Preoperative Endocrine Research Articles

Preoperative concurrent endocrine therapy with chemotherapy in luminal B-like breast cancer.

Luminal B-like breast cancer is sensitive to both chemotherapy and endocrine therapy. We aimed to assess the safety and efficacy of concomitant chemotherapy and endocrine therapy compared with chemotherapy alone in the preoperative setting in luminal B-like breast cancer. This two-arm randomized clinical trial enrolled patients with luminal B-like human epithelial growth factor 2-negative breast cancer, who were randomly assigned at a 1:1 ratio to receive preoperative chemotherapy alone or preoperative endocrine therapy concurrent with chemotherapy for 24weeks before surgery. The primary endpoint was the pathological complete response (pCR) rate. The secondary endpoints included the clinical response rate, toxicity, and health-related quality of life (HRQOL). Overall, 70 patients were randomly assigned to the chemotherapy and chemo-endocrine therapy groups. The pCR rates were 9.7% and 3.0% (P = 0.319), and the clinical complete response rates were 5.9% and 5.6% (P = 0.745) in the chemotherapy and chemo-endocrine therapy groups, respectively. There were no clear differences in treatment-related adverse events or HRQOL between the two groups. In patients with luminal B-like breast cancer, the pCR, clinical response rate, toxicity, and HRQOL with the concomitant administration of endocrine therapy and chemotherapy were not superior to chemotherapy alone in the preoperative setting.

Abstract P6-16-06: Improved early stratification of invasive cancer risk using MRI in a ductal carcinoma in-situ short-term active surveillance cohort treated with neoadjuvant endocrine therapy

Abstract Purpose Standard treatment for ductal carcinoma in situ (DCIS) involves surgical excision and radiation treatment, and often adjuvant endocrine therapy (ET). However, this may constitute overtreatment for some women. The purpose of this neoadjuvant ET study in patients with biopsy-proven DCIS was to evaluate the relationship between the primary outcome of upstaging at surgery (invasive disease) and changes in the pre- and post-ET MRI appearances of both (1) lesion and (2) background parenchymal enhancement (BPE), with the goal to better inform de-escalated therapy. Methods Outcomes of patients with DCIS who were prospectively enrolled in a neoadjuvant ET trial between 2002 and 2009 were retrospectively analyzed with IRB approval. All patients had dynamic contrast-enhanced breast MRI prior to and following an average of 3.1 months of ET (range 1.9 – 5 months), followed by surgical excision within one year of the second MRI. Pathology reports were used to confirm initial biopsy results and to determine the nature and extent of disease postoperatively. Surgeon and radiologist’s reports were used to assess improvement of lesion after ET based on 1) less prominently enhancing pattern or 2) reduction in size of DCIS lesion after treatment. BPE response to ET on imaging was assessed by two radiologists specialized in breast imaging who compared pre- and post-ET MRI’s, blinded to all imaging reports. The change in BPE of the ipsilateral breast with treatment was scored subjectively as increased, decreased, or unchanged. Readers reached a consensus on discordant classifications of the change in BPE. The correlation between imaging change (of lesion and BPE) and incidence of invasive ductal carcinoma (IDC) at surgery was determined using Fisher’s exact test. Results: Of 34 patients evaluated, six (18%) had IDC at surgery. The prevalence of IDC in each group is shown in Table 2. Those with improvement of lesion on MRI had a lower likelihood of IDC at surgery compared to patients with no imaging improvement (Table 2, p= 0.048). Addition of change in BPE to the evaluation of lesion improvement significantly increased the chance of identifying specific patients who were much more likely to have an underlying invasive cancer at surgery (Table 2, p= 0.032). The risk of having IDC at surgery was considerably higher in the group whose lesion was assessed as not improved and who had decreased BPE scores on MRI (Table 2, p= 0.018). Conclusion: In our unique population of patients with mostly ER+ DCIS receiving pre-operative endocrine therapy, the combination of lack of lesion improvement and reduction in BPE score in blinded reads was significantly associated with the finding of invasive disease at surgical excision. This result may reflect the unmasking of a more aggressive lesion in those with underlying IDC and help identify patients with a higher likelihood of the presence of IDC at surgery. Although this study is small, it suggests that risk-stratifying patients with DCIS based on lesion and parenchymal imaging features associated with treatment response may aid in tailoring therapy for DCIS. We are testing this prospectively in an active surveillance cohort. Table 1. Incidence of IDC at surgery depending on image features (n= 34)Improvement of lesion in MRINo Improvement of lesion in MRIP-value (Fisher’s Exact Test)& No Reduction in BPE& Reduction in BPE& No Reduction in BPE& Reduction in BPEIncidence of IDC at surgery (n)0204Incidence of Not IDC at surgery (n)121024%IDC at surgery when assessing lesion only (%)9.1%40%0.048*%IDC at surgery when assessing lesion AND BPE (%)0%16.7%0%50%0.032*%IDC at surgery when assessing lesion AND BPE (%)8.3%50%0.018* Citation Format: Paul Kim, Heather I. Greenwood, Rita I. Freimanis, Gillian L Hirst, Megan Fischer-Colbrie, Jessica Gibbs, Nola M Hylton, Christina Yau, Eun-Sil Shelley Hwang, Laura J. Esserman, Rita A Mukhtar. Improved early stratification of invasive cancer risk using MRI in a ductal carcinoma in-situ short-term active surveillance cohort treated with neoadjuvant endocrine therapy [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 P6-16-06.

