Background Breast conserving therapy and mastectomy have been shown to have similar overall survival outcomes in large trials. After many years of decline, mastectomy rates are on the rise for a variety of reasons. In this context, there is increasing discussion that the risk of loco-regional recurrence is complex and varies by breast cancer subtype. Several, pre-trastuzumab-era, reports have shown that loco-regional recurrence is higher for HER2+ and triple negative breast cancer (TNBC) patients who undergo breast conserving therapy (BCS) compared with women with hormone receptor positive (HR+) disease. Other literature has suggested that some breast cancer subtypes have better outcomes with BCS. To provide the most recent data on surgical choice by breast cancer subtype, we report BCS and mastectomy rates from 2010 SEER data. Surgical choice is presented for ductal carcinoma in situ (DCIS) and invasive breast cancer. For women with invasive disease the subcategories of HR+, HER2+ and TNBC are reported. Methods SEER data were used to identify incident breast cancer patients diagnosed in 2010. Only pathologically confirmed cases were included. In addition, individuals were excluded if they were diagnosed at autopsy or by death certificate, did not receive surgery or if the type of surgery was unknown. Patients were categorized as having received BCS or mastectomy and, for invasive disease, by receptor subtype (HR+, HER2+ and TNBC). For invasive cancers, patients with unknown receptor subtypes were excluded. Results SEER data for 2010 included 65,598 women, 13,849 (21.1%) women had DCIS and 51,749 (78.9%) had invasive disease (Table 1). For invasive cancers after excluding 5,062 patients with unknown receptor status, 12.1% were TNBC, 14.4% were HER2+, and 83.5% were HR+. Overall, 43.5% of women underwent mastectomy (33.2% for DCIS). Mastectomy rate increased by stage at diagnosis: 33.5% for Stage I, 53.9% for Stage II disease and 77.8% for Stage III (OR = 0.49, p<0.001 for Stage 1 compared to other stages). By age, mastectomy rates were 69.0% for <30, 53.4% for 30-49, 43.3% for 50-59, 39.0% for 60-69, 39.4% for 70-79 and 41.1% for 80+ (OR = 2.90, p<0.001 for women under 30 compared to older women). Conclusions In this large, recent series, 43.5% of women underwent mastectomy. This rate is among the highest reported from population-based registries and suggests a continued trend of increasing mastectomy rates. Women with HER2+ and TNBC were younger and significantly more likely to have mastectomy than their HR+ counterparts. Women with HER2+ breast cancer, in this trastuzumab-era cohort, were the subtype most likely to choose to undergo mastectomy. Monitoring for relapse events could contribute to a better understanding of how loco-regional recurrence risk might vary by subtype and surgical choice. Table 1: Percent receiving BCS and mastectomy by subtype for invasive cancersReceptor StatusNMean AgeBCS (%)Mastectomy (%)Odds Ratio*p valueFull cohort51,74961.354.145.9  HR+38,98161.855.744.30.68<0.001HER2+6,73858.143.056.01.61<0.001TNBC5,65858.849.150.91.26<0.001* Odds Ratio of undergoing mastectomy versus lumpectomy for this subtype compared to those not of this subtype. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-18-12.

