Preoperative Endocrine Prognostic Index Research Articles

Abstract PL2: Neoadjuvant Endocrine Therapy: The Times They are A-Changing

Abstract Neoadjuvant endocrine therapy (NET) in hormone-receptor positive breast cancers (HR+ BC) has been, in general, under-utilized, mostly because the majority of HR+ BC are diagnosed as stage I or II, and undergo surgical management as their first strategic step. However, NET is a suitable therapeutic choice for HR+ BC in cases where downsizing of the tumor is necessary (i.e. achievement of breast conservation). A seminal clinical trial comparing NET with neoadjuvant chemotherapy (NAC) in post-menopausal patients with HR+ BC revealed that the rates of overall response and breast conservation surgery were almost identical. NET also allows clinicians to infer prognosis based on simple pathologic characteristics: several clinical trials, including the phase III POETIC clinical trial (n=4486) showed that low Ki67 (less than 10%) at baseline and after 2 weeks had excellent long term outcome, whereas Ki67 larger than 10% at baseline and after 2 weeks had significantly worse long term outcome. Additionally, the Preoperative Endocrine Prognostic Index (PEPI), which is based on pathologic tumor size, node status, Ki67 level and ER status (Allred score) at the time of surgery, post NET, can accurately predict long term outcome. Interestingly, the early (about 2 weeks) Ki67 levels post NET has consistently predicted results of several phase III adjuvant or metastatic endocrine therapy trials (IMPACT - ATAC; Z1031 - MA-27) even in combination with targeted agents (LORELEI - SANDPIPER; NET + everolimus - BOLERO-2). Results of the ALTERNATE (A011106), a NET comparing AI with fulvestrant in post-menopausal patients with stage II and III HR+ BC is eagerly awaited, as it is bound to mimic the results of phase II and III trials comparing fulvestrant and AI in HR+ MBC (FIRST, FALCON, FACT, SWOG0226). Ultimately, these tools help clinicians decide if the addition of chemotherapy is necessary or not in patients with HR+ BC. Finally, NEC is an excellent tool in providing insights into the biologic basis of endocrine therapy efficacy (biomarkers of response and mechanisms of resistance studied in the post-treatment residual cancer). NET incorporating targeted therapies such as PI3K pathway inhibitors have yielded somewhat disappointing results compared to endocrine therapy alone (LORELEI, Neo-ORB), considering that PIK3CA mutations are the most common genomic alterations seen in HR+ BC. However, several ongoing trials of NET with CDK4/6 inhibitors were recently completed or are ongoing (NeoPalAna, NeoMONARCH, PALLET, PELOPS), and these trials may be instrumental not only in predicting the success of the large phase III adjuvant endocrine therapy with or without CDK4/6 inhibitors clinical trials. Ultimately, relatively small NET clinical trials could help with the design of more intelligent large clinical trials, providing the opportunity of residual tissue availability as a platform of discovery for biomarkers of sensitivity and resistance, an excellent platform for the development of investigational drugs and triaging of novel combinations. Citation Format: Mayer I. Neoadjuvant Endocrine Therapy: The Times They are A-Changing [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 PL2.

Abstract P4-14-07: Neoadjuvant exemestane or exemestane plus docetaxel and cyclophosphamide tailored by clinicopathological response to 8–12 weeks' exemestane exposure for ER+/HER2– postmenopausal breast cancer patients

Abstract Aim To investigate the efficacy and safety of initial neoadjuvant endocrine therapy with exemestane (EXE) alone followed by tailored treatment: continued EXE monotherapy for responders or EXE plus docetaxel–cyclophosphamide (TC) combination therapy for non-responders. Methods This open-label phase II study enrolled postmenopausal patients with primary invasive estrogen receptor (ER)-positive, HER2-negative, stage I–IIIA (T1c–T3 N0–2 M0) breast cancer and Ki67 index ≤30%. Patients first received EXE 25 mg/day for 12 weeks. Based on clinical response and change in Ki67 index, responders were defined as patients who achieved complete response (CR), partial response (PR) with Ki67 index ≤5% after treatment, or stable disease (SD) with Ki67 index ≤5% both before and after treatment. Non-responders were defined as patients with PR and Ki67 index >5% after treatment, or SD and Ki67 index >5% before or after treatment. For the subsequent 12 weeks, responders continued EXE monotherapy (continued EXE group) and non-responders received EXE plus 4 cycles of TC (docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks) (EXE+TC group). Primary endpoint was clinical response (CR and PR) at week 24. Results A total of 58 patients (median age 60 years, range 53–67 years) were enrolled between December 2010 and May 2016. Five patients discontinued treatment in the initial 12-week EXE monotherapy period; therefore 53 received the subsequent treatment. After 8–12 weeks of initial EXE monotherapy, 15 patients were classified as responders (8 with PR and Ki67 index ≤5% after treatment, 7 with SD and Ki67 index ≤5% before and after treatment) and 38 as non-responders (5 with PR and Ki67 index >5% after treatment, 33 with SD and Ki67 index >5% before or after treatment). Clinical response rates at weeks 12 and 24 were 71% (10/14, 95%CI 41.9–91.6%) and 57% (8/14, 95%CI 28.9–82.3%), respectively, in the continued EXE group, and 16% (4/25, 95%CI 4.5–36.1%) and 56% (14/25, 95%CI 34.9–75.6%), respectively, in the EXE+TC group. At week 24, no significant difference was found in median Ki67 index between the continued EXE and EXE+TC groups (1.4% and 2.0%, respectively). The proportion of patients with preoperative endocrine prognostic index (PEPI) 0 was higher in the continued EXE than in the EXE+TC group (60% vs 29%), but not significantly so (P=0.058, Fisher's exact test). The breast-conserving surgery rate was 93% and 56% (continued EXE and EXE+TC groups, respectively). Adverse events (AEs) ≥grade 3 were reported in 40% (21/53) of patients (continued EXE group 8%, 1/15; EXE+TC group 53%, 20/38). The most common AEs were leukopenia (37%, 14/38), neutropenia (32%, 12/38), and febrile neutropenia (16%, 6/38) during chemotherapy (EXE+TC group). Conclusion Tailored treatment maintained the favorable clinical response to EXE alone in responders and improved subsequent clinical response in non-responders. EXE+TC was associated with higher incidence of hematological AEs, but these were manageable. The results show the effectiveness of tailored neoadjuvant endocrine and chemoendocrine therapy in postmenopausal ER-positive breast cancer patients. (JBCRG-11TC; UMIN000004752) Citation Format: Yasojima H, Sato N, Masuda N, Morimoto T, Ueno T, Kanbayashi C, Kaneko K, Saji S, Sasano H, Morita S, Ohno S, Toi M. Neoadjuvant exemestane or exemestane plus docetaxel and cyclophosphamide tailored by clinicopathological response to 8–12 weeks' exemestane exposure for ER+/HER2– postmenopausal breast cancer patients [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 P4-14-07.

