered histology-like imaging of unprocessed human breast specimens., The goal of breast-conserving surgery is to completely remove all of the cancer. Currently, no intraoperative tools can microscopically analyze the entire lumpectomy specimen, which results in 20 to 60% of patients undergoing second surgeries to achieve clear margins. To address this critical need, we have laid the foundation for the development of a device that could allow accurate intraoperative margin assessment. We demonstrate that by taking advantage of the intrinsic optical contrast of breast tissue, photoacoustic microscopy (PAM) can achieve multilayered histology-like imaging of the tissue surface. The high correlation of the PAM images to the conventional histologic images allows rapid computations of diagnostic features such as nuclear size and packing density, potentially identifying small clusters of cancer cells. Because PAM does not require tissue processing or staining, it can be performed promptly and intraoperatively, enabling immediate directed re-excision and reducing the number of second surgeries.

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.

Background The Society of Surgical Oncology and American Society of Radiation Oncology consensus statement was the first professional guideline in breast oncology to declare "no ink on tumor" as a negative margin in patients with stages I/II breast cancer undergoing breast-conservation therapy. We sought to analyze the financial impact of this guideline at our institution using a historic cohort. Study Design We identified women undergoing re-excision after breast-conserving surgery for invasive breast cancer from 2010 through 2013 using a prospectively maintained institutional database. Clinical and billing data were extracted from the medical record and from administrative resources using CPT codes. Descriptive statistics were used in data analysis. Results Of 254 women in the study population, 238 (93.7%) had stage I/II disease and 182 (71.7%) had invasive disease with ductal carcinoma in situ. A subcohort of 83 patients (32.7%) who underwent breast-conservation therapy for stage I/II disease without neoadjuvant chemotherapy had negative margins after the index procedure, per the Society of Surgical Oncology and American Society of Radiation Oncology guideline. The majority had invasive ductal carcinoma (n = 70 [84.3%]) and had invasive disease (n = 45 [54.2%]), and/or ductal carcinoma in situ (n = 49 [59.0%]) within 1 mm of the specimen margin. Seventy-nine patients underwent 1 re-excision and 4 patients underwent 2 re-excisions, accounting for 81 hours of operative time. Considering facility fees and primary surgeon billing alone, the overall estimated cost reduction would have been $195,919, or $2,360 per affected patient, under the guideline recommendations. Conclusions Implementation of the Society of Surgical Oncology and American Society of Radiation Oncology consensus guideline holds great potential to optimize resource use. Application of the guideline to a retrospective cohort at our institution would have decreased the overall re-excision rate by 5.6% and reduced costs by nearly $200,000. Additional analysis of patient outcomes and margin assessment methods is needed to define the long-term impact on surgical practice.

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.

Background Meaningful data to help guide resource allocation for staged tissue expander/implant-based breast reconstruction are currently lacking. The authors seek to differentiate uneventful from successful reconstruction and identify common outcome pathways and factors that portend a deviation from an uneventful, two-stage, two-operation course. Methods A retrospective analysis of expander/implant reconstructions with or without acellular dermal matrix (2003 to 2009) was performed. Related postreconstructive events (including mastectomy flap necrosis, seroma, wound dehiscence, cellulitis, explantation, hematoma, and capsular revisions) were assessed for 2 years. Uneventful reconstruction was defined as exchange to breast implant within 2 years of tissue expander placement without complications, whereas successful reconstruction was defined as exchange to breast implant within 2 years with or without complications. Factors affecting reconstructive success were analyzed, and patterns of postreconstructive events were summarized as outcome pathways. Results Four hundred thirteen patients (295 with acellular dermal matrix and 118 without), with 602 breasts (432 with acellular dermal matrix and 170 without) underwent reconstruction. Forty-six percent of patients (48 percent with acellular dermal matrix and 40 percent without), experienced uneventful reconstruction. Reconstructive success was achieved in 337 patients (82 percent; 82.0 percent with acellular dermal matrix and 80.5 percent without), with reconstructive failure occurring in 58 patients. Multiple logistic regression analyses determined that cellulitis, seroma, and skin necrosis (OR, 15.8, 7.7, and 8.4, respectively) were highly predictive of reconstructive failure. The authors identified 10 distinct pathways experienced by tissue expander/implant patients that were characterized by specific postreconstructive events. Conclusion The present study will facilitate discussions among patients, providers, and payers by providing a framework for understanding the myriad outcome pathways in implant-based reconstruction. Clinical question/level of evidence Therapeutic, III.

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.

This first-in-human study was designed to evaluate the safety and dosimetry of the progesterone analog 21-18F-fluoro-16α,17α-[(R)-(1′-α-furylmethylidene)dioxy]-19-norpregn-4-ene-3,20-dione (18F-FFNP), as well the feasibility of imaging tumor progesterone receptors (PRs) by PET in breast cancer. Methods: Women with breast cancer underwent PET with 18F-FFNP. Tumor 18F-FFNP uptake was assessed semiquantitatively by determining maximum standardized uptake value and tumor-to-normal breast (T/N) activity ratio and by Logan graphical analysis. The PET results were correlated with estrogen receptor (ER) and PR status, assessed by in vitro assays of the tumor tissue. The biodistribution of 18F-FFNP was measured in patients by whole-body PET, and human dosimetry was estimated. Results: Twenty patients with 22 primary breast cancers (16 PR-positive [PR+] and 6 PR-negative [PR–]) were evaluated. Tumor maximum standardized uptake value was not significantly different in PR+ and PR− cancers (mean ± SD, 2.5 ± 0.9 vs. 2.0 ± 1.3, P = 0.386), but the T/N ratio was significantly greater in the PR+ cancers (2.6 ± 0.9 vs. 1.5 ± 0.3, P = 0.001). In addition, there was a significant correlation between distribution volume ratio and T/N ratio (r = 0.89; P = 0.001) but not between distribution volume ratio and either PR status or standardized uptake value, likely because of small sample size. On the basis of whole-body PET data in 12 patients, the gallbladder appeared to be the dose-limiting organ, with an average radiation dose of 0.113 mGy/MBq. The whole-body dose was 0.015 mGy/MBq, and the effective dose was 0.020 mSv/MBq. No adverse effects of 18F-FFNP were encountered. Conclusion:18F-FFNP PET is a safe, noninvasive means for evaluating tumor PRs in vivo in patients with breast cancer. The relatively small absorbed doses to normal organs allow for the safe injection of up to 440 MBq of 18F-FFNP.

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.