The run-in phase of the prospective WSG-ADAPT HR+/HER2- trial demonstrates the feasibility of a study design combining static and dynamic biomarker assessments for individualized therapy in early breast cancer.

Background:Endocrine sensitivity, as determined by response of the proliferation marker Ki-67 to short-term preoperative endocrine therapy (ET), is currently not included in adjuvant treatment decisions in hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)− breast cancer (BC).Methods:The prospective WSG-ADAPT HR+/HER2− trial included patients with N0/N1 early BC who were candidates for adjuvant chemotherapy based on clinical–pathological criteria alone. The trial utilized a genomic assessment [the Recurrence Score (RS)] plus endocrine sensitivity testing to guide treatment. All patients received 3 (±1) weeks of preoperative induction ET. According to protocol, patients with RS 0–11 or RS 12–25 plus endocrine proliferation response (EPR, post-induction Ki-67 ⩽ 10%) were to be spared adjuvant chemotherapy.Results:The ADAPT HR+/HER2− trial run-in phase included 407 patients with baseline RS, of whom 386 (median age: 54 years) had complete data for Ki-67 at both baseline and post-induction. RS distribution: 23.1% RS 0–11, 58.3% RS 12–25, and 18.7% RS 26–100. EPR occurred in 84.3%, 76.0%, and 36.1% of these RS groups, respectively. Differences in EPR proportions (RS 26–100 versus others, RS 0–11 versus others) were significant (both p < 0.001); Ki-67 quotients were higher for RS 26–100 (p = 0.02, Mann–Whitney). In premenopausal women (n = 146, mostly tamoxifen-treated), median quotient of Ki-67 level (post/pre) was significantly higher than in postmenopausal women (n = 222, mostly aromatase-inhibitor treated; 0.67 versus 0.25, p < 0.001). EPR was significantly associated with baseline estrogen-receptor status as determined by immunohistochemistry (p = 0.002) or real-time polymerase chain reaction (p < 0.001). Also, a strong correlation was observed between RS measured pre- and post-ET (RS = 0.7, n = 181).Conclusions:This phase of the WSG-ADAPT HR+/HER2− trial confirms trial design estimates of RS and EPR. It indicates that the ADAPT concept of combining static and dynamic biomarker assessment for individualized therapy decisions in early BC is feasible using the EPR criterion post-induction Ki-67 ⩽ 10%.Clinicaltrials.gov identifier:NCT01779206.

Dynamics of pathological factors after «test» course of preoperative endocrine therapy in menopausal patients with earlyer positive breast cancer and its effect on survival

Dynamics of pathological factors after «test» course of preoperative endocrine therapy in menopausal patients with earlyer positive breast cancer and its effect on survival

Clinical Trials for Ductal Carcinoma In Situ of the Breast.

