Adjuvant Chemoendocrine Therapy Research Articles

300 (PB-116) Poster - Real-world analysis of genomic signature indications and impact on adjuvant chemoendocrine therapy (CET) decisions: experience from the French LISE cohort (n = 301)

300 (PB-116) Poster - Real-world analysis of genomic signature indications and impact on adjuvant chemoendocrine therapy (CET) decisions: experience from the French LISE cohort (n = 301)

Estimating the overall survival benefit of adjuvant chemo-endocrine therapy in women over age 50 with pT1-2N0 early stage breast cancer and 21-gene recurrence score ≥26: A National Cancer Database analysis.

Validation studies of the 21-gene recurrence score (RS) previously demonstrated that adjuvant chemotherapy plus endocrine therapy (CET) was associated with a significant survival benefit in women with node negative breast cancer (BC) and RS >31. However, the TAILORx trial, did not quantify the benefit of adjuvant CET in older women with node negative hormone receptor positive (HR+) BC with RS ≥26. We hypothesized that CET would be associated with improved overall survival (OS) compared to endocrine therapy (ET) in women >50 with HR+/HER2-node negative BC and RS ≥26. The National Cancer Database (NCDB) was queried to identify women >50 with RS ≥26 ER+/HER2-BC pT1-2N0M0. Chi-square and logistic regression analysis determined the difference between ET and CET. OS was analyzed using a multivariable Cox model. We included 16,745 women-4740 (28.3%) received ET and 12,005 (71.7%) received CET. Women who received CET had: moderately (OR = 1.853, p < 0.001) or poorly/undifferentiated tumors (OR = 3.875, p < 0.001), pT2 (OR = 1.356, p < 0.001), or lymph-vascular invasion (OR = 1.206, p = 0.001). After accounting for demographic and oncologic factors, 5-year OS rates were significantly superior in women receiving CET vs. ET alone (95.4% vs. 92.0%, Hazard Ratio = 0.680, p < 0.001). We observed that CET was associated with a clinically and statistically significant higher OS compared to ET alone in women >50 years of age with RS ≥26 pT1 and pT2 N0M0 HR+/HER2-breast cancer, and which suggests that cytotoxic chemotherapy has an impact on reducing mortality that is independent of induction of premature ovarian failure.

Adjuvant chemotherapy is associated with an overall survival benefit regardless of age in ER+/HER2- breast cancer pts with 1-3 positive nodes and oncotype DX recurrence score 20 to 25: an NCDB analysis.

The RxPONDER trial found that among breast cancer patients with estrogen receptor positive (ER+) breast cancer, 1-3 positive axillary nodes, and a recurrence score of ≤25, only pre-menopausal women benefitted from adjuvant chemoendocrine therapy; postmenopausal women with similar characteristic did not benefit from adjuvant chemotherapy. We aimed to replicate the RxPonder trial using a larger patient cohort with real world data to determine whether a RS threshold existed where adjuvant chemotherapy was beneficial regardless of age. The National Cancer Database (NCDB) was queried for women with ER+, human epidermal growth factor receptor 2 (HER2) negative breast cancer, 1-3 positive axillary nodes, and RS ≤25 who received endocrine (ET) only or chemo-endocrine therapy (CET). Cox regression interaction was explored between CET and age as a surrogate for menopausal status. The final analytic cohort included 28,427 eligible women: 7,487 (26.3%) received adjuvant CET and 20,940 (73.7%) ET. In the entire cohort, RS had a normal distribution, with a median score of 14. After correcting for demographic and clinical variables, a threshold effect was observed with RS >20 being associated with a significantly inferior overall survival (OS) (P value range: < 0.001-0.019). In women with RS of 20-25, CET was associated with a significant improvement in OS compared to ET alone, regardless of age (age <=50: HR = 0.334, P=0.002; age>50: HR=0.521, P=0.019). Among women with ER+/HER2- breast cancer with 1-3 positive nodes, and a RS of 20-25-in contrast to the RxPONDER trial-we observed that CET was associated with an OS benefit in women regardless of age.

Validation of the prognosis of patients with ER‑positive, HER2‑negative and node‑negative invasive breast cancer classified as low risk by Curebest™ 95GC Breast in a multi‑institutional registry study.

Curebest™ 95GC breast (95GC) is a multigene classifier we developed for the prognostic prediction of patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative and node-negative (ER+/HER2-/n0) invasive breast cancer treated with adjuvant endocrine therapy alone. The aim of the preset study was to evaluate the clinical utility of 95GC in a multiinstitutional registry study. Patients (n=215) with ER+/HER2-/n0 invasive breast cancer who had undergone the 95GC assay in seven hospitals were consecutively recruited in the registry study at various postoperative times. At recruitment, no patients had disease recurrences and were prospectively followed up for a median of 62 (range, 6-91) postoperative months. Of the 124 patients classified as 95GC low risk, 118 received adjuvant endocrine therapy alone and six received adjuvant chemo-endocrine therapy. Only two patients developed distant recurrences, and the 5-year distant recurrence-free survival (DRFS) was as high as 98.0%. Of the 91 patients classified as 95GC high risk, 81 received adjuvant chemo-endocrine therapy and 10 received adjuvant endocrine therapy alone. A total of four of these patients developed distant recurrences (5-year DRFS=95.5%). Among the 95GC high-risk patients, prognosis was significantly improved for the 81 treated with adjuvant chemo-endocrine therapy compared with for the 77 (historical controls) treated with adjuvant endocrine therapy alone (P=0.0002; hazard ratio, 0.24). Compared with the St. Gallen 2013 guideline, a significant de-escalation from 73.1% (155/212) to 40.6% (86/212) in adjuvant chemotherapy was achieved. The excellent prognosis of patients with ER+/HER2-/n0 invasive breast cancer classified as 95GC low risk could be validated in the present registry study, indicating that 95GC is useful for safe de-escalation of adjuvant chemotherapy in patients with ER+/HER2-/n0 invasive breast cancer.

Adjuvant chemotherapy is associated with an overall survival benefit regardless of age in patients with ER+/HER2-breast cancer with 1-3 positive nodes and Oncotype DX recurrence score 20 to 25: A National Cancer Database analysis.

540 Background: Based on the results of the RxPonder trial, post-menopausal women over age 50 with estrogen receptor (ER)+ breast cancer, 1-3+ nodes, and a 21-gene Oncotype DX recurrence score (RS) score of &lt;25, did not benefit from receiving adjuvant chemotherapy. By contrast, adjuvant chemotherapy was beneficial in premenopausal women. We aimed to replicate the RxPonder trial using a larger sample sizes with real world data to determine whether a threshold with RS exists where adjuvant chemoendocrine therapy (CET) is beneficial regardless of age. Methods: The National Cancer Database (NCDB) was queried for women with ER+, human epidermal growth factor receptor 2 (HER2) negative breast cancer, 1-3 positive axillary nodes, and RS &lt;25 who received endocrine therapy (ET) only or CET. Interaction was explored between CET and age as a surrogate for menopausal status in the Cox regression models. Results: The final analytic cohort included 28,427 eligible women: 7,487 (26.3%) received adjuvant CET and 20,940 (73.7%) ET. In the entire cohort, RS had a normal distribution, with a median score of 14. After correcting for demographic and clinical variables, a threshold effect was observed with RS &gt;20 being associated with a significantly inferior overall survival (OS) (P value range: &lt; 0.001-0.019). In women with RS of 20-25, CET was associated with a significant improvement in OS compared to ET alone, regardless of age (age &lt; = 50: HR = 0.334, P = 0.002; age &gt; 50: HR = 0.521, P = 0.019). Conclusions: Among women with ER+/HER2- breast cancer with 1–3 positive nodes, and RS of 20-25, in contrast to the RxPonder trial we observed that CET was associated with an OS benefit in women regardless of age.

Abstract OT1-08-01: Concurrent versus sequential chemo-endocrine therapy in er positive and her2 negative non-metastatic breast cancer- an open-label, phase III, randomized controlled trial

Abstract Background-Traditionally, endocrine therapy follows chemotherapy for hormone receptor (HR) positive breast cancer (BC) in the adjuvant setting. Concurrent chemo-hormonal therapy fell into disrepute due to previous studies showing a probable, small detriment in survival. (Albain et al, Lancet, 2009; Bedognetti et al, JNCI, 2009; Pico et al, Ann Oncol, 2004) However, the early studies are fraught with biases. The biological rationale was that endocrine therapy is cytostatic, pushing cancer cells into G0 phase which was feared to reduce the efficacy of chemotherapy which is known to act best on rapidly dividing cells. Thus, the two mechanisms of actions were thought to be antagonistic. However, this fear may be irrational and evidence at molecular level is contradictory. The current sequential strategy delays the start of an equally effective treatment modality in HR+ BC patients. Recent studies have shown that concurrent chemo-endocrine therapy is safe in metastatic HR+ setting. (Sledge et al, J Clin Oncol, 2000) One also needs to rethink neoadjuvant strategies in these patients to improve the current dismal pathological complete response (pCR) rates in this subset. (Cortazar et al, Lancet, 2014) Concurrent treatment seems to have improved pCR rate. (Sagiu K et al, Acta Med Okayama, 2015) Here, we describe a phase III, randomized study aimed to evaluate the efficacy of concurrent chemo-endocrine therapy in the adjuvant and neoadjuvant setting. (CTRI/2018/09/015643) Aims and Objectives- The primary objective is to assess the improvement in disease-free survival by administering concurrent versus sequential, (neo) adjuvant chemo-endocrine therapy in HR+, HER2 negative, non-metastatic BC. The secondary objectives are to assess improvement in overall survival, pCR rates, breast conservation rates. Biomarkers of response to treatment and tumour dormancy in HR+ BC will be studied in a subset of patients.Patients and methods-This is a prospective, open label study where non-metastatic, biopsy proven, HR+, HER2- BC patients who warrant chemotherapy in the adjuvant or neoadjuvant setting are considered. The study started accrual in December 2018 and 285 patients are randomized till date. Pregnant or lactating women and those with inflammatory breast carcinoma are excluded. After obtaining informed consent, patients are randomized to receive concurrent versus sequential chemo-endocrine treatment. Patients will receive all chemo and endocrine therapy as per the institutional standard protocols otherwise. Stratification criteria are neoadjuvant vs adjuvant therapy, pre vs postmenopausal status, node positive vs node negative status, 1st gen (anthracyclines alone) versus 2nd gen (including taxanes) chemotherapy. A two-sided log-rank test with an overall sample size of 2316 (2432 with a 5% dropout rate) (1158 in control and 1158 in treatment group) achieves 80% power at a 0.05 significance level to detect a hazard ratio of 0.80 when the proportion surviving in the control group is 0.70. An interim with respect to safety is planned in the protocol. Expected results and conclusion-Ours is a large, prospective trial evaluating the efficacy of concurrent chemo-endocrine therapy in HR+ BC patients. This has the potential to improve pCR rates in the neoadjuvant setting and change the standard of care in the management of HR+ BC patients. The biomarker analysis will help us further understand the biology of HR+ BC and shed light upon tumour dormancy signatures. Citation Format: Shalaka Joshi, Sridevi Murali-Nanavati, Vaibhav Vanmali, Rohini Hawaldar, Mujahid Gafur Shaikh, Mohammad Sadique Ansari, Sushmita Rath, Jaya Ghosh, Seema Gulia, Jyoti Bajpayi, Nita Nair, Vani Parmar, Purvi Thakkar, Garvit Chitkara, Tanuja Shet, Sangeeta Desai, Ayushi Sahay, Sudeep Gupta, Rajendra Badwe. Concurrent versus sequential chemo-endocrine therapy in er positive and her2 negative non-metastatic breast cancer- an open-label, phase III, randomized controlled trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-08-01.