Background Although recent work using observational data has shown survival benefits for breast conserving surgery plus radiation (BCS+RT) over mastectomy in early stage breast cancer for elderly women, only one report has compared all four treatment modalities available to these women: BCS+RT, BCS without radiation (BCS-RT), mastectomy with radiation (M+RT), and mastectomy without radiation (M-RT). This study utilized risk adjustment (RA) methods to control for variation in observed characteristics. However, RA methods may result in biased estimates if unobserved characteristics affect both the probability of receiving treatment and survival. Other statistical methods have been developed to address this issue. When valid, Instrumental Variable (IV) analysis can mitigate this bias by effectively randomizing patients into treatment through instruments. Thus our objective is to use IV methods to assess the comparative effectiveness of these treatment modalities on overall survival for elderly women with early stage breast cancer. Methods Using SEER-Medicare data, we identified 35,452 patients diagnosed 1992-1998 with Stage I or II breast cancer. We classified primary therapy as M+RT, M-RT, BCS+RT and BCS-RT using registry data and claims and estimated the effect of primary therapy on 7-year overall survival, with 6 and 8 years as robustness checks. We utilized an instrumental variables (IV) approach to address unobserved confounding. First, we estimated treatment rates for each treatment in an area by including the 50 patients closest to each beneficiary's zip code and adjusting for patient and area characteristics. These areas were then ranked and divided into quintiles, which formed the instruments for our IV analysis. In addition, we control for a number of patient (age, race, comorbidity, chemotherapy use, marital status, urban/rural residence, SEER area, diagnosis year), tumor (size, stage, grade, histology, use ER/PR status, # of positive nodes), physician (sex, specialty, medical school graduation year, foreign graduate status), and hospital characteristics (bed size, ownership, urban/rural location, teaching status, medical school affiliation, cancer center, participation in clinical trials). Results Our IV analysis showed overall survival benefits for elderly women who received BCS+RT compared to M-RT (Table 1). We estimate a 17.5% increase in the probability of surviving 7 years for those who were affected by our instrument. No survival benefit was shown for any other treatment. Conclusion We use IV analysis to address unobserved confounding in treatment and survival for elderly, early stage breast cancer patients. Consistent with previous RA estimates, we find that BCS+RT provides 7-year survival benefits over M-RT. The magnitude of the survival benefits continue to grow, even after 8 years. We find no difference in overall survival for those who received M+RT or BCS-RT compared to M-RT. Table 1. Instrumental Variables results reporting percent change in overall survival by treatment typeOverall SurvivalM-RTM + RTBCS + RTBCS aloneyears% change (p-value)% change (p-value)% change (p-value)% change (p-value)6ref-4.3 (0.61)10.7 (0.008)-0.008 (0.90)7ref-4.5 (0.66)17.5 (0.0003)0.005 (0.95)8ref-2.1 (0.84)19.0 (0.0001)0.008 (0.92) Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-15-01.

Introduction: Pathologic complete response (pCR) following neoadjuvant systemic chemotherapy (NAC) serves as a measure of tumor responsiveness and is a recognized surrogate for improved long-term outcomes. Some, but not all, studies have found a positive association between vitamin D (VD) and disease-free survival. We investigated if VD at diagnosis or during chemotherapy impacts pCR following neoadjuvant chemotherapy for operable breast cancer. Methods: Patients from Iowa were eligible if they were enrolled in one of two Iowa registries and had serum from before or during NAC tested for VD. French patients enrolled in a previous study of the impact of NAC on vitamin D and bone metabolism were considered for this study. VD deficiency was defined as <20 ng/ml. pCR was defined as no residual invasive disease in breast and lymph nodes. Firth-penalized logistic regression multivariable model was used. Results: The final cohort included 144 women. 84.7% of VD levels were obtained before initiation of chemotherapy. There was no difference between the French and Iowa cohorts with regard to age (p=0.20), clinical stage (p=0.22), disease receptor status (HER2+ [Hormone receptor (HR)+ or HR-], HR+/HER2-, and Triple Negative) (p=0.32) and rate of pCR (p=0.34). French women had lower body mass index (mean 24.8 vs 28.8, p<0.01), lower VD levels (mean 21.5 vs 27.5, p<0.01) and underwent lumpectomy instead of mastectomy more frequently (75.3% vs 47.8%, p<0.01) than Iowa women. Only pCR differed between the VD sufficient and deficient groups (Table 1). In multivariate analysis, after adjusting for the effects of cohort, clinical stage, and disease type by receptor status, VD deficiency put a woman at 2.68 times increased odds of not attaining a pCR (95%CI: 1.12-6.41, p=0.03) (Table 2). This variable remained significant with VD deficiency defined as <30 ng/ml and when considering this variable continuously. Conclusion: In this retrospective cohort, VD level before or during NAC was associated with pCR. Prospective trials could elucidate if maintaining VD levels during NAC, a highly modifiable variable, can be utilized to improve cancer outcomes in addition to benefiting other established health outcomes. Table 1: VD Deficient and Sufficient Groups  Vitamin D (ng/ml)   Deficient (< 20)Sufficient (≥ 20)pN 5391 BMIUnderweight-Normal27 (50.9)47 (51.6)0.93 Overweight-Obese26 (49.1)44 (48.4) VD LevelBefore Chemotherapy45 (84.9)77 (84.6)0.96 During Chemotherapy8 (15.1)14 (15.4) GradeG1-224 (47.1)41 (46.1)0.91 G327 (52.9)48 (53.9) Clinical StageI-II37 (69.8)61 (67)0.73 III16 (30.2)30 (33) Receptor StatusHER2+ (HR+ or HR-)12 (22.6)29 (32.2)0.20 HR+/HER2-30 (56.6)37 (41.1)  Triple Negative11 (20.8)24 (26.7) SurgeryBreast Conserving32 (60.4)58 (63.7)0.69 Mastectomy21 (39.6)33 (36.3) pCRNo43 (81.1)53 (58.2)<.01 Yes10 (18.9)38 (41.8) AgeMean (SD)48 (10.9)51 (10.3)0.15 Table 2: Odds of Not Attaining a pCR: Multivariable Results  NOdds Ratio95% CIp-valueCohortIowa661.170.522.630.71 France77Ref   Vitamin D (<20)Deficient532.681.126.410.03 Sufficient90Ref   Clinical StageI-II97Ref    III463.251.308.110.01Receptor StatusHER2+ (HR+ or HR-)411.060.402.810.91 HR+/HER2-675.502.0414.85<0.01 Triple Negative35Ref    Citation Format: Thomas A, Thezenas S, Mott SL, Raman R, Viala M, Pouderoux S, Schroeder MC, Lamy P-J, Jacot W. Vitamin D level impacts odds of pathologic complete response following neoadjuvant therapy in operable breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-24.

