Background: Given that many patients with more locally advanced breast cancer are receiving neoadjuvant therapy, predictors of local recurrence will be important for learning how to optimize the use of local regional therapy. We investigated the local regional recurrence (LRR) rates in patients treated with neoadjuvant chemotherapy in the I SPY1 trial. Methods: Data were analyzed from 221 women that were enrolled in I-SPY1 and completed treatment. Final surgical procedure was not randomized. Multiple clinicopathologic factors were investigated in both the lumpectomy (BCS) and mastectomy cohorts. Logistical regression was applied to identify factors predicting LRR although this was not a specified endpoint for the I-SPY parent trial. Results: At 3.9 years median followup, 123 patients (56%) had mastectomy, 93 patients (42%) had breast conservation and 5 did not have a surgical procedure. The majority of patients in both groups received radiation with 77% and 94% in the mastectomy and breast conservation (BC) group respectively. Within the mastectomy group, there was no correlation between whether pts received PMRT and predictors of high LRR risk: LVI, grade, stage and nodal disease following neoadjuvant chemotherapy. Rates of PMRT in each residual cancer burden (RCB) category were 78%(RCB0), 80%(RCB 1), 81%(RCB2) and 66%(RCB3, highest residual burden of disease) for the mastectomy group. Median tumor size before chemotherapy was 6.0 cm and 5.0 cm mastectomy and BC groups, respectively. Fewer patients had pCR in the mastectomy group, compared to the BC group. LRR rates were very low for both the mastectomy and BC groups, with 9 (7.5%) and 7 (7.3%) total recurrences, respectively. Only 2 patients in each group had LLR without distant recurrence (2% total). For the mastectomy and BC groups, 4/7 and 3/5 patients had synchronous presentation of their local and distant disease. For patients with distant recurrence 44% and 29% had a local recurrence in the BC and mastectomy groups respectively. In a logistical regression model, patients with local progression in the BC group were 17 times more likely to develop distant progression (p=0.005) while in the mastectomy group, those with LLR were 10.5 times more likely to develop distant progression (p=0.001). Individual factors that appeared to be predictive of local recurrence included clinical size of tumor at presentation (p=0.032) for the BC group, and final pathologic tumor size in the mastectomy group (p=0.002). Patients with low risk molecular features (wound healing quiescent, luminal A, NKI low, and ROR-S low) did not have any local recurrences. Conclusion: Although the sample size was small, and the ability to discriminate between the two surgical groups was limited, in this high risk group of locally advanced breast cancer pts, BC does not appear to lead to an increased rate of LRR. In fact tumor biology that predicts for high risk of distant progression might be able to be applied to risk stratification for LRR. Patients with low risk of distant recurrence (e.g. those with pCR, RCB1or low-risk molecular markers) may be those that we can consider testing PMRT vs not in future neoadjuvant trials. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD06-03.

#1163 Background: Ductal carcinoma in situ (DCIS) accounts for about 20% of all female breast cancers and is now diagnosed 10 times more frequently than prior to the use of increased screening mammography. Although magnetic resonance imaging (MRI) has proven to be a useful imaging modality for invasive cancer, its role and impact in preoperative surgical planning for DCIS is unclear. Our aim is to determine if women diagnosed with pure DCIS on core-biopsy who have preoperative MRI are more likely to undergo mastectomy and sentinel lymph node biopsy (SLNB). Methods: Retrospective survey of women diagnosed with pure DCIS on stereotactic core biopsy between 2000-2007 at an academic tertiary referral center. All women underwent definitive surgical treatment for DCIS. Patient characteristics, surgical planning and surgical outcomes were compared between patients who underwent preoperative MRI and those without MRI. Continuous variables among the two groups were compared using the t-test. Differences in dichotomous variables between groups were compared using the chi-square test. Significance was determined if p<0.05. Results: Of 137 women diagnosed with DCIS, 39 underwent preoperative MRI. Mean age, DCIS size and grade, and presence of invasive cancer on surgical specimen were compared between the two groups. The only significant difference between the two groups was younger mean age in the group with preoperative MRI (51 vs 59 yrs, p=0.001). On univariate analysis, mastectomy and SLNB were more commonly employed in the MRI group. The mastectomy rate was 55% for women who had preoperative MRI and 17% for those who did not (p<0.0001). The SLNB rate was 46% for women had preoperative MRI and 23% for those who did not (p=0.009). Number of re-excisions, margin status and size were compared between the two groups. Preoperative MRI was not significantly associated with wider surgical margins or higher proportion of patients with negative margins. However, the mean number of re-excisions was lower in women who underwent preoperative MRI (0.7 vs. 1.2, p=0.003). The only independent factor associated with likelihood of preoperative MRI in the setting of DCIS was patient age. On multivariate analysis, use of SLNB was independently associated with mastectomy, DCIS size and DCIS grade (p=0.0001, p=0.011, p=0.024, respectively). In contrast, independent predictors of mastectomy were DCIS size and use of MRI (OR 5.1, 95% CI 2.0-13.2)). Conclusion: Women who underwent preoperative MRI for DCIS were younger and more likely to undergo mastectomy. However, women who had preoperative MRI required a lower number of re-excisions to obtain negative margins. Our study cannot address whether the strong association between preoperative MRI and mastectomy is a causal one. Nevertheless our data support a critical need for future studies to further define the benefit as well as consequences of the use of MRI for DCIS evaluation and treatment. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1163.