Sequential versus concurrent adjuvant chemo-endocrine therapy for HR+ early breast cancer: a systematic review and Bayesian network meta-analysis

Sequential versus concurrent adjuvant chemo-endocrine therapy for HR+ early breast cancer: a systematic review and Bayesian network meta-analysis

A 95-gene signature stratifies recurrence risk of invasive disease in ER-positive, HER2-negative, node-negative breast cancer with intermediate 21-gene signature recurrence scores.

A subset of patients with intermediate 21-gene signature assay recurrence score may benefit from adjuvant chemoendocrine therapy, but a predictive strategy is needed to identify such patients. The 95-gene signature assay was tested to stratify patients with intermediate RS into high (95GC-H) and low (95GC-L) groups that were associated with invasive recurrence risk. Patients with ER-positive, HER2-negative, node-negative breast cancer and RS 11-25 who underwent definitive surgery and adjuvant endocrine therapy without any cytotoxic agents were included. RNA was extracted from archived formalin-fixed, paraffin-embedded samples, and 95-gene signature was calculated. 206 patients had RS of 11-25 (95GC-L, N = 163; 95GC-H, N = 43). In Cox proportional hazards model, 95GC-H was significantly associated with shorter time to recurrence than was 95GC-L (HR 5.94; 95%CI 1.81-19.53; P = 0.005). The correlation between 95-gene signature and 21-gene signature assay scores was not strong (correlation coefficient r = 0.27), which might suggest that 95-gene signature reflects biological characteristics differing from what 21-gene signature shows. The 95-gene signature stratifies patients with ER-positive, HER2-negative, node-negative invasive breast cancer and intermediate RS of 11-25 into high and low groups that are associated with recurrence risk of invasive disease. Further retrospective analysis in the prospectively accrued TAILORx population is warranted to confirm that 95-gene signature can identify patients who would benefit from adjuvant chemoendocrine therapy.

Abstract PS6-24: Are we missing something? Increased recurrence rates in patients with an oncotype DX score &amp;lt; 26 and a modified magee score &amp;gt; 18: A multi-institutional study

Abstract INTRODUCTION: Oncotype DX® (ODX) is a multigene assay estimating risk of distant recurrence and chemotherapy benefit in estrogen receptor (ER) positive breast cancer patients. Cost ($4,620.00) impedes its adoption in poorer countries, and the cost is unnecessary in certain patients. TAILORx results suggest that adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-positive, HER2-negative, node-negative invasive breast carcinomas with an ODX recurrence score &amp;lt; 26. Bhargava et al. and Turner et al. have suggested that a Magee scoreTM or a modified Magee score, respectively, of &amp;lt; 18 will identify patients who are highly likely to have an ODX recurrence score of &amp;lt; 26, and we previously presented data at SABCS 2019 (Abstract P3-07-06) that there is no significant difference in recurrence rate between patients with a modified Magee score of ≤ 18 and patients with an ODX recurrence score &amp;lt; 26 (in preparation for publication). We now present additional recurrence data on patients with a modified Magee score of &amp;gt; 18. METHODS: A total of 301 consecutive patients with ER+ invasive breast cancer from the University of Rochester and the University of Louisville were included in this study, with a mean of 6.6 years of follow-up. All patients had at least 5 years of follow-up (range 5-11 years) except for seven patients , who had a breast cancer recurrence prior to five years. Information on ER, PR, HER-2, Ki-67, Nottingham score , and tumor size were extracted from the pathology report in order to calculate the modified Magee score. Information, on hormone therapy, chemotherapy, radiation therapy, recurrence status, and mortality were extracted from the medical record. For all results, a p-value of &amp;lt; 0.05 was considered significant. RESULTS: 117/301 (39%) patients had a modified Magee score of &amp;gt; 18. The recuurence rate for patients with a modified Magee score &amp;gt; 18 was 11.1%. There was no significant difference in recurrence rate between patients with both a modified Magee score &amp;gt; 18 and ODX recurrence score &amp;lt; 26 compared to patients with both a modified Magee score &amp;gt;18 and ODX recurrence score ≥ 26 (p = 0.547, Table 1). CONCLUSIONS: Patients with a modified Magee score &amp;gt; 18 may be at increased risk for breast cancer recurrence, even if the ODX recurrence score is &amp;lt; 26. Additional studies are necessary to further evaluate these findings. Table 1: Modified Magee score &amp;gt; 18, Oncotype DX recurrence score (ODXRS), and outcomeRecurrenceNo recurrenceModified Magee score &amp;gt; 18 and ODXRS &amp;lt; 26870Modified Magee score &amp;gt; 18 and ODXRS ≥ 26633 Citation Format: Bradley M Turner, Mary Ann Gimenez-Sanders, Ioana Moisini, Huina Zhang, Xi Wang, Linda Schiffhauer, Hani Katerji, Kristin Skinner, Jessica Gooch, Michelle Shayne, Marilyn Ling, Carla Falkson, David Hicks. Are we missing something? Increased recurrence rates in patients with an oncotype DX score &amp;lt; 26 and a modified magee score &amp;gt; 18: A multi-institutional study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-24.

Implications of the 21-gene recurrence score assay (Oncotype DX) on adjuvant treatment decisions in ER-positive early-stage breast cancer patients: experience of Kuwait Cancer Control Center

BackgroundThe Oncotype DX is a quantitative assay of the expression of 16 tumor-related genes and 5 reference genes that predicts the potential of adjuvant chemotherapy benefit in estrogen receptor (ER)-positive early breast cancer patients. The study aims to evaluate the impact of Oncotype DX as a tool for adjuvant treatment decision of ER-positive, HER2-negative, N0/N1 early-stage breast cancer patients and to determine which clinicopathological criteria derived the greatest advantage.ResultsA hundred patients at a median age of 50 years were included. TNM stage distribution was 34, 63, and 3 patients for stages I, II, and IIIA respectively. Fifty-four patients had luminal A and 46 had luminal B tumors. The recurrence score (RS) results were low, intermediate, and high risk in 54, 34, and 12 patients respectively. Before the test results, adjuvant chemoendocrine therapy (CET) was recommended for 46 patients while 54 were advised for endocrine therapy (ET). After getting the test results, 25 patients received CET (1, 12, and12 patients in the low-, intermediate-, and high-risk groups respectively) and 75 received ET. Treatment change was documented in 37 patients (8 patients from ET to CET and 29 from CET to ET; p = 0.001, McNemar test). Treatment change was significant among patients ≤ 50 years, luminal B tumors, stage II and IIIA disease, and node-positive disease.ConclusionOncotype DX testing resulted in significant changes in the adjuvant treatment decisions in ER-positive, HER2-negative early breast cancer particularly in the case of young, luminal B, N1, and stage II–IIIA disease.

Abstract P3-07-06: ER+ patients with an average modified Magee score ≤ 18 have a low likelihood of breast cancer recurrence and a high likelihood of an Oncotype Dx® recurrence score &amp;lt; 26

Abstract INTRODUCTION: The recent TAILORx results suggest that adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-positive, HER2-negative, node-negative invasive breast carcinomas with an Oncotype Dx® recurrence score &amp;lt; 26. Oncotype Dx® is an expensive test (current list price of $4,620.00). Although the Oncotype Dx® test has gained widespread acceptance, cost may be an impediment to its adoption in certain areas of the world, and it may not be the most cost-effective or cost-efficient option in certain subsets of breast cancer patients. Based on a modification of the new Magee equations, we published an algorithmic approach in 283 ER+ cases using an average modified Magee equation (Turner BM, et al. Mod Pathol. 2015;28(7):921-31), and subsequently published a validation of this algorithmic approach in an additional 620 ER+ cases (Cancer Med. 2019 Jun 14. doi: 10.1002/cam4.2323. [Epub ahead of print]), supporting only reflex Oncotype Dx® testing for certain subsets of breast cancer patients. We now have recurrence data and at least five years of outcome data on 310 cases. METHODS: A total of 310 cases with ER+ invasive breast cancer, all with Oncotype Dx® recurrence scores, were included in this study from the University of Rochester and the University of Louisville. The outcome analysis included all patients who had at least five years of follow-up data, and all patients who had a breast cancer recurrence. In order to calculate the average modified Magee score, information on the Nottingham score, ER, PR, Ki-67, HER-2, and tumor size was extracted from the pathology report. RESULTS: 255/310 cases had an Oncotype Dx® &amp;lt; 26, and 4% (10/255) of these cases were associated with a breast cancer recurrence. 187/310 cases had an average modified Magee score ≤ 18, and 184 of these 187 cases (98%) had an Oncotype Dx® recurrence score &amp;lt; 26. Only 2% (n = 4) of these 184 cases were associated with a breast cancer recurrence. On average, the Nottingham score and Ki-67 were lower for cases with an average modified Magee score ≤ 18 compared to cases with an Oncotype Dx® recurrence score &amp;lt; 26 (Table 1). On average, the modified ER and PR H-scores were higher for cases with an average modified Magee score ≤ 18 compared to cases with an Oncotype Dx® recurrence score &amp;lt; 26 (Table 1). CONCLUSION: If the average modified Magee score is ≤ 18, the patient has a low likelihood of recurrence, and the Oncotype Dx® recurrence score will likely be &amp;lt; 26. Given the recent TAILORx findings, we suggest that patients with an average modified Magee score ≤ 18 not be sent out for Oncotype Dx® testing if an Oncotype Dx® recurrence score &amp;lt; 26 is the basis on which the clinician will use to decide whether or not to give chemotherapy. The information needed to use the average modified Magee equation is already generated by many pathology laboratories during the initial assessment of breast cancer, and the Magee equations are free of charge (https://path.upmc.edu/onlineTools/mageeequations.html). Based on the Genomic Health 2017 Annual Report, our data suggests that not sending out cases with an average modified Magee score ≤ 18 would have resulted in a potential cost savings to the health-care system in 2018 of almost 300 million dollars. Table 1: Average Nottingham score, modified ER H-score, modified PR H-score, and Ki-67, with number and percent recurrence for cases with an average modified Magee score ≤ 18 and cases with an Oncotype Dx® recurrence score &amp;lt; 26AVERAGERecurrence Sore typeNNS**ER***PR***Ki-67Recurrence N (%)Average modified Magee score ≤ 18*1875.2262.3235.410.34 (2)Oncotype Dx® recurrence score &amp;lt; 262555.5253.2192.613.610 (4)*98% (184/187) of patients with an average modified Magee score ≤ 18 had an Oncotype Dx® recurrence score &amp;lt; 26**Nottingham score***modified H-score (Turner BM, et al. Mod Pathol. 2015;28(7):921-31) Citation Format: Hasan Khatib, Mary Ann G Sanders, Andrea Breaux, Armen Soukiazian, Nyrie Soukiazian, David Hicks, Bradley M Turner. ER+ patients with an average modified Magee score ≤ 18 have a low likelihood of breast cancer recurrence and a high likelihood of an Oncotype Dx® recurrence score &amp;lt; 26 [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 P3-07-06.