Introduction: Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is associated with improved long-term outcomes. Vitamin D (VD) deficiency has been associated with carcinogenesis as well as poorer outcomes in breast cancer (bc) particularly in luminal-type bc. In addition, replacement of VD during adjuvant chemotherapy was found to improve disease-free survival. However, VD deficiency was not associated with pCR following NAC in one series which included patients (pts) with human epidermal growth factor receptor-2 (HER2) negative bc only. We report the relationship between VD deficiency and pCR in a cohort that includes all bc subtypes and report how VD deficiency varied by clinical and pathologic parameters. Methods: Patients (pts) prospectively enrolled in the University of Iowa Breast Molecular Epidemiologic Resource between 2010-14 with invasive bc, receiving at least one cycle of NAC, and who had serum collected at enrollment or during NAC were eligible. VD deficiency was defined as < 20 ng/dl. pCR was defined as no residual invasive disease in breast and lymph nodes. Patients were stratified by their BMI as normal (≤ 25 kg/m2) or overweight-obese (>25 kg/m2). To investigate the relationship between VD, clinical parameters, and NAC outcomes, chi-square, Fisher's exact, and t-tests were used. Results: 73 pts were eligible. 52 (71%) pts had Stage I-II bc. All pts received a combination of taxanes with other agents (Cytoxan, 5FU, Carboplatin, Gemcitabine) with or without an anthracycline or anti-HER 2 therapy. 62/73 (85%) received an anthracycline. 65/73 (89%) received at least 75% of intended NAC. pCR was achieved in 25/73 (34%) pts. VD deficiency was found in 17/73 (23%) pts and was more frequent among overweight-obese pts (Table 1). VD deficiency occurred significantly more often in estrogen receptor (ER)+/progesterone receptor (PR)+/HER2- and ER+ or PR+ bc but not in HER2+ bc. Results suggest VD deficient pts may be at increased odds of not achieving a pCR (OR=3.02, p=0.10). In this cohort, VD deficient pts were at increased odds of having residual disease in the breast (OR=3.76, p=0.05), but not in the nodes (OR=1.43, p=0.53), (Table 2). Conclusion: Being overweight-obese was associated with VD deficiency and may warrant screening in this group. VD deficiency was significantly associated with ER+/PR+/HER2-bc and ER+ or PR+ disease. Notably, these pts are candidates for bone-injuring anti-estrogen agents as part of their overall course of therapy. VD deficiency was not significantly associated with pCR after NAC though a trend was suggested. Table 1: VD and clinical parameters   VD Sufficient VD Deficientp  N=56N=17 Age (mean in years) 52470.16BMI≤2526(46%)3(18%)0.03 >2530(54%)14(82%) Ellis-Ellison grade1-224(43%)7(41%)0.90 332(57%)10(59%) Tumor receptorER+/PR+/HER2-15(27%)10(59%)0.02 ER+ or PR+/HER2+6(11%)3(18%)0.43 ER-/PR-/HER2+10(18%)0(0%)0.10 ER-/PR-/HER2-17(31%)3(18%)0.36 ER+ or PR+29(52%)14(82%)0.02 HER2+16(84%)3(16%)0.53 Table 2: VD and NAC Outcomes   VD SufficientVD Deficientp  N=56N=17 pCRNo34(61%)14(82%)0.10 Yes22(39%)3(18%) Breast Residual DiseaseNo25(45%)3(18%)0.05 Yes31(55%)14(84%) Node Residual DiseaseNo28(50%)7(41%)0.52 Yes28(50%)10(59%)  Citation Format: Raman R, Link BK, Mott SL, Schroeder MC, Thomas A. Vitamin D deficiency in various breast cancer subtypes and its impact on response to neoadjuvant chemotherapy in operable breast cancer. [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 P5-08-48.

Node negative microscopically invasive breast cancer (BC) is frequently associated with ductal carcinoma in situ (DCIS) and considered to have a similar prognosis. We evaluated women with T1micN0M0 (T1mic), DCIS and Stage I BC and report clinical characteristics, risk for subsequent contralateral breast cancer (CBC) and overall survival (OS). Methods: The study cohort included women diagnosed 1998-2012 and reported to Surveillance, Epidemiology, and End Result (SEER) data with DCIS, T1mic, or Stage I BC (not including T1mic). Subsequent CBCs were identified in patients with known laterality without contralateral mastectomy. Kaplan Meier models were used to estimate survival and time to CBC. Log-rank tests assessed differences in survival across groups Results: During the study period, 9,785 women were diagnosed with T1mic. Clinical features and risk of CBC are shown in the Table 1. Women with DCIS and T1mic were younger than those with Stage I BC. T1mic was more likely to be hormone receptor (HR) negative. Women with T1mic underwent mastectomy significantly more often than women with DCIS or Stage 1 BC. T1mic occurred more frequently in non-white women. Women with T1mic were significantly more likely to develop subsequent CBC than women with Stage 1 BC with a trend for increased CBC compared to women presenting initially with DCIS. Of those who develop CBCs 5.9% (DCIS), 11.2% (T1mic), and 14.6% (Stage 1) developed within 1 year (YR) of diagnosis of the index cancer. At 10 YRS these numbers were 73.7%(DCIS), 82.7%(T1mic) and 83.2% (Stage 1) (DCIS vs T1mic, p<0.001 T1mic vs Stage 1, P= 0.048). At 10 YRS OS for women with CBC after initial BC was 89.5%(DCIS), 86.6%(T1mic) and 84.3%(Stage1) (DCIS vs T1mic, p=0.077, T1mic vs Stage1 p=0.293), Table 2. Table 1 DCIS, T1mic, Stage I BC: Clinical Features and Contralateral Breast Cancer DCIST1micStage 1 (excluding T1mic)   %%%p ^p ^^N49,6829,785248,307  Median Age5858620.719<0.001HR positive85.0%72.8%86.5%<0.001<0.001Grade     Well-moderately differentiated56.3%61.1%76.6%  Poorly-undifferentiated43.7%38.9%23.4%<0.001<0.001Mastectomy22.7%36.7%24.1%<0.001<0.001Race     White79.7%77.3%84.2%  Black10.8%11.0%7.9%<0.001<0.001Other9.4%11.6%7.9%  CBC*4.1%4.3%3.4%0.317<0.001CBC**57.9%72.9%77.0%<0.0010.021* Portion of full sample, **Of those who had a subsequent BC (ipsilateral or contralateral),^ DCIS vs T1mic,^^ stage I vs T1mic Table 2 OS by Initial Stage and with CBC  5 YR10 YRp*  OSOS DCISall97.3%88.4%  develop CBC97.8%89.5%0.037T1micall96.3%88.9%  develop CBC95.0%86.6%0.036Stage1 (excluding T1mic)all95.9%85.0%  develop CBC86.9%84.3%0.001*Comparing survival of the stage cohort (all) with women diagnosed with that stage who develop CBC Conclusion: Women with T1mic were at increased risk for subsequent CBC relative to women with Stage I BC. When subsequent CBC occurred it developed earlier in women with T1mic than those with DCIS. Time course for this second event and survival with CBC at 10 years matched more closely with women diagnosed with Stage 1 BC. These findings offer suggestions about the biology of T1mic and may have implications for counseling these women on risk reducing strategies. Citation Format: Thomas A, Weigel RJ, Leone JP, Spanheimer PM, Schroeder MC. Increased risk of contralateral breast cancer after diagnosis of microscopically invasive breast cancer: SEER 1998-2012. [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 P1-07-24.