BACKGROUND: Growing evidence indicates that base pair mutations in ESR1 are relatively uncommon in newly diagnosed, treatment-naive breast cancer, but frequently acquired in hormone-resistant metastatic breast cancer (MBC). We and others have recently identified ESR1 gene fusion and amplification in MBC, with the ESR1 fusions generally encompassing AF1 and the DNA binding domain. The genomic break required for gene fusions often results in an imbalance in the DNA copy number of exons around the break. We examined ESR1 amplification and 5' and 3' exon copy number imbalance in MBC. MATERIALS and METHODS: We designed NanoString DNA hybridization probes against coding and non-coding exons (n=9) in ESR1 and 15 reference probes. We analyzed 128 samples consisting of 61 ER-positive and 44 ER-negative metastases, and 23 primary breast cancers. DNA copy number (CN) was determined using nSolver, with >2.7CN as copy number gain, and >10 as CN amplification. ESR1 CN was calculated by averaging the DNA copy number obtained from all coding exons. The 5'-3' copy number ratio was the average copy number of the 5' exons (3-6) divided by the 3' exons (7-10). RESULTS: 8 (13%) ER positive metastatic breast cancers showed ESR1 amplification with 5 (8%) having >2.7CN, and 3 (5%) with >10CN. In contrast, in ER-negative metastases, we did not detect any samples with amplification >10CN, and a gain (>2.7 CN) in one case. Similarly, in ER+ primary cancers we did not detect any samples with >10 CN amplifications and 2 samples with CN gain (>2.7 CN). ESR1 showed 5'-3' CN imbalance in 1 primary (5%) and in 5 metastatic (5%) breast cancers. We are currently confirming and expanding these data in a larger dataset. CONCLUSIONS: In addition to ESR1 mutations, ESR1 CN amplifications and 5'-3' imbalance are represent frequent occurrences in endocrine resistant breast cancer. Future studies are aimed at understanding whether the observed exon imbalances are associated with generation of fusion proteins, and whether and how ESR1 amplifications cause changes in endocrine treatment response. Citation Format: Oesterreich S, Basudan A, Preideigkeit N, Hartmaier RJ, Bahreini A, Gyanchandani R, Leone JP, Lucas PC, Hamilton RL, Brufsky AM, Lee AV. ESR1 amplification and 5'-3' exon imbalance in metastatic 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 P6-07-07.
Background: There is sparse data on how mainstay treatments for brain metastasis (BM) are used in clinical practice and whether their usage has changed over time. Our population-based study presents the rates of surgical resection, radiation therapy, and chemotherapy in a large cohort of women with breast cancer BM. Methods: Women diagnosed with breast cancer between 1973 and 2013 were identified from the NCI linkage between the SEER program and Medicare claims data. Identification of BM was via ICD-9 diagnosis codes for secondary CNS malignancy on claims, and was defined as at least one inpatient claim and/or two or more outpatient claims. Treatment was defined as any claim filed with a procedure code for surgical resection of a BM, chemotherapy, and BM-directed radiation therapy. We excluded women without continuous Medicare coverage for a year before to 60 days after their first BM claim and women diagnosed with primary cancer other than breast cancer. Results: The proportion of women receiving treatment after BM claim increased from a low of 50.4% in 1992 to 66.8% in 2013 (p<0.0001). Further analysis of this period revealed rates of surgical resection rose from 7.8% to 11.5%, radiation therapy rose from 39.7% to 54.8%, and chemotherapy rose from 11.9% to 22.2% of women (p<0.002). We used adjusted logistic regression to explore associations between patient/tumor characteristics and treatment. Younger age and fewer comorbidities were associated with increased odds of receiving any of the three treatments. Compared with ER-/PR-, a woman whose index cancer was ER+/PR+ had lower odds of receiving any of the three treatments. Women with extracranial metastasis had greater odds of radiation or chemotherapy and lower odds of resection compared to women with BM only. Receiving any care at an Academic Medical Center (AMC) was associated with greater odds of resection, and lower odds of radiation and chemotherapy. Table 1 OR; 95% CI RadiationResectionChemotherapyAge: Per 5 years0.8; 0.8-0.90.8; 0.7-0.90.8; 0.7-0.8Race: Black vs. white0.7; 0.6-0.90.6; 0.5-0.90.9; 0.8-1.2Stage: Distant vs. localized1.2; 1.0-1.40.6; 0.5-0.91.1; 0.9-1.3Comorbidities: ≥2 vs. 10.7; 0.6-0.80.6; 0.4-0.80.6; 0.5-0.8ER/PR: +/+ vs. -/-0.5; 0.4-0.50.6; 0.5-0.70.8; 0.7-0.9Lifetime BC burden: ≥2 vs. 10.9; 0.8-1.21.0; 0.8-1.41.0; 0.8-1.3SEER Registry: 2000+ vs. 1973+1.1; 0.9-1.21.2; 0.9-1.40.9; 0.7-1.0Extracranial metastasis: Y vs. N2.9; 2.5-3.40.8; 0.6-0.95.4; 3.8-7.4Year of BM: Per 5 years1.1; 1.1-1.21.0; 0.9-1.11.1; 1.0-1.2Original reason for Medicare enrollment: Disability or ESRD vs. Age0.9; 0.7-1.10.9; 0.6-1.30.6; 0.5-0.8Marital status: Married vs. not1.0; 0.9-1.11.1; 0.9-1.41.2; 1.0-1.3Interval from BC to BM: ≥1 year vs. <1 year0.8; 0.7-0.91.4; 1.0-1.80.8; 0.6-0.9Rurality of patient's home: Less urban vs. Big metro1.3; 1.0-1.61.0; 0.7-1.50.7; 0.5-0.9Care at an AMC: Y vs. N0.7; 0.7-0.81.5; 1.2-1.80.9; 0.7-1.0Chemotherapy in year before BM: Y vs. N1.4; 1.2-1.50.7; 0.6-0.86.0; 5.2-6.9 Conclusions: We found that the proportion of women with breast cancer BM who received treatment has increased over time. Further, logistic regression revealed multiple noteworthy contrasts, including a positive relationship between care at an AMC and surgical resection, while women who received care at an AMC had lower odds of radiation or chemotherapy. Citation Format: Haraldsson B, Leone JP, McDowell BD, Chrischilles EA. Treatment patterns for breast cancer brain metastasis [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 P5-08-26.
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.
Background: Male breast cancer (MaBC) is a relatively uncommon disease, representing less than 1% of all breast cancers. Given its rarity, information about prognostic factors is unclear and mainly extrapolated from data from female breast cancer. This represents an important challenge for the risk assessment and treatment decisions in men. The aim of this study was to analyze the characteristics of patients with MaBC and factors associated with prognosis over the past decade. Methods: We evaluated men with microscopically confirmed invasive breast cancer diagnosed between 2003 and 2012, reported to the Surveillance, Epidemiology and End Results (SEER) 18 registries program. Patients (pts) with other primary malignancy either before or after breast cancer were excluded. Pt characteristics were compared between tumor grades. Univariate and multivariate analyses were performed to determine the effects of each variable on overall survival (OS). Results: We included 2992 pts. Median age was 65 years (range 23-97). Median follow-up was 36 months (range 0-119). At diagnosis, ductal histology represented 85% of cases, ER positive 95.1% and PR positive 86%. Thirty-one percent were Stage I, 42% stage II, 18% stage III and 9% stage IV. Only 12.8% of pts had breast conservation and 23.7% received adjuvant radiotherapy. Tumor grade distribution was: 12.4% grade 1, 51.5% grade 2 and 36% grade 3/4. Pts with grade 3/4 tumors were more likely mixed ductal and lobular histology (p<0.0001), more often ER and PR negative (p<0.0001), presented with more advanced stage (p<0.0001), were more likely to have mastectomy and radiotherapy (p<0.0001 and p=0.001, respectively) and to die from breast cancer (p<0.0001). Univariate analysis showed that older age, black race, grade 3/4 tumors, stage IV disease, no surgery, no radiotherapy, ER negative tumors, PR negative tumors and unmarried pts had worse prognosis. Most deaths in the ER negative group occurred within the first 5 years (OS rate at 5 years 66.2%). OS rates between ER positive and ER negative groups were similar after 7.5 years (60.9% and 61.9%, respectively). In multivariate analysis, older age, grade 3/4 tumors, stage IV disease, no surgery, no radiotherapy, ER negative tumors and unmarried pts had shorter OS. Univariate pMultivariate pAge<0.0001<0.0001Race0.0001NSGrade<0.00010.006Stage<0.0001<0.0001Surgery<0.00010.0001Radiation0.020.004ER0.030.04PR0.005NSMarital status<0.0001<0.0001HistologyNS Conclusions: MaBC is most commonly diagnosed at early stages of disease. Tumors are frequently ductal in histology with high rates of ER positivity, however grade 1 is uncommon. We observed significant differences in pt characteristics according to tumor grade. The main difference in OS by ER status is seen during the first 5 years. Age at diagnosis, tumor grade, stage, surgery, radiotherapy, ER and marital status have clear influence on OS in MaBC over the past decade. Citation Format: Leone JP, Zwenger AO, Iturbe J, Leone J, Leone BA, Vallejo CT, Bhargava R. Prognostic factors in male breast cancer: A population-based study. [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 P6-19-01.
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