Use of Adjuvant Chemoendocrine Therapy vs Adjuvant Endocrine Therapy in Node-Negative Early-Stage Breast Cancer Patients Stratified as Midrange Risk by 21-Gene Oncotype DX Breast Recurrence Score Assay: A Meta-Analysis Study

Gonong, Patrick Adrian G. MD; Torillo, Maila Rose L. MD, FACS; Lao, Linelle Stacy T. MD; Soliven, Albert U. MD Author Information

A novel 95-gene signature (Curebest 95GC Breast) that predicts recurrence-risk in patients with ER-positive, HER2-negative, node-negative, early-stage primary invasive breast cancer with an intermediate Oncotype DX Recurrence Score.

542 Background: The TAILORx trial demonstrated that adjuvant endocrine and chemoendocrine therapies had similar efficacy in patients with hormone receptor-positive, HER2-negative, node-negative breast cancer with an Oncotype DX recurrence score (RS) of 11-25. However, a predictive strategy is needed to identify patients with intermediate RS who may benefit from adjuvant chemoendocrine therapy. Curebest 95GC Breast (95GC) is a 95-gene signature that can stratify patients into two groups with high (95GC-H) and low (95GC-L) groups to predict the risk of recurrence. Our primary objective was to show that 95GC can classify patients with intermediate RS into binary recurrence risk groups. Methods: Patients with ER-positive, HER2-negative, node-negative invasive breast cancer and RS 11-30 who underwent definitive surgery and adjuvant endocrine therapy were included. RNA was derived from archived formalin-fixed, paraffin-embedded samples, and 95GC was calculated as reported previously. The Fisher exact and Brunner-Munzel tests were used to compare variables between 95GC groups. A Kaplan-Meier estimate with a log-rank test was used for recurrence-free survival (RFS) analysis. Results: The analysis included 178 patients from five institutions. The 5-year RFS rate in patients with RS 18-30 was higher in the 95GC-L group (n = 129, 96.3%) than in the 95GC-H group (n = 49, 90.9%; p = 0.002), which was consistent with results in an independent Japanese population (n = 224; p &lt; 0.001). RFS rates significantly differed between the groups among patients with RS 11-25 as well (95GC-L, 97.4%; 95GC-H, 87.1%; p = 0.001). RFS rates did not differ between patients with RS 18-25 (94.8%) and those with RS 26-30 (93.8%; p = 0.33). Conclusions: 95GC can predict recurrence risk in patients with ER-positive, HER2-negative, node-negative invasive breast cancer and intermediate RS. Further prospective retrospective studies in the TAILORx population are warranted to confirm that 95GC can identify patients who may benefit from adjuvant chemoendocrine therapy.