Background: Among women with unilateral cancer, rates of contralateral prophylactic mastectomy (CPM) are continuing to increase. However, little is known about whether rates and types of complications differ between patients undergoing unilateral mastectomy or bilateral mastectomy, limiting the surgical outcomes evidence that can be presented in pre-surgical decision making for women considering CPM. This study was undertaken to determine whether surgical complications are increased in women undergoing CPM compared to those without CPM. Methods: Between the years 2005–2010, all patients at UCSF undergoing mastectomy with immediate reconstruction were entered into a prospective database. This database was queried for patients with unilateral cancer who had mastectomy and immediate reconstruction with or without CPM. Surgical outcomes, including implant loss, admission for IV antibiotics, and return to OR were evaluated and compared between patients who did and did not undergo CPM. Patients with bilateral cancer or bilateral prophylactic surgery were excluded; analyses were limited to patients with a minimum of 1 year follow-up. Results: 468 patients were identified who met study criteria, totaling 667 breasts. Mean follow-up time was 22 months (range 12 - 69 months). 269 of the 468 (57.5%) patients had unilateral mastectomy only, while 199 of 468 (42.5%) patients also had CPM. There were no differences in tumor grade, stage, follow-up time, smoking history, or radiation (prior or post-surgery) between the two groups. The only significant differences between the unilateral and bilateral groups were median age at diagnosis (50.7 vs. 45.9 respectively; p < .0001) and receipt of neoadjuvant chemotherapy (34.7% vs. 41.3% respectively; p < .01). Surgical outcomes were compared between groups. The overall rate of major complications differed significantly due to an increased rate of infectious complications and unplanned return to surgery in the CPM group (Table 1). Nevertheless, this did not result in a higher implant loss rate in the CPM group. In patients undergoing bilateral mastectomy, overall complication rates were comparable between the index breast and the CPM breast; however, there was a higher implant loss rate in the index breast (22/177 vs. 11/188; p=0.05). Conclusions: While CPM is an increasingly common procedure, it is associated with an increased risk of major post-operative surgical complications. In this cohort, patients undergoing bilateral mastectomy for unilateral cancer had higher rates of overall complications, greater use of IV antibiotics, and more frequent return to the operating room. Since the majority of CPM cases are not at sufficiently high risk for a second breast cancer to meet clinical criteria for prophylactic surgery, guidelines and clinical recommendations should consider these increased complication rates when counseling women contemplating CPM. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD02-01.

#302 Background: Both circulating tumor cells (CTCs) in peripheral blood and disseminated tumor cells (DTCs) in bone marrow have been detected in primary breast cancer, but typically not quantitatively, simultaneously and using the same methodology. Here, we simultaneously assessed CTC and DTC levels in 390 primary breast cancer patients (Stages I-III), including treatment-naïve and post-neoadjuvant patients.
 Materials and Methods: CTCs/DTCs were enumerated via a novel two-step assay (IE/FC) consisting of immunomagnetic enrichment (IE) and flow cytometry. First, samples were enriched for epithelial cells using magnetic beads coated with anti-EpCAM monoclonal antibody (mAb). Next, fluorescently labeled mAb specific for an alternate EpCAM epitope was combined with a mAb against CD45 and a nucleic acid stain in multiparameter flow cytometry. Tumor cells were also isolated by IE followed by FACS sorting.