Changes in Recurrence Score by neoadjuvant endocrine therapy of breast cancer and their prognostic implication

BackgroundNeoadjuvant endocrine therapy (NET) can improve surgical outcomes in postmenopausal patients with hormone receptor-positive breast cancer. The Ki67 labelling index after NET has a better prognostic power than that at baseline. However, it remains unknown whether a multigene assay with post-treatment samples could predict the prognosis better than that with pretreatment samples.MethodsThe prognostic value of the multigene assay Oncotype DX Recurrence Score (RS) was investigated using pretreatment and post-treatment samples from a multicentre NET trial, JFMC34-0601 (UMIN C000000345), where exemestane was given at 25 mg/day for 24 weeks.ResultsBoth pretreatment and post-treatment RSs were significantly associated with disease-free survival (DFS) (p=0.005 and 0.002, respectively). The combination of pretreatment and post-treatment RSs was also a predictor of DFS (p=0.002) and superior to preoperative endocrine prognostic index (PEPI). Furthermore, combined RS was the only independent prognostic factor in the multivariate analysis among the three RSs (p=0.04). In addition, combined RS could differentiate early recurrence in the high-risk group from mid/late recurrence in the intermediate-risk group, suggesting possible differential treatment strategies based on the risk categories indicated by the combined RS.ConclusionsThe combination of pretreatment and post-treatment RSs could provide pivotal information for predicting DFS and differentiating early recurrence in the high-risk group from mid/late recurrence in the intermediate-risk group in patients with hormone receptor-positive breast cancer. A larger study is required to validate the results.

Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer

BackgroundPalbociclib is a CDK4/6 inhibitor with demonstrated efficacy and safety in combination with endocrine therapy in advanced luminal breast cancer (LBC). We evaluated the respective efficacy and safety of chemotherapy and letrozole–palbociclib (LETPAL) combination as neoadjuvant treatment in patients with high-risk LBC. Patients and methodsNeoPAL (UCBG10/4, NCT02400567) is a randomised, parallel, non-comparative phase II study. Patients with ER-positive, HER2-negative, Prosigna®-defined luminal B, or luminal A and node-positive, stage II–III breast cancer, not candidate for breast-conserving surgery, were randomly assigned to either letrozole (2.5 mg daily) and palbociclib (125 mg daily, 3 weeks/4) during 19 weeks, or to FEC100 (5FU 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2)×3 21-day courses followed by docetaxel 100 mg/m2×3 21-day courses. Primary end point was residual cancer burden (RCB 0–I rate). Secondary end points included clinical response, proliferation-based markers, and safety. ResultsOverall, 106 patients were randomised [median Prosigna® ROR Score 71 (22–93)]. RCB 0–I was observed in four and eight patients in LETPAL [7.7% (95% CI 0.4–14.9)] and chemotherapy [15.7% (95% CI 5.7–25.7)] arms, respectively. Pathological complete response rates were 3.8% and 5.9%. Clinical response (75%) and breast-conserving surgery rates (69%) were similar in both arms. Preoperative Endocrine Prognostic Index 0 scores (breast cancer-specific survival) were observed in 17.6% and 8.0% of patients in LETPAL and chemotherapy arms, respectively. Safety profile was as expected, with 2 versus 17 serious adverse events (including 11 grade 4 serious AEs in the chemotherapy arm). ConclusionLETPAL combination was associated with poor pathological response but encouraging clinical and biomarker responses in Prosigna®-defined high-risk LBC. Contemporary chemotherapy regimen was associated with poor pathological and biomarker responses, with a much less favourable safety profile. LETPAL combination might represent an alternative to chemotherapy in early high-risk LBC. Clinical Trial NumberNCT02400567.

Impact of combining the progesterone receptor and preoperative endocrine prognostic index (PEPI) as a prognostic factor after neoadjuvant endocrine therapy using aromatase inhibitors in postmenopausal ER positive and HER2 negative breast cancer.

The preoperative endocrine prognostic index (PEPI) predicts survival after neoadjuvant endocrine therapy (NAE) using aromatase inhibitors (AIs) for women with postmenopausal estrogen receptor (ER)-positive breast cancer irrespective of the human epidermal growth factor receptor 2 (HER2) status. Although the progesterone receptor (PgR) is also a prognostic factor for ER-positive breast cancer, the PgR status was not considered a prognostic factor in the original PEPI scoring system. In this study, we investigated the utility of a modified PEPI including the PgR status (PEPI-P) as a prognostic factor after NAE for postmenopausal patients with ER-positive and HER2-negative breast cancer. We enrolled 107 patients with invasive ER-positive and HER2-negative breast cancer treated with exemestane for ≥4 months as NAE. We initially assessed PEPI and compared survival between the groups. Additionally, we obtained an effective cutoff for PgR through survival analysis. Then, we assessed the survival significance of PEPI-P. A PgR staining rate of 50% was the most significant cutoff for predicting recurrence-free survival (RFS) and cancer-specific survival (CSS). PEPI was a significant prognostic factor; moreover, PEPI-P was the most significant prognostic indicator for RFS and CSS. PEPI-P is a potent prognostic indicator of survival after NAE using AIs for postmenopausal patients with ER-positive and HER2-negative breast cancer. This modified PEPI may be useful for therapeutic decision-making regarding postmenopausal ER-positive and HER2-negative breast cancer after NAE.

5-years RFS and prognostic factors study in HR-positive HER2-negative breast cancer patients treated with neoadjuvant endocrine therapy : Pooled analysis of two phase II trials

Background Few data are available on survival of breast cancer (BC) patients (pts) treated with neoadjuvant endocrine therapy (NET). Understanding how tumor response to NET is related to relapse risk would help clinicians make decisions about additional treatments for these pts. Methods The primary objective was to assess 5-years relapse-free survival (RFS) in previously published two sister phase II studies evaluating anastrozole and fulvestrant as NET in post-menopausal HR-positive/HER2-negative BC pts (CARMINA02 NCT00629616 ; HORGEN NCT00871858 ). Prognostic factors of RFS were explored by pooling the two databases : age ( 70), tumor and node staging, histological type and grade, clinical response, pathological response according to the Sataloff classification, baseline and surgical ER Allred score and Ki-67 expression, treatment arm, preoperative endocrine prognostic index (PEPI) score, adjuvant chemotherapy. The factor study (Horgen vs. Carmina02) was also introduced in the model as covariate. Univariate and multivariate Cox regression analysis (covariates from univariate model with P-value Results Intention-to-treat analysis is available for 217 of 236 pts included in the two trials. Post-menopausal pts with T2–T4, N0–N1, M0, HR-positive/HER2-negative BC were randomized to receive anastrozole (PO, 1 mg daily) or fulvestrant (IM, 500 mg on D1, D15 and D29 and then every 4 weeks) for 4 to 6 months before surgery. Mean age at diagnosis was 71.2 years. Baseline tumor characteristics were : 73.7 % T2, mean tumor size 44.3 mm, 66.4 % N0, 19.4 % SBR grade 1, 98.6 % ER Allred score 6-8, mean Ki67 score 17.5 % with Ki67 > 20 % in 29.5 % of cases. A clinical response (complete or partial) was observed in 50.2 % of pts and pathological response rate defined as TA or TB and NA or NB was 15.7 %. Mean Ki67 at surgery was 8.8 % (11.4 % of cases > 20 %). Among the pts, 12.4 % were classified in PEPI risk group I (risk score 0), 35.5 % in group II (score 1–3) and 30.4 % in group III (score > 4) (PEPI not available for 21.7 % of pts) ; 21.7 % of pts received adjuvant chemotherapy. Median follow-up is 65.2 months. RFS and overall survival at 5 years are 83.7 % [95 % CI : 77.9–88 %] and 92.7 [95 % CI : 88.2–95.6 %] respectively. On univariate analysis, tumor staging (T3–4 versus T2, P = 0.0001) and PEPI score (I + II versus III, P = 0.0004) are associated with RFS. So far, no relapses/death have been observed in pts with pathological response (n = 34, 15.7 %). Multivariate analysis (T, baseline Ki67, ER Allred score at surgery, PEPI and study) shows that PEPI group III is associated with significantly worse RFS (P = 0.0014, HR : 3.9 [95 % CI : 1.7–9.0]). Conclusion Post-menopausal HR-positive/HER2-negative BC pts receiving NET have a very favorable outcome. Within this population eligible for NET, the PEPI score identifies a subset of pts of poorer prognosis who are candidate for further additional treatment like chemo/or targeted therapies. The PEPI may be a tool routinely used for individualization of adjuvant treatment in NET setting. According to recent published studies, further analysis will be performed with Ki67 > 10 % and PEPI risk (group I versus groups II–III).

Using a Neoadjuvant Approach for Evaluating Novel Therapies for Patients With Breast Cancer.

Preoperative systemic therapy, though primarily used to downstage breast cancers, can offer, using pathologic complete response (pCR) as an endpoint, a rapid assessment of efficacy of a given therapeutic approach, particularly in triple-negative (TNBC) and HER2-positive breast cancers. Recently, this approach resulted in the approval of pertuzumab for HER2-positive cancers, in a considerably quicker timeline than would have been possible with its assessment in the adjuvant setting. However, the use of preoperative systemic therapy remains controversial, as the higher response rates noted with newer approaches have not routinely translated into improved longer-term outcomes, nor have they been confirmed in larger adjuvant trials. Almost all trials have demonstrated that pCR is a robust prognostic marker in patients with TNBC and HER2-positive cancers, so part of this discrepancy may be due to inadequate power in the preoperative trials and/or due to the heterogeneous nature of breast cancers. PCR following preoperative chemotherapy is not prognostic in many hormone receptor (HR)-positive breast cancers, especially those with a luminal A phenotype, which typically has minimal response to chemotherapy. Given this lack of response to chemotherapy, there is considerable interest in the use of neoadjuvant endocrine therapy (NET). The rate of pCR to NET in HR-positive cancers is low, leading to the use of surrogate markers, including changes in Ki-67 and the preoperative endocrine prognostic index (PEPI) score, as biomarkers of efficacy. Overall, the use of neoadjuvant approaches offers a rapid assessment of efficacy of novel therapies and remains a useful research tool for drug evaluation.

Current Status of Neoadjuvant Endocrine Therapy in Early Stage Breast Cancer.

Neoadjuvant endocrine therapy (NET) with Ki67-based response monitoring is a practical, cost-effective approach to the management of clinical stage II and III estrogen receptor-positive (ER+) breast cancer. In addition to marked improvements in rates of breast conservation, the identification of extreme responders on the basis of the preoperative endocrine prognostic index (PEPI) provides a rationale to avoid chemotherapy on the basis of highly favorable prognosis in some patients. Finally, samples accrued from patients treated with neoadjuvant therapy are providing valuable insights into the molecular basis for intrinsic resistance to endocrine therapy and promise a more rational basis and precise approach to the systemic treatment of ER+ breast cancer.

Abstract P4-12-04: Cost-effectiveness analysis of locally advanced estrogen receptor-positive, HER-2 negative breast cancer care using a tailored treatment approach in Brazil