Abstract P4-14-05: Confirmation of the TAILORx 21-gene expression trial using a real world observational database

Abstract Background: The TAILORx study (NCT00310180)(TRx) has demonstrated the efficacy of endocrine therapy alone in early stage, lymph node negative, hormone receptor positive, her2neu oncogene negative breast cancer harboring an intermediate recurrence score (RS) on a 21-gene profile (OncotypeDx), obviating the need for adjuvant chemotherapy in a large subset of women. The study randomized and followed 6711 patients (pts) and required 9 years to reach its conclusion endpoints. The availability of the electronic health record (EHR) permits automated reviews, facilitating more rapid “real world” hypothesis testing (but not a replacement for randomized clinical trials), especially when there are clear variations in common practice patterns. However physician bias in treatment selection needs to be considered. Methods: A retrospective review of the Cota Observational Cancer database, drawn from EHRs, of female pts with breast cancer who were 18 to 75 years of age; had hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer harboring an OncotypeDx RS 11-25 receiving adjuvant therapy following surgical resection of a 11-50 mm primary tumor (similar to TRx eligibility). Results: 1009 pts from 23 cancer centers (107 oncologists) were identified, 850 (84.2%) received adjuvant endocrine therapy alone (E) and 159 (15.8%) received adjuvant chemoendocrine therapy (CE) as part of standard care (no randomization). 285 pts were age &amp;lt;50 yrs (E:218, CE:67) and 601 pts has RS 16-25 (E:453, CE:148). Treatment selection was imbalanced with oncologists more likely to utilize CE in younger pts (median age E: 59 yrs, CE: 53 yrs; p&amp;lt;0.01), larger tumors (median tumor size E: 16mm, CE: 20mm; p&amp;lt;0.001) and higher RS (median RS E: 16, CE: 21; p&amp;lt;0.001). With a median follow-up for survival since diagnosis of 3.7 years, the Kaplan-Meier estimated 5 yr overall survival rates were 98.9% with E and 97.8% with CE (p=0.23); the corresponding 5-yr OS in TRx were E: 98% and C: 98.1%. With a median 1.7 years follow-up for recurrence, 19 pts have suffered a disease distant or local recurrence (E: 13, CE: 6) yielding a 5-year recurrence-free survival of E: 95.2% and CE: 91% (p=0.05); the corresponding TRx result was E: 96.9% and CE: 97%. The 5-yr invasive disease-free survival (IDFS = death, local/distant, second primary) with 32 events was E: 92.7% and CE: 81.9% (p= 0.05); corresponding TRx E: 92.8 % and CE: 93.1%. Given the imbalance in treatment allocations, a multivariate analysis was performed, with older age (&amp;lt;0.001), CE choice (&amp;lt;0.006) and larger tumor size (p&amp;lt;0.05) remaining significant, but not increased RS (p=0.16) for 5-year IDFS. Among women age &amp;lt;50 with RS 16-25 (E: 118; CE: 60) the 5-yr IDFS was E: 95% and CE: 94%; the corresponding RS 16-20 TRx E: 92% and CE: 94.7% and RS 21-25 E: 86.3% and CE: 92.1%. Conclusions: Using a real world data source, endocrine therapy alone appears to yield excellent 5-yr survival rates among pts with 21-gene RS 11-25 similar to the TAILORx trial. Treatment selection bias (with perceived higher risk pts allocated to CE) and shorter median follow-up limits full confirmation by this dataset. Citation Format: Waintraub SE, Isaacs C, Norden AD, Graham DA, McNamara DM, O'Neill SC, Lakshmanan A, Wu T, Maresca A, Pecora AL, Goy AH, Goldberg SL. Confirmation of the TAILORx 21-gene expression trial using a real world observational database [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-05.

Concurrent versus sequential adjuvant chemo-endocrine therapy in hormone-receptor positive early stage breast cancer patients: a systematic review and meta-analysis

BackgroundAlthough in clinical practice adjuvant chemotherapy (CT) and endocrine therapy (ET) are administered sequentially in patients with hormone-receptor positive breast cancer, the optimal timing, i.e. concurrent or sequential administration, of these treatments has been scarcely investigated. To better clarify this issue we conducted a systematic review and meta-analysis of randomized studies comparing these two modalities of administrations in terms of disease-free survival (DFS) and overall survival (OS). MethodsRelevant studies were identified by searching PubMed, Web of Knowledge and the proceedings of the major conferences with no date restriction up to March 2016.The summary risk estimates (pooled hazard ratio [HR] and 95% confidence intervals [CI]) for DFS and OS were calculated using random effect models (DerSimonian and Laird method). ResultsA total of three randomized studies were eligible including 2021 breast cancer patients. Overall, 755 DFS events were observed, 365 in the sequential arm and 390 in the concomitant arm, with a pooled HR of 0.95 (95% CI = 0.76 to 1.18, P = 0.643).No association between timing of treatment and OS was observed (HR = 0.95; 95% CI = 0.80 to 1.12, P = 0.529). ConclusionOur pooled analysis showed no association between the timing of administration of adjuvant CT and ET and DFS and OS in breast cancer patients candidates for both adjuvant treatments. Because of the small number of published trials, the lack of data on the timing with modern adjuvant treatments, i.e. taxane-containing CT and aromatase inhibitors, this topic remain still controversial and requires further studies to be clarified.

