Leela Elavathil

HER-2 and Topoisomerase II As Predictors of Response to Chemotherapy

HER2 overexpression or amplification has been shown to be associated with a poor prognostic effect in women with breast cancer. At least eight analyses based on randomized trials have examined the relationship between HER2 and the differential effect of anthracycline compared with non-anthracycline-containing regimens. Only three of these studies were sufficiently powered to show a significant interaction between HER2 and anthracycline- versus non-anthracycline-containing treatments, but because all of the study results tended to be in the same direction, it is not surprising that three recent meta-analyses of published data have suggested that anthracycline-containing regimens provide more benefit than non-anthracycline-containing regimens in women whose tumors are overexpressed or amplified (positive) for HER2. Since topoisomerase II is a known target of the anthracyclines, it has been postulated that this relationship is actually based on the proximity of HER2 to the topoisomerase II alpha gene (TOP2A) in the 17q chromosome. At least four recent studies have suggested that deletion and amplification of the TOP2A gene are associated with poor prognosis and are predictive of greater response to anthracycline-containing than to non-anthracycline-containing regimens. However, in at least one of those studies, HER2 positivity was as or more predictive. Although it has been suggested that HER2 positivity is predictive of better response to higher-dose anthracycline-containing regimens compared with standard anthracycline-containing regimens and to taxane- compared with non-taxane-containing regimens, these relationships have not been robust or consistent. Additional studies will be required to clarify these relationships.

HER2/ neu in systemic therapy for women with breast cancer: a systematic review

BackgroundAmplification and/or overexpression of the HER2/neu gene is associated with a poor prognosis in breast cancer. Many studies have suggested that this gene may be associated with the relative efficacy of chemotherapy and endocrine therapy options.MethodsA systematic review of the evidence was conducted. MEDLINE, EMBASE, the Cochrane Library, the American Society of Clinical Oncology annual meeting proceedings, and the San Antonio Breast Cancer Symposia proceedings were all searched to November 2006 for reports of analysis by HER2/neu status of the relative efficacy of the treatment arms in randomized controlled trials.ResultsThirty-five trials were identified. A meta-analysis of trials of tamoxifen versus observation found no significant interaction between treatment and HER2/neu status, although one trial not included in the meta-analysis did find interaction. A meta-analysis of adjuvant anthracycline-based chemotherapy trials found a significant interaction (difference in disease-free survival log-hazard ratios −0.31, 95% confidence interval −0.50 to −0.13; difference in overall survival log-hazard ratios −0.34, 95% confidence interval −0.53 to −0.14). Significant interaction was also found in a meta-analysis of disease-free survival in trials of adjuvant taxane therapy versus non-taxane therapy (difference in disease-free survival log-hazard ratios −0.36, 95% confidence interval −0.68 to −0.04). HER2/neu overexpression and/or amplification was associated with greater efficacy of the anthracycline or taxane regimen.ConclusionsCurrent evidence supports the conclusion that the benefit of both anthracycline-based and taxane-based adjuvant chemotherapy is associated on HER2/neu status, with patients with HER2/neu-positive cancers benefiting more from these therapies than those with HER2/neu-negative cancers.

Long-term outcomes of hypofractionation versus conventional radiation therapy after breast-conserving surgery for ductal carcinoma in situ of the breast.

PURPOSE Whole-breast radiation therapy (XRT) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) may decrease the risk of local recurrence, but the optimal dose regimen remains unclear. Past studies administered 50 Gy in 25 fractions (conventional); however, treatment pattern studies report that hypofractionated (HF) regimens (42.4 Gy in 16 fractions) are frequently used. We report the impact of HF (vs conventional) on the risk of local recurrence after BCS for DCIS. METHODS AND MATERIALS All women with DCIS treated with BCS and XRT in Ontario, Canada from 1994 to 2003 were identified. Treatment and outcomes were assessed through administrative databases and validated by chart review. Survival analyses were performed. To account for systematic differences between women treated with alternate regimens, we used a propensity score adjustment approach. RESULTS We identified 1609 women, of whom 971 (60%) received conventional regimens and 638 (40%) received HF. A total of 489 patients (30%) received a boost dose, of whom 143 (15%) received conventional radiation therapy and 346 (54%) received HF. The median follow-up time was 9.2 years. The median age at diagnosis was 56 years (interquartile range [IQR], 49-65 years). On univariate analyses, the 10-year actuarial local recurrence-free survival was 86% for conventional radiation therapy and 89% for HF (P=.03). On multivariable analyses, age <45 years (hazard ratio [HR] = 2.4; 95% CI: 1.6-3.4; P<.0001), high (HR=2.9; 95% CI: 1.2-7.3; P=.02) or intermediate nuclear grade (HR=2.7; 95% CI: 1.1-6.6; P=.04), and positive resection margins (HR=1.4; 95% CI: 1.0-2.1; P=.05) were associated with an increased risk of local recurrence. HF was not significantly associated with an increased risk of local recurrence compared with conventional radiation therapy on multivariate analysis (HR=0.8; 95% CI: 0.5-1.2; P=.34). CONCLUSIONS The risk of local recurrence among individuals treated with HF regimens after BCS for DCIS was similar to that among individuals treated with conventional radiation therapy.

Multigene Expression Assay and Benefit of Radiotherapy After Breast Conservation in Ductal Carcinoma in Situ.