Abstract Introduction: Breast cancer is the most common cancer in women worldwide, and 70% of breast cancer deaths occur in women from low-income and middle-income countries. In Brazil there were 14388 deaths due to this disease in 2013 and an estimate of over 58000 new cases in 2016. Neoadjuvant endocrine therapy (NET) is an attractive alternative to Neoadjuvant chemotherapy (NAC) for Hormone Receptor-positive tumors and could be a resources-saving strategy of treatment. Methods: We built a decision analysis model of breast cancer treatment to compare a NET schema, with response based on the evaluation of Ki-67, against the surgery followed by adjuvant chemotherapy (AC) and radiation therapy (RT) standard-of-care as two competing approaches to breast cancer management. Our objective is to determine whether tailoring chemotherapy treatment based on response to neoadjuvant endocrine therapy is a cost-effective approach. The NET schema is based on the ACOSOG Z1031B trial, in which post-menopausal women with estrogen receptor-positive, HER-2 negative disease would receive 4 weeks of NET followed by a core-needle biopsy for Ki-67 evaluation. If Ki-67 were lower than 10%, patients would continue in NET for 16-18 weeks followed by surgery and RT according to international guidelines. The indication of AC in these patients would be based on the preoperative endocrine prognostic index (PEPI). Patients with a PEPI score equal to zero would be spared from AC. If Ki-67>10%, patients would be triaged to NAC or surgery. The cost-effectiveness analysis was conducted using a Markov model from the provider's perspective, in this case the Brazilian Health ministry. Healthcare costs, in the form of charges from the hospitals to the health ministry, were obtained from cost tables available at the federal government's webpage. In the Markov model, possible health states were disease-free, local relapse, metastatic disease and death.Transition probabilities and mortality rates were extracted from randomized studies. Our assumptions were that both treatment strategies have similar clinical outcomes and that Ki-67 is a reliable method to triage patients to NAC or surgery. We performed one-way sensitivity analysis to assess the impact of the failure of the Ki-67 test on cost-effectiveness. Results: Our model shows that the NET schema dominates the standard-of-care strategy. Costs were R$ 47799.89 per patient for the NET strategy and R$79809.24 for the standard-of-care strategy. There was an incremental cost saving of R$32009.36 per patient for the NET strategy compared to the standard-of-care strategy. Cost-effectiveness of the NET strategy was R$2612.63 and R$4369.11 for the standard-of-care. Considering the willingness-to-pay of R$ 85494.00, defined by the World Health Organization as three times the gross domestic product per capita, the standard-of-care strategy would only be more cost-effective in the scenario of a Ki-67 test that misclassifies patients more than 9.1% of the time. Conclusion: The use of response to neoadjuvant endocrine treatment based on Ki-67 analysis as a way to tailor locally advanced breast cancer treatment is a cost-saving strategy in the presence of robust biomarkers. Citation Format: Goncalves R, Reinert T, Ellis MJ, Sarian LO, Filassi JR. Cost-effectiveness analysis of locally advanced estrogen receptor-positive, HER-2 negative breast cancer care using a tailored treatment approach in Brazil [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-12-04.

Abstract P3-13-06: Tailored neoadjuvant endocrine and chemo-endocrine therapy for postmenopausal patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative primary breast cancer

Abstract Aims We investigated the efficacy and safety of initial neoadjuvant endocrine therapy with exemestane (EXE) alone followed by subsequent tailored treatment with EXE alone for responders or EXE plus oral metronomic cyclophosphamide (CPA) for non-responders. Methods In this multicenter open-label phase II study, we enrolled postmenopausal patients with primary invasive estrogen receptor (ER)-positive, HER2-negative, stage I–IIIA (T1c–T3 N0–2 M0) breast cancer and Ki67 index ≤ 30%. Patients first received EXE 25mg/day for 12 weeks. Based on clinical response and change in Ki67 index in response to the initial therapy, patients who achieved complete response (CR), partial response (PR) with Ki67 index ≤5% after treatment, or stable disease (SD) with Ki67 index ≤5% both before and after treatment were defined as responders. Non-responders were defined as patients with PR and Ki67 index >5% after treatment, or SD and Ki67 index >5% before or after treatment. For the subsequent 24 weeks, responders continued the EXE monotherapy (continued EXE group), whereas non-responders switched to combination therapy with EXE plus CPA 50mg/day (EXE+CPA group). The primary endpoint was clinical response (CR and PR) at weeks 24 and 36. Results A total of 59 patients (median age 69 years, range 53–86 years) were enrolled between January 2011 and July 2015. After exclusion of 3 (2 with progressive disease, 1 with an adverse event, AE) who discontinued treatment in the initial 12-week EXE monotherapy period, 56 remained enrolled to receive subsequent treatment. After 8–12 weeks of the initial EXE monotherapy, 14 patients were classified as responders (9 with PR and Ki67 index ≤5% after treatment; 5 with SD and Ki67 index ≤5% before and after treatment), whereas 42 were classified as non-responders (3 with PR and Ki67 index >5% after treatment; 39 with SD and Ki67 index >5% before or after treatment). Clinical response rates at weeks 24 and 36 were 85% (12/14, 95%CI 57.2–98.2%) and 76% (10/13, 95%CI 46.2–95.0%), respectively, in the continued EXE group, and 56% (23/41, 95%CI 39.7–71.5%) and 76% (30/39, 95%CI 60.7–88.9%), respectively, in the EXE+CPA group. At week 36, no significant difference was found in median Ki67 index between the continued EXE and EXE+CPA groups (3.5% and 4.0%, respectively). The proportion of patients with preoperative endocrine prognostic index (PEPI) 0 was also similar between the continued EXE and EXE+CPA groups (21.4% and 23.8%, respectively). The breast-conserving surgery rate was 71.4% and 69.0%, respectively. Grade 3 AEs were elevated liver enzymes (1 patient) in the continued EXE group, and gastritis, hypertriglyceridemia, and bone mineral density loss (1 patient each) in the EXE+CPA group. Conclusion Switching from EXE monotherapy to EXE+CPA combination therapy based on clinical response and biological response (change in Ki67 index) to initial therapy improved subsequent clinical response in non-responders. Favorable clinical response to EXE alone was maintained in responders. Tailored neoadjuvant endocrine and chemo-endocrine therapy was shown to be effective in postmenopausal ER-positive breast cancer patients. (JBCRG-11CPA; UMIN000004751) Citation Format: Masuda N, Sato N, Morimoto T, Ueno T, Kanbayashi C, Kaneko K, Yasojima H, Saji S, Sasano H, Morita S, Ohno S, Toi M. Tailored neoadjuvant endocrine and chemo-endocrine therapy for postmenopausal patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative primary breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-13-06.

Impact of clinical response to neoadjuvant endocrine therapy on patient outcomes: a follow-up study of JFMC34-0601 multicentre prospective neoadjuvant endocrine trial

BackgroundNeoadjuvant endocrine therapy (NET) has been demonstrated to improve breast-conserving rate and is a widely accepted treatment option for postmenopausal patients with hormone receptor-positive breast cancer. There are few reports on the association of NET response and long-term outcomes.ObjectivesTo investigate the prognostic value of clinical response to NET.MethodsLong-term outcomes of NET were examined in 107 patients who participated in the multicentre prospective neoadjuvant exemestane study, JFMC34-0601. Patients were treated with 25 mg/day exemestane for 16 weeks followed by an 8-week extension depending on the treatment response.ResultsClinical response included partial response (PR) in 58 patients, stable disease in 41 patients and progressive disease (PD) in 8 patients. Clinical response was significantly associated with disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS) (P<0.0001 for all). Especially, patients with PD showed markedly poor outcomes with median DFS=17.8 months (HR (vs PR): 7.7 (95% CI 1.6 to 33)) and median OS=37.7 months (HR (vs PR): 26.3 (95% CI 2.4 to 655)). Preoperative endocrine prognostic index (PEPI) were associated with DFS and marginally with OS (P=0.022 and 0.066, respectively). PEPI=0 indicated an excellent prognosis with 95% 5-year DFS (95% CI 73 to 99). In the multivariate analysis including T stage, nodal status and Ki67, clinical response was an independent prognostic factor for DFS, DDFS and OS (P=0.032, 0.0007 and 0.020, respectively), whereas PEPI was marginally associated with DFS and OS (P=0.079 and 0.068, respectively).ConclusionsClinical response to NET showed an independent prognostic value. Patients with PD had markedly poor prognosis, indicating a need of additional therapy. PEPI=0 indicated an excellent prognosis. The integration of clinical response and PEPI would improve decision-making with regard to treatment options for endocrine-responsive breast cancer when these results are validated in a larger clinical trial.Trial registration numberUMIN C000000345.

Abstract IA23: Lessons for ER+ breast cancer from neoadjuvant endocrine therapy trials

Abstract For postmenopausal women with clinical stage II/III estrogen receptor positive (ER+) breast cancer, neoadjuvant endocrine therapy (NET) is an underutilized and low-toxicity alternative to chemotherapy for increasing breast conservation rates (1). Several studies from a decade or more ago showed marked improvements in breast conservation after 3 to 4 months of treatment with an aromatase inhibitor with a 50% reduction in the mastectomy rate in patients designated for a mastectomy at presentation. More recently the American College of Surgeons Oncology Group (ACOSOG) Z1031 study confirmed that for patients who are told they need a mastectomy, about half can undergo successful breast-conserving surgery after 16 to 18 weeks of AI treatment (2). Improvements in surgical outcomes are not the only advantage of NET since individual responses to endocrine therapy can be used to tailor patient treatment. The Preoperative Endocrine Prognostic Index (PEPI) was developed to identify extreme responders to NET such that subsequent management could be modified to avoid chemotherapy in a population at low risk of relapse post NET (3). Z1031 therefore provided an opportunity to further evaluate the PEPI. This study was run in two phases, Z1031A enrolled postmenopausal women with stage II/III ER+ (Allred 6 to 8) breast cancer (BC) whose treatment was randomized to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For Z1031B the protocol was amended to include a tumor Ki67 determination after 2-4 weeks of AI. If the Ki67 was &amp;gt;10%, patients were switched to neoadjuvant chemotherapy because the chance of a PEPI=0 score (best prognostic group) is very low in this subpopulation. A pCR rate of &amp;gt;20% was the predefined efficacy threshold. Only two of the 35 patients on Z1031B switched to neoadjuvant chemotherapy experienced a pCR (5.7%, 95%CI: 0.7-19.1%). After 5.5 years of median follow-up, 4 of the 109 (3.7%) patients with a PEPI=0 score relapsed versus 49 of 341 (14.4%) PEPI&amp;gt;0 patients, recurrence hazard ratio (PEPI=0/PEPI&amp;gt;0) = 0.27 (p=0.014; 95%CI: 0.092-0.764). Chemotherapy efficacy was therefore lower than expected in ER+ tumors exhibiting AI-resistant proliferation. For patients with PEPI=0 disease the relapse risk over 5 years was only 3.6% without chemotherapy supporting the study of adjuvant endocrine monotherapy in this group (4). These Ki67 and PEPI triage approaches are being definitively studied in new studies. In particular, new approaches are needed for the poor responders given the low efficacy of chemotherapy. Preliminary studies demonstrate that tumors that exhibit AI-resistant proliferation in the neoadjuvant setting often remain sensitive to CDK4/6 inhibition (5). Serial Ki67 monitoring could logically be considered as an approach to tailored use of adjuvant CDK4/6i treatment. Finally, serial sampling of the tumor inherent in the PEPI approach allows us to study of the genomic evolution of the tumor and to identify new therapeutic targets (6) and monitor tumor evolution in response to AI therapy (7).

Lessons in precision oncology from neoadjuvant endocrine therapy trials in ER+ breast cancer

For post-menopausal women with clinical stage II/III estrogen receptor positive (ER+) breast cancer neoadjuvant endocrine therapy (NET) is an under-utilized and low-toxicity alternative to chemotherapy for increasing breast conservation rates. Individual responses to endocrine therapy can also be used to tailor systemic treatment. The Preoperative Endocrine Prognostic Index (PEPI) was developed to identify patients at low risk of relapse after NET so that adjuvant chemotherapy can safely be avoided. In a recent validation study, patients with pathological stage 1 or 2A breast cancers with a Ki67 value of 2.7% or less in the surgical specimen (PEPI = 0) after 16–18 weeks of aromatase inhibitor therapy had a 97% disease free survival after 5.5 years of median follow up. Two approaches are currently underway to extend the PEPI model. The first is to determine whether fulvestrant increases the PEPI-0 rate versus anastrozole, as this would increase the number of patients who could be safely managed without adjuvant chemotherapy. The second is to develop new approaches for tumors that exhibit endocrine therapy resistance identified during NET. Preliminary studies demonstrate that tumors that exhibit AI resistant proliferation in the neoadjuvant setting is often sensitive to palbociclib, a CDK4/6 inhibitor. Serial Ki67 monitoring before surgery is therefore logical approach to tailored use of adjuvant CDK4/6i adjuvant treatment. Finally serial sampling of the tumor inherent in the PEPI approach facilitates the identification of new therapeutic targets, mechanisms of resistance and monitoring of tumor evolution in response to AI therapy.

Development of a Ki-67-based clinical trial assay for neoadjuvant endocrine therapy response monitoring in breast cancer

PurposeThe recent publication of the ACOSOG Z1031 trial results demonstrated that Ki-67 proliferation marker-based neoadjuvant endocrine therapy response monitoring could be used for tailoring the use of adjuvant chemotherapy in ER+HER2-negative breast cancer patients. In this paper, we describe the development of the Ki-67 clinical trial assay used for this study.MethodsKi-67 assay assessment focused on reproducing a 2.7% Ki-67 cut-point (CP) required for calculating the Preoperative Endocrine Prognostic Index and a 10% CP for poor endocrine therapy response identification within the first month of neoadjuvant endocrine treatment. Image analysis was assessed to increase the efficiency of the scoring process. Clinical outcome concordance for two independent Ki-67 scores was the primary performance metric.ResultsDiscordant scores led to a triage approach where cases with complex histological features that software algorithms could not resolve were flagged for visual point counting (17%). The final Ki-67 scoring approach was run on T1/2 N0 cases from the P024 and POL trials (N = 58). The percent positive agreement for the 2.7% CP was 87.5% (95% CI 61.7–98.5%); percent negative agreement 88.9% (95% CI: 65.3–98.6%). Minor discordance did not affect the ability to predict similar relapse-free outcomes (Log-Rank P = 0.044 and P = 0.055). The data for the 10% early triage CP in the POL trial were similar (N = 66), the percentage positive agreement was 100%, and percent negative agreement 93.55% (95% CI: 78.58–99.21%). The independent survival predictions were concordant (Log-rank P = 0.0001 and P = 0.01).ConclusionsWe have developed an efficient and reproducible Ki-67 scoring system that was approved by the Clinical Trials Evaluation Program for NCI-supported neoadjuvant endocrine therapy trials. Using the methodology described here, investigators are able to identify a subgroup of patients with ER+HER2-negative breast cancer that can be safely managed without the need of adjuvant chemotherapy.