F12 - Concurrent versus sequential adjuvant chemo-endocrine therapy in early stage hormone receptor-positive breast cancer patients: a systematic review and meta-analysis

F12 - Concurrent versus sequential adjuvant chemo-endocrine therapy in early stage hormone receptor-positive breast cancer patients: a systematic review and meta-analysis

Abstract P3-06-12: Predicting residual risk of recurrence after neoadjuvant chemotherapy- a retrospective analysis of EndoPredict® in the GeparTrio trial

Abstract Background: Patients (pts) with breast cancer who do not achieve a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) have a poor prognosis and might be candidates for post-neoadjuvant clinical trials investigating novel agents. The CPS-EG score (Mittendorf et al. JCO 2011) – a combination of clinical/pathological parameters - is currently used as criterion for selecting patients with highest risk of recurrence after NACT. Here, we examined whether the gene expression test EndoPredict (EP) performed on surgical specimen after NACT provides independent prognostic information for predicting the likelihood of recurrence in breast cancer patients with ER-positive, HER2-negative (ER+/HER2-) disease. Methods:The molecular EP score was determined by qRT-PCR in 76 available surgical specimen classified as ER+/HER2- from breast cancer pts with residual disease after NACT participating in the neoadjuvant GeparTrio trial. The pre-specified clinical/molecular hybrid score EPclin was determined using ypT and ypN after NACT as clinical variables. Patients were classified as having low or high risk according to pre-defined cut-off values. CPS-EG score was calculated based on stage before and after NACT and pretreatment grade and ER status. Primary endpoint was disease-free survival (DFS). Associations were assessed with uni- and multivariate Cox proportional hazard models. The unbiased c-index was estimated for common clinical/pathological parameters and EP/EPclin scores. Results: Among the 76 ER+/HER2- breast cancer pts evaluated, EP classified 50% of all pts (n=38) as low risk. EP high-risk patients had a significantly increased risk for relapse compared to the low-risk group (continuous EP HR 1.14 [95% CI 1.05-1.27] p-value 0.02; log-rank p=0.015). Multivariable Cox regression and unbiased c-index estimates (using EP and CPS-EG score as continuous variable) showed that the EP-score (HR 1.15 [95% CI 1.03-1.29 p=0.014] and CPS-EG (HR 1.51 [95% CI 1.07-2.13] p=0.019) provide independent prognostic information. Using the composite EPclin score 13 pts (17%) were classified as being EPclin low. The risk of relapse was significantly higher for EPclin high compared to low (continuous EPclin HR 1.78 [95% CI 1.29-2.46] p&amp;lt;0.001; log-rank p=0.047). Bivariate Cox regression analysis including the CPS-EG and EPclin score (both as continuous variables) showed that only EPclin (HR 1.63 [95% CI 1.14-2.31] p=0.0068) but not the CPS-EG (HR 1.25 [95%CI 0.85-2.31] p=0.26) was significantly associated with worse DFS. Results were similar for overall survival. Conclusions: Our study shows that EPclin performed on surgical specimen of ER+/HER2- pts after NACT is an independent predictor of recurrence in pts not achieving a pCR after NACT. EP/EPclin low risk patients are probably sufficiently treated with (neo-)adjuvant chemo-endocrine treatment alone, whereas EP(clin) high risk patients have an increased risk of recurrence, despite receiving standard (neo-)adjuvant chemo-endocrine therapy. The identification of molecular luminal high-risk patients could help to identify high risk patients as candidates for novel drug-based approaches in addition to endocrine therapy to overcome resistance in post-neoadjuvant trials. Citation Format: Sibylle Loibl, Jan C Brase, Stephan Gade, Jens Huober, Kristin Krappmann, Knut Engels, Falko Fend, Berit Maria Pfitzner, Joern Hilfrich, Christoph Thomssen, Hans Juergen Holzhausen, Silvia Darb-Esfahani, Christian Schem, Keyur Mehta, Ralf Kronenwett, Gunter von Minckwitz, Carsten Denkert. Predicting residual risk of recurrence after neoadjuvant chemotherapy- a retrospective analysis of EndoPredict® in the GeparTrio trial [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 P3-06-12.

Intrinsic subtype and its clinical significance in early node-negative breast cancer: Results from two randomized trials of adjuvant chemoendocrine therapy.

504 Background: Gene expression profiling has identified four main intrinsic subtypes of breast cancer which have distinct clinical behaviours and responses to therapy. A simplified immunohistochemical (IHC) panel can provide meaningful discrimination and help guide patient management. Methods: Using tissue microarrays (TMA) created from two randomized trials of adjuvant chemoendocrine therapy in node negative early breast cancer (IBCSG VIII and IX,n= 1220) we assessed intrinsic subtype as follows: “luminal A” (LA): ER and/or PR present, Ki-67 low (&lt;median: 19%), HER2-; “Luminal B” (LB): ER and/or PR present, Ki-67 high(&gt;=19% median) and/or HER2+ (IHC 3+ or FISH amplified); HER2 enriched: ER and PR negative, HER2 positive (IHC 3+ or FISH amplified), Triple Negative (TNP): ER, PR and HER2 negative. p53+ and high cyclin D1 expression were then assessed to determine if they provided any further additive discriminatory value. Results: The standard definitions of intrinsic subtype demonstrated a significant difference in disease-free survival between the subtypes in both trials VIII and IX (p= 0.02), but this was not significant in multivariate analysis. The discrimination between luminal A and B tumors could not be improved upon by the addition of p53 or cyclin D1 expression. The standard definitions demonstrated that TNP and HER2-enriched tumors benefited from the addition of chemotherapy to endocrine therapy, but LA and LB did not. p53+ was associated with a poorer prognosis in ER+ luminal tumors but improved prognosis in ER- non-luminal tumors (Interaction p = 0.002). Conclusions: Intrinsic subtyping using a panel of ER, PR, HER2 and Ki67 provides meaningful prognostic information to help guide patient management in early breast cancer. Whilst it predicts benefit from the addition of chemotherapy in TNP and HER2-enriched tumors it did not in this series do so for LB. Although p53 status did not improve the definition of luminal tumors, p53+ appeared to have a divergent effect on outcome dependent on ER status.