 Results: The assay quantitatively detected tumor cells in either blood or bone marrow obtained at time of breast surgery. Tumor cells were detected with greater frequency and at generally higher levels in bone marrow than in blood. In blood, CTCs ranged from 0 to 33.7 cells/mL (mean = 0.9 ± 2.4 cells/mL) and in bone marrow DTCs ranged from 0 to 501.8 cells/mL (mean = 16.8 ± 38.7 cells/mL). Direct comparisons in each patient revealed complex but significant correlation (Spearman's rank correlation = 0.12, p = 0.02) between CTC and DTC levels. In the subgroup of patients receiving neoadjuvant therapy (N=84), 51/79 (64%) were considered positive for DTC (>5.5 cells/mL, with range 0.3-262.2, mean 34±17.1) while 15/79 (19%) were considered positive for CTC (>0.8 cells/mL, with range 0-38.7, mean 1.4±5.7.) Treatment-naïve patients were more likely to be considered positive in the blood (29% vs 19%, p=0.03.) than neoadjuvant patients, possibly reflecting treatment effect. CTCs or DTCs were isolated from selected patients with high cell burden and subjected to expression or genomic analyses, which confirmed the malignant nature of the cells and indicated the feasibility of molecular profiling of isolated CTCs/DTCs.
 Discussion: This approach provides quantitative detection and isolation of CTCs/DTCs in blood and bone marrow, and may be useful for analysis of early events in cancer progression. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 302.

Background: There is often a substantial delay between the presentation of clinical trial results and change in practice. Reasons for slow adoption include the disruption of practice routines, doubt about the validity of results, financial disincentive, and resistance to change. We propose a decision-making process to inform adoption that considers three factors: likelihood the trial's conclusions will not change with longer follow up, and consequences of early and late adoption. We apply this framework to the published 4-year results of the international TARGIT-A trial, which compares intraoperative radiation therapy (IORT) to external beam radiation therapy (EBRT). Methods: To find whether the trial results will remain robust, we reviewed the TARGIT-A trial's annual hazards for local recurrence (LR). We then reviewed 5–10 year LR rates from recent clinical trials with similar patient populations undergoing RT, no RT or partial breast RT. To assess the impact of an early change in practice, a Markov model was used to evaluate life expectancy, quality adjusted life years (QALYs), and cost. Sensitivity analysis estimated the impact of varying the LR rate 1–20x the TARGIT-A 4 year results. To estimate the impact of late adoption, we generated the expected number of N0, grades 1 & 2, ductal cancers in postmenopausal women (>50 yrs) from SEER and US Census Bureau data. Using Medicare rates, costs of EBRT vs. IORT were compared and potential savings to the health care system calculated. Results: The TARGIT-A peak hazard for LR for IORT and EBRT occurred at 3 years. In the START and ATAC trials, the peak local recurrence Kaplan Meier estimates are between 2 and 3 years. In other trials (ATAC, and in the 2005 RT Lancet overview) there is no second peak of recurrence, making it unlikely that longer follow up will change the conclusion of the TARGIT-A results. The LRR in similar trials have dropped steadily over time for post menopausal, stage I patients with or without RT. Impact of early adoption: If treatment were adopted early, the impact on life expectancy and QALYs would be minimal unless IORT LR rate exceeds 20% over a 10 year period of time. Impact of late adoption: In the US, 45% of new breast cancer cases fit the described population. EBRT costs $6,400 more than IORT per patient on average. If adoption were delayed 5 years to allow the trial results to mature, 70,136 patients per year are expected to receive EBRT resulting in a societal burden of >$2.2 billion barring the capital investment required for new technology. This also assumes that patients have equal utility for a single dose of IORT as they do for 3–6 weeks of postoperative radiation therapy. If IORT utility is higher than that of EBRT, then the IORT strategy is both more effective and less costly. Conclusion: The process of modeling the impact of both early and late adoption when considering the stability of trial results can serve as a tool to evaluate whether to change practice. This analysis was tested on the results of the TARGIT-A trial, and demonstrated that prompt adoption of the IORT intervention would cause minimal harm, provide an improved quality of life, and offer significant societal savings. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD06-08.