Abstract P2-10-01: Genomic profiling of residual ER+ breast cancers treated with prolonged neoadjuvant letrozole reveals novel alterations in clinically resistant tumors

Abstract Background: Approximately 20% of patients with early ER+ breast cancer (BC) treated with adjuvant antiestrogen therapy eventually relapse with endocrine-resistant metastatic disease. We hypothesized that profiling newly diagnosed ER+ BC that persist following prolonged estradiol deprivation with letrozole would identify genomic alterations associated with endocrine resistance. Methods: We treated 57 postmenopausal women (median 77 years; range 60-86) with ER+/HER2– BC with neoadjuvant letrozole (median 7.5 months; range 3-36) followed by surgery and adjuvant endocrine therapy. Patients were followed with serial ultrasounds and defined as non-responders if they developed recurrent locally or metastatic disease, or had a preoperative endocrine prognostic index (PEPI) ≥4 (composite score of post-treatment ER, Ki67, T and N status). Post-treatment specimens were profiled by RNA-seq and targeted capture NGS of &amp;gt;300 cancer-related genes. We screened for variants with a high probability of disrupting protein function (GERP score &amp;gt;4) and excluded likely germline variants by filtering out every alteration not present in COSMIC, if the variant had an allele frequency &amp;gt;0.1% as per the ExAC dataset. Results: Ten patients (17.5%) had a PEPI 0 score, 31 (54%) were PEPI 1-3, and 16 (28%) were PEPI ≥4. After a median follow-up of 50 months (12-100), 9 patients (15.7%) had recurred with metastatic disease (4 with PEPI 1-3, 5 with PEPI ≥4). We identified 294 variants with a median coverage &amp;gt;250x (206 nonsynonymous, 21 nonsense, 58 indels, 8 splice site). Recurrent mutations included PIK3CA (38%), KMT2C (28%), CDH1 (15%), NF1 (12 %), TP53 (10%), MAP3K1 (7%), ERBB2 (7%) and ESR1 (5%). Recurrent amplifications were identified in MCL1 (31%), GNAS (19%), CCND1 (16%), FYN (14%), AURKA (12%), and ERBB2 (10%), while recurrent deletions were found in DUSP4 (12%), NCOR1 (8%) and NF1 (6%). Compared to alterations reported in untreated ER+ breast cancers in TCGA, we observed a significant increase in KMT2C, NF1, MCL1 and FYN alterations (FDR&amp;lt;0.05). MCL1, GNAS and FYN amplifications, DUSP4 deletions, MAP3K1 mutations, and ERBB2 and NF1 alterations were enriched in the non-responder group. Differential expression analysis of the RNA-seq data revealed an enrichment of E2F and MYC target genes, and genes involved in the G2/M checkpoint, TORC1 signaling, EMT and immunosuppression in non-responding tumors. PEPI 0 tumors were enriched with Luminal A subtype tumors, whereas PEPI 4 tumors were enriched with Luminal B, basal and HER2-enriched subtypes. Luminal A tumors exhibited improved disease free survival compared to other subtypes (HR 0.28, 95% CI 0.10-0.64). Gains in the proximal portion of chromosome 1q were associated with poor long-term outcomes as the relapse-free survival rate at 40 months for patients with 1q gains was 89% versus 41% for patients with no 1q gain (p=0.001). Conclusions: Genomic profiling of residual ER+ breast cancers treated with prolonged neoadjuvant letrozole revealed a different mutational landscape than primary untreated ER+ BC. These alterations may be associated with poor response to estrogen deprivation in early breast cancer and deserve further study. Citation Format: Guerrero AL, Stricker T, Hutchinson KE, Formisano L, Giltnane J, Fidalgo A, Schwarz LJ, Gavila J, Guillen V, Lluch A, Ruiz A, Arteaga CL. Genomic profiling of residual ER+ breast cancers treated with prolonged neoadjuvant letrozole reveals novel alterations in clinically resistant tumors [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 P2-10-01.

Abstract OT3-02-06: Femara plus ribociclib or placebo as neo-adjuvant endocrine therapy for women with ER+, HER2-negative early breast cancer - The Feline trial