Background Most women with ductal carcinoma in situ (DCIS) will receive breast-conserving surgery (BCS) and radiation (RT). RT can be omitted for women at low risk of local recurrence (LR). The Oncotype DX DCIS score (DS) predicts LR risk after BCS alone. This study assesses the impact of RT and DS on LR risk. Methods Population-based cohort analysis of individuals with DCIS treated by BCS ± RT from 1994-2003. Treatment and outcomes were determined by linkage and chart review. We used a propensity score-adjusted multivariable model to examine associations between DS and LR and evaluate the impact of RT. All statistical tests were two-sided. Results The cohort includes 571 individuals treated by BCS alone, 689 cases treated with BCS + RT. Median follow-up was 9.4 years. On multivariable analysis, factors associated with LR include RT, age at diagnosis, tumor size, and multifocality. Adjusting for these factors, the DS risk group was statistically significantly associated with LR risk (hazard ratio high/intermediate = 1.75, 95% confidence interval = 1.28 to 2.41, P < .001). Women with a low-risk DS treated by BCS alone had an LR risk of 10.6% at 10 years and a small benefit from RT, while those with a high DS had a higher risk of LR (25.4%) after BCS alone and greater benefit from RT. A subgroup of patients with favorable clinicopathological features had a high-risk DS; these patients had a higher than expected risk of LR after BCS alone and a greater benefit with RT. Conclusions The DS molecular assay improves risk stratification and estimates of RT benefit in individuals with DCIS treated with breast-conserving therapy.Abstract Background: Most women with ductal carcinoma in situ (DCIS) will receive breast-conserving surgery (BCS) and radiation (RT). RT can be omitted for women at low risk of local recurrence (LR). The Oncotype DX DCIS score (DS) predicts LR risk after BCS alone. This study assesses the impact of RT and DS on LR risk. Methods: Population-based cohort analysis of individuals with DCIS treated by BCS ± RT from 1994–2003. Treatment and outcomes were determined by linkage and chart review. We used a propensity score–adjusted multivariable model to examine associations between DS and LR and evaluate the impact of RT. All statistical tests were two-sided. Results: The cohort includes 571 individuals treated by BCS alone, 689 cases treated with BCS + RT. Median follow-up was 9.4 years. On multivariable analysis, factors associated with LR include RT, age at diagnosis, tumor size, and multifocality. Adjusting for these factors, the DS risk group was statistically significantly associated with LR risk (hazard ratio high/intermediate = 1.75, 95% confidence interval = 1.28 to 2.41, P < .001). Women with a low-risk DS treated by BCS alone had an LR risk of 10.6% at 10 years and a small benefit from RT, while those with a high DS had a higher risk of LR (25.4%) after BCS alone and greater benefit from RT. A subgroup of patients with favorable clinicopathological features had a high-risk DS; these patients had a higher than expected risk of LR after BCS alone and a greater benefit with RT. Conclusions: The DS molecular assay improves risk stratification and estimates of RT benefit in individuals with DCIS treated with breast-conserving therapy.

Abstract S5-04: A large prospectively-designed study of the DCIS score: Predicting recurrence risk after local excision for ductal carcinoma in situ patients with and without irradiation

Background: DCIS patients need better tools to align the aggressiveness of treatment with the aggressiveness of their disease. The DCIS Score (DS) was validated as a predictor of ipsilateral breast recurrence (IBR; DCIS or invasive) in 327 E5194 patients treated by breast-conserving surgery (BCS) without radiation (RT) (Solin,2013). This Ontario population based DCIS study of 3335 women with DCIS from 1994 to 2003 (Rakovitch,2013) was conducted to test the DCIS Score as a predictor of recurrence risk in patients treated with BCS alone and in patients treated with BCS+RT. Methods: REMARK guidelines were followed. Breast pathologists centrally reviewed all HE 718 received BCS without RT (N=571 with CM) and 846 received BCS+RT (N=689 with CM). Median follow-up was 9.4 years. Among 1260 pts with CM, 100 pts treated with BCS alone had an IBR (DCIS, N=44; invasive, N=57); 86 pts treated with BCS+RT had an IBR (DCIS, N=32; invasive, N=55). In the primary analysis, among 571 patients treated by BCS alone with CM the continuous DS was significantly associated with IBR in ER+ patients (HR 2.26; 95%CI 1.41,3.59; P=0.001) and in all patients (HR 2.15; 95%CI 1.43,3.22; P= Conclusions: DCIS Score quantifies recurrence risk for DCIS patients treated by BCS with or without RT. Integrating the DCIS Score with established risk factors, such as multifocality, age, and tumor size, can help identify DCIS patients treated with BCS alone with low 10 year risk ( Citation Format: Eileen Rakovitch, Sharon Nofech-Mozes, Wedad Hanna, Frederick L Baehner, Refik Saskin, Steven M Butler, Alan Tuck, Sandip Sengupta, Leela Elavathil, Prashant A Jani, Michel Bonin, Martin C Chang, Elzbieta Slodkowska, Joseph M Anderson, Farid Jamshidian, Diana B Cherbavaz, Steven Shak, Lawerence Paszat. A large prospectively-designed study of the DCIS score: Predicting recurrence risk after local excision for ductal carcinoma in situ patients with and without irradiation [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 S5-04.