P2-12-26: Impact of the Recurrence Score on Adjuvant Decision-Making in ER-Positive Early Breast Cancer – Results of a Large Prospective Multicentre Decision Impact Study in Node Negative and Node Positive Disease.

Abstract Background Oncotype DX® has become part of clinical routine in the diagnosis and decision-making progress in early breast cancer (EBC). Prospective data on its clinical use and impact on treatment decisions in ER-positive (ER+) node negative (N0) disease from various controlled clinical trials in different countries have been published recently. The Recurrence Score® (RS) has also been validated as a prognostic and predictive marker for patients with ER+ node positive (N+) disease. As of today no prospective data have been reported on its impact on decision making in these patients. We performed a large prospective study to evaluate RS-guided adjuvant therapy in N0 and N+ ER+ EBC. Material and Methods: Patients (pts) with ER+, HER2−negative N0 and N+ (1-3 positive lymph nodes) EBC and no contraindication for adjuvant chemotherapy were included in the study. Physicians’ adjuvant treatment recommendations and their confidence in these as well as patients’ decisional conflicts were assessed before and after knowledge of the results of the test using standardized questionnaires. Actual treatment data were collected to perform pharmacoeconomic analyses. Analyses were performed on the per-protocol population for whom a Recurrence Score result and treatment recommendations pre and post-test were available. Results: Overall 379 pts were recruited. In 11 pts Oncotype DX could not be performed and 2 pts dropped out leaving 366 pts in the per protocol population. Of these, 244 (66.7%) were N0 and 122 (33.3%) N+. Median age was 56 years (Range 25–85). Overall, 54.1% had low, 38.0% intermediate and 7.9% high RS values. For N0 disease, the distribution of RSs was 53.7%, 38.9%, 7.4% and for N+ disease 54.9%, 36.9% and 9.0%, respectively. Initial treatment recommendation changed in 33.1% of all cases; 30.3% in N0 and 38.5% in N+ disease, and in 36.4% for pts with low, 30.9% with intermediate and 20.7% with high RSs. In 21.6% of all pts a recommendation for adjuvant chemoendocrine therapy (CHT) was changed to endocrine therapy (HT), 10.7% of recommendations changed from HT to CHT. For N0 disease change rates were 18.4% from CHT to HT and 11.5% from HT to CHT. For N+ disease 27.9% of recommendations changed from CHT to HT and 9.0% of recommendations changed from HT to CHT. In 25% of all, 22% of N0 and 39% of N+ pts initially recommended HT the post-RS recommendation changed to CHT; in 38% of all, 39% of N0 and 37% of N+ pts initially recommended CHT the recommendation changed to HT. Overall, physicians’ confidence increased in 45.1% of all (p=0.047) and 44.7 of N0 and 45.9% of N+ cases, respectively. There was a moderate decrease of the decisional conflict score in all pts and subgroups that reached statistical significance for all pts (p=0.029) and the low RS subgroup (p=0.003). Conclusions: Results of this large prospective study show an impact of the RS on adjuvant treatment decision making in German clinical practice for patients with ER+ EBC. Recommendations were predominantly changed from chemoendocrine to endocrine adjuvant therapy resulting in a net reduction of chemotherapy usage. This effect was more pronounced for patients with 1–3 positive nodes. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-26.

Increased fracture rate in women with breast cancer: a review of the hidden risk

BackgroundWomen with breast cancer, particularly individuals diagnosed at a relatively early age, have an increased incidence of fractures. Fractures can have serious clinical consequences including the need for major surgery, increased morbidity and mortality, increased cost of disease management, and reduced quality of life for patients. The primary cause of the increased fracture risk appears to be an accelerated decrease in bone mineral density (BMD) resulting from the loss of estrogenic signaling that occurs with most treatments for breast cancer, including aromatase inhibitors. However, factors other than BMD levels alone may influence treatment decisions to reduce fracture risk in this setting. Our purpose is to review current evidence for BMD loss and fracture risk during treatment for breast cancer and discuss pharmacologic means to reduce this risk.ResultsFracture risk during treatment for breast cancer may be influenced by the rate of BMD loss and the consequent rapid alterations in bone microarchitecture, in addition to the established fracture risk factors in postmenopausal osteoporosis. The rapid decrease in BMD during adjuvant chemoendocrine therapy for breast cancer may necessitate more aggressive pharmacotherapy than is indicated for healthy postmenopausal women who develop osteoporosis. Over the last few years, clinical trials have established the effectiveness of bisphosphonates and other antiresorptive agents to preserve BMD during adjuvant therapy for early breast cancer. In addition, some bisphosphonates (eg, zoledronic acid) may also delay disease recurrence in women with hormone-responsive tumors, thereby providing an adjuvant benefit in addition to preserving BMD and potentially preventing fractures.ConclusionsIt is likely that a combined fracture risk assessment (eg, as in the WHO FRAX algorithm) will more accurately identify both women with postmenopausal osteoporosis and women with breast cancer who require bone-protective therapy.