Abstract Background: In early ER+ breast cancer, neo-adjuvant (NA) endocrine therapy (ET) may identify a subset of patients with endocrine sensitive disease with excellent outcomes without chemotherapy. In patients receiving a NA aromatase inhibitor, on- therapy, short term (day 14) Ki-67 of &amp;lt;10% and post NA pre-operative endocrine prognostic index (PEPI) 0 at surgery are associated with low relapse rates without chemotherapy. Ribociclib, a novel CDK4/6 inhibitor is active in ER+ metastatic breast cancer. We hypothesize that ribociclib+letrozole as NA ET for stage II-III breast cancer will increase the number of women with a PEPI 0 at surgery. Trial Design: Randomized, placebo-controlled, multi-center, phase II, investigator initiated trial of NA letrozole +/- ribociclib in postmenopausal women with ER+, HER2-, breast cancer. Subjects will be randomized 1:1:1 to letrozole 2.5 mg daily + placebo, letrozole 2.5mg daily + ribociclib 600mg daily on D1-21 of a 28 day cycle (intermittent dosing), or letrozole 2.5mg daily + ribociclib 400mg daily (continuous dosing). Treatment will be continued for 6 months followed by surgery. Research core biopsies and blood will be collected at baseline, at day 14, and at surgery. A Ki67 &amp;gt;10% at day 14 will result in discontinuation of the subject from the protocol as this may be an early indicator of resistance to endocrine therapy. An MRI will be done after 2 months of therapy to assess response/progression. Primary endpoint is a PEPI score of 0 at surgery. Key Eligibility Criteria: Postmenopausal (natural or surgical) women with stage II/III ER+, HER2- breast cancer. Must have a palpable breast mass of at least 2 cm. Multicentric/contralateral invasive disease not allowed. Ipsilateral/contralateral DCIS is allowed. Inflammatory breast cancer is excluded. Specific Aims: Primary objective: To determine if ribociclib+letrozole as a 24 week NA ET increases rate of PEPI score of 0 at surgery compared to letrozole. Secondary objectives: To determine if ribociclib+letrozole as a 24 week NA ET increases the proportion of tumors with complete cell cycle arrest compared to letrozole; to determine if ribociclib in combination with letrozole for 24 weeks results in improved 5 year RFS compared to letrozole; to examine differences in response rates between the two ribociclib containing arms vs letrozole. Statistical Methods: The two ribocilib containing arms (n=80) will be combined for analysis against placebo + letrozole (n=40). Assuming that addition of ribociclib will increase the rate of PEPI 0 by 20%, and setting Type I error rate at 10% and Type II error rates at 20% in the final analysis, a sample size of 80 women in the treatment arms (40 in each arm) and 40 women in the control arm are needed to show significance. Patient accrual and target accrual: Participating sites include The Univ of Kansas Med Ctr, City of Hope National Med Ctr, Massachusetts General Hospital, University of Miami Sylvester Comprehensive Cancer Ctr, University of Arkansas for Medical Sciences, and University of Wisconsin. The trial has accrued 16 patients with a target accrual of 120 patients. Accrual should be complete in 2/2017. Contact information: Qamar Khan, MD (qkhan@kumc.edu). Citation Format: Khan QJ, Prochaska LH, Mohammad J, Yuan Y, O'Dea A, Bardia A, Wisinski K, Hard M, Baccaray S, Makhoul I, Wagner J, Laura S, Ma C, Sharma P. Femara plus ribociclib or placebo as neo-adjuvant endocrine therapy for women with ER+, HER2-negative early breast cancer - The Feline trial [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 OT3-02-06.

Abstract P4-01-03: Predictive value of FDG-PET/CT after neoadjuvant endocrine treatment in breast cancer

Abstract Background: Neaodjuvant endocrine therapy (NET) has demonstrated efficacy in terms of clinical response and outcome in hormone-receptor positive (HR+) post-menopausal patients (pts) with breast cancer (BC) not eligible for primary breast conservative surgery (BCS). However, the monitoring of tumor response to NET is challenging and clinical response is the current gold standard. The aim of the present study was to investigate the contribution of the early metabolic response (eMR) at one month in FDG-PET/CT in a NET setting for post-menopausal pts with HR+, HER2- BC compared to morphological and pathological responses. We also aimed to evaluate the prognostic value of eMR. Methods: This was a prospective and ancillary study of CARMINA 02, UCBG0609 (Cancer in press), a phase II clinical trial evaluating the efficacy of 4 to 6 months neoadjuvant anastrozole or fulvestrant. FDG-PET/CT exams were performed at baseline (M0), after 1 month of treatment (M1: eMR) and pre-Op (late metabolic response: lMR) in 11 pts (74.2 years ± 3.6) from 2007 to 2010. Pts were classified “metabolic responders” (mR) if SUVmax values decrease was ≥ 40% at M1 and “non-metabolic responders” (mNR) if otherwise; lMR was also assessed in mR and mNR groups defined at M1. We compared eMR to morphological response (clinical, breast US and MRI) at M1 and pre-op, to the pathological response according to Sataloff classification and to Ki67 score variation during treatment. Early metabolic response was also correlated with the PEPI (Preoperative Endocrine Prognostic Index) score and survival (overall survival, OS and relapse free survival, RFS). Results: Main results are summarized in Table I. There was a significant difference between mR and mNR pts at M1 (eMR) and pre-op (lMR). One patient with a complete metabolic response at pre-op had the best pathological response (Sataloff TB). Also, mR pts had a better clinical response: 2 partial response (PR) in mR vs 1 in mNR group and 2 mNR patients were classified PD (progressive disease). There was a trend toward better survival for mR pts in OS and RFS (Kaplan-Meier p=0.18 and 0.06, respectively) and all the pejorative events occurred in the mNR group: 3 deaths and 3 metastatic progressions. Besides, no difference in eMR was observed regarding the histological subtype (ductal or lobular; p&amp;gt;0.05) nor the treatment group (p&amp;gt;0.05). Table I: Metabolic, morphological and pathological response at M1, Pre-Op and on the surgical specimen. MR : 5ptsmNR : 6ptsP valueM1SUVmax2.6±1.13.9±1.40.00017 Clinical size42.5mm±11.951.7mm±7.50.19 US size22.6mm±6.334.2mm±2.40.02 MRI size21.2mm±4.239.7mm±4.79.16 E-5 Ki 673.6%±1.98.2%±80.19Pre-OpSUVmax2±1.33.3±1.40.018 Clinical size31mm±12.448.3mm±10.80.035 US size18.5mm±7.331.3mm±9.50.07 MRI size17.9mm±7.134.8mm±7.70.003Surgical SpecimenSataloff (TA+TB vs TC+TD)20% vs 80%0 vs 100%1 PEPI score (I+II vs III)80% vs 20%33 vs 67%0.048 Ki 678.6%±9.812.3%±7.90.41 Conclusions: These preliminary results showed the value of the early metabolic response in FDG- PET/CT in a NET setting compared to the morphological or the pathological responses alone. Early metabolic responders patients had better OS, RFS and PEPI scores. Citation Format: Boughdad S, Champion L, Becette V, Cherel P, Fourme E, Edeline V, Lemonnier J, Lerebours F, Alberini JL. Predictive value of FDG-PET/CT after neoadjuvant endocrine treatment in 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 P4-01-03.

Abstract P5-13-05: The relationship between the expression of FOXA1 and GATA3 and the efficacy of neoadjuvant endocrine therapy

Abstract Background. The estrogen receptor (ER)/ GATA3/ Forkhead box A1 (FOXA1) network is necessary for the ERα functional signature specific to luminal type breast cancers. High expression of FOXA1 indicates a good prognosis in ER-positive breast cancer. However, little is known about the association between the expression of FOXA1 and GATA3, and the efficacy of neoadjuvant endocrine therapy (NAE). This study investigated their predictive potential for NAE and the changes of their expression after NAE. Methods. The expression of ER, progesterone receptor (PgR), Ki67, FOXA1, and GATA3 were analyzed by immunohistochemistry in 66 patients with hormone receptor-positive/ human epidermal growth factor receptor 2 (HER2)-negative breast cancer who had been treated with NAE between March 2003 and December 2012 at Kyushu University Hospital, National Kyushu Cancer Center, and Sagara Hospital. The association between the expression of biological marker and the efficacy of NAE, and their expression changes after NAE were evaluated. Results. The median age of the patients was 60 years (range, 30–84 years). Pre- and post-menopausal patients were 24 (36.4%) and 42 (63.6%). Endocrine agents that were administered are as follows: aromatase inhibitors (AIs) for 42 patients (63.6%), luteinizing hormone-releasing hormone (LHRH) agonist plus AI for 10 patients (15.2%), LHRH agonist plus tamoxifen for 13 patients (19.7%). NAE yielded a partial response (PR) in 21 patients (31.8%) and stable disease (SD) in 45 patients (68.2%). Breast conserving surgery was performed in 56 patients (84.8%) and mastectomy was performed in 10 patients (15.2%). Preoperative Endocrine Prognostic Index (PEPI) score was 0 in 10 patients (15.2%) and 1 or greater (score 1 ≤) in 56 patients (84.8%). Pre-treatment FOXA1 expression was positively correlated with GATA3 (P = 0.0003) and PgR (P = 0.0138). Post-treatment Ki67 expression was significantly lower in tumors, which achieved PR compared with those with SD (P = 0.0007). The expression of PgR, Ki67, and FOXA1 was significantly lower in post-treatment tumors compared with those in pre-treatment samples (p &amp;lt; 0.0001, p &amp;lt; 0.0001 and p &amp;lt; 0.0001, respectively). The expression of PgR, Ki67, and FOXA1 was significantly reduced in both tumors with PR and those with SD (PR: P = 0.0004, P &amp;lt; 0.0001, and P = 0.0417, respectively; SD: P &amp;lt; 0.0001, P = 0.0001, and P &amp;lt; 0.0001, respectively). The expression of PgR, Ki67, and FOXA1 was significantly decreased in post-treatment tumors in both patients with the PEPI score 0 and those with score 1 ≤ (score 0: P = 0.0078, P = 0.0059, and P = 0.0098, respectively; score 1 ≤: P &amp;lt; 0.0001, P &amp;lt; 0.0001, and P = 0.0002, respectively). In tumors with PgR &amp;gt; 20%, the expression of Ki67 and FOXA1 were significantly lower in post-treatment tumors (P &amp;lt; 0.0001 and P &amp;lt; 0.0001, respectively). Conclusions. FOXA1 expression correlated with PgR expression, and was reduced significantly after NAE. These results suggest that blocking the effect of estrogen might reduce FOXA1 expression. Citation Format: Tanaka K, Tokunaga E, Inoue Y, Ueo H, Yamashita N, Sagara Y, Ohi Y, Taguchi K, Ohno S, Okano S, Kitao H, Oki E, Oda Y, Maehara Y. The relationship between the expression of FOXA1 and GATA3 and the efficacy of neoadjuvant endocrine therapy. [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 P5-13-05.

Abstract P5-13-06: Concurrent gonadotropin-releasing hormone (GnRH) agonist administration with chemotherapy improves neoadjuvant chemotherapy responses in young premenopausal breast cancer patients

Abstract Background Gonadotropin-releasing hormone (GnRH) agonist therapy for ovarian function preservation shows promising results. This study aimed to determine the oncologic efficacy of GnRH agonist treatment concurrent with chemotherapy in a neoadjuvant setting. Patients and Methods A retrospective analysis was performed on 332 cases of invasive breast cancer in patients who were &amp;lt;40 years old at diagnosis and received GnRH agonists concurrent with neoadjuvant chemotherapy (GnRH agonist group) or neoadjuvant chemotherapy alone (neochemotherapy-alone group) at Asan Medical Center from December 2010 to September 2014. Pathologic complete response rates (pCR) and Ki-67 changes were evaluated between the two groups. For hormone receptor (HR)-positive tumors, the clinical response and preoperative endocrine prognostic index (PEPI) score also were evaluated. Results The median age was 32 ± 3.9 and 36 ± 3.0 years old in the GnRH agonist group and neochemotherapy-alone group, respectively (P &amp;lt; .001). Adjusted for tumor size, grade, lymph node metastasis, HR status, and chemotherapy regimen, the GnRH agonist group exhibited a higher pCR rate with an odds ratio (OR) of 2.98 (95% CI, 1.37–6.34) and more decreased Ki-67 expression during treatment (P = 0.05) than the neochemotherapy-alone group. In HR-negative tumors, the GnRH agonist group showed a higher pCR rate (multivariate OR = 3.50; 95% CI, 1.37–8.95) and more decreased Ki-67 expression (P = 0.047). In HR-positive breast cancer, the pCR rate, change in Ki-67 index, and clinical response were higher and preoperative prognostic index (PEPI) scores were lower in the GnRH agonist group, but not significant between the two treatment groups. Conclusion Concurrent administration of GnRH agonists during neoadjuvant chemotherapy improved pCR rates and suppressed Ki-67 expression especially in HR-negative tumors. Citation Format: Yoon TI, Kim HJ, Yu JH, Sohn G, Ko BS, Lee JW, Son BH, Ahn SH. Concurrent gonadotropin-releasing hormone (GnRH) agonist administration with chemotherapy improves neoadjuvant chemotherapy responses in young premenopausal breast cancer patients. [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 P5-13-06.

Abstract ES7-1: Neoadjuvant endocrine therapy

Abstract Neoadjuvant endocrine therapy has become a standard approach in clinical practice to improve the chance of breast conservation in postmenopausal women with locally advanced estrogen receptor positive breast cancer based on results from several neoadjuvant endocrine trials. Although data is limited, neoadjuvant endocrine therapy appears to as effective as chemotherapy in converting mastectomy to lumpectomy. In addition, neoadjuvant endocrine therapy allows an early assessement of tumor responsiveness to endocrine therapy so that adjuvant treatments could be tailored accordingly. Persistent cell proliferation on neoadjuvant endocrine therapy predicts a high risk of early relapse, for whom novel treatment strategies are in great need. In contrast, the Preoperative Endocrine Prognostic Index score of 0 (pathologic T2/3 N0 Ki67 &amp;lt;2.7% ER+) in response to neoadjuvant endocrine therapy is being prospectively evaluated in the ongoing Alliance A011106 (ALTERNATE) as a marker of endocrine sensitive disease, for whom chemotherapy could be avoided. Furthermore, neoadjuvant endocrine trials provide a unique research platform for biomarker studies and the testing of novel therapeutic hypothesis. Citation Format: Ma CX. Neoadjuvant endocrine therapy. [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 ES7-1.