Ductal carcinoma in situ (DCIS) of the breast is a non-obligatory precursor to invasive breast carcinoma, with a variable natural history and biological potential for progression to invasive disease. Over the past 30years, clinical trials have applied the therapeutic principles used for invasive carcinoma to treat DCIS (surgery, with or without breast radiotherapy, and post-operative endocrine therapy), with excellent survival outcomes, and in-breast recurrence rates that range from 0.5 to 1% annually. However, half of such recurrences are again in-situ lesions, and intensive therapy is likely not necessary for all patients. Current clinical research is focused on a better characterization of the potential of individual lesions to progress to invasive disease, and to identify women who would do well with lesser treatment. Three ongoing trials in the United States and Europe randomize women to active surveillance (with or without endocrine therapy) versus usual treatment with surgery and radiotherapy. The use of pre-operative endocrine therapy has been evaluated in a recently completed trial of letrozole use in postmenopausal women with DCIS; and in on-going trials of tamoxifen, used either orally, or as a 4-hydroxytamoxifen gel formulation for application to the breast skin. This review summaries the major past and current clinical trials of DCIS, and the likely trajectories of DCIS management in the near future.

Abstract GS6-04: The EndoPredict score predicts residual cancer burden after neoadjuvant chemotherapy and after neoendocrince therapy in HR+/HER2- breast cancer patients from ABCSG 34

Abstract Background: In the neoadjuvant treatment setting of ER+/HER2- breast cancer (BC) the choice between preoperative endocrine - (NET) or preoperative chemotherapy (NCT) is largely based on the expression of hormone receptors (HR), grading and possibly Ki-67. The EndoPredict 12-gene molecular score (EP) is a validated prognostic score based on the expression of genes involved in cellular processes including proliferation and ER signaling/differentiation. The application of the EP molecular score may thus provide additional insight into neoadjuvant response of tumors. Methods: This prospective translational study was carried out as an exploratory endpoint within the ABCSG 34 protocol (SABCS 2016, Singer et al.) and included only the HR+ subset of women. ABCSG 34 was a randomized 2-arm academic phase-II trial including 400 patients (250 ER+) with HER2 negative early BC. Patients were selected for either NET or NCT according to the study protocol reflecting standard of care: postmenopausal women with ER+++, or ER++ and Ki67 &amp;lt;14%, and G1,2,X tumors received 6 months of Letrozole. Postmenopausal patients with ER-(and PgR+) or ER low and Ki67 ≥14%, and with G3 tumors, and premenopausal patients, received 8 cycles of anthracycline/taxane based chemotherapy. Primary endpoint was Residual Cancer Burden score (RCB0/I vs RCBII/III) at surgery in women with or without Tecemotide (L-BLP25). EP was assessed from diagnostic cores and the predefined risk groups (EP low-risk vs EP high-risk; cutoff value: 5.0) and the score as a continuous variable (EPc) were applied to all patients with both full molecular - and RCB data (n=217). Results: 134 patients (EP low-risk:9; EP high-risk:125) with HR+ tumors received NCT. Stage I: 14.9%, II/III: 84%; G3: 56%; mean Ki-67: 40.4%. No patient with EP low-risk score showed RCB0/I (NPV: 100%) whereas 26.4% of EP high-risk showed full response. In logistic regression EP as a continuous score (EPc) was a significant predictor of RCB0/I, showed an AUC (95% CI) of 0.736 (0.63 - 0.84) and revealed close correlation with Ki-67. 83 patients (EP low-risk:44; EP high-risk:39) received NET. Stage I: 38.6%, II/III: 60.2%; G3: 4.8%; mean Ki-67: 14.9%. 27.3% (n=12/44) with EP low-risk and 7.7% (n=3/39) with EP high-risk showed RCB0/I. EPc was a significant predictor of RCB0/I with an AUC (95% CI) of 0.726 (0.60 - 0.85). In all multivariate analyses low anatomic stage was the most powerful predictor of RCB0/I. Conclusions: Clinical standard of care separated ABCSG 34 patients into two HR+ cohorts with differing clinical features and treated distinctly with either NET or NCT: In women treated with neoadjuvant Letrozole a high molecular score indicated a very low possibility of endocrine response. In women clinically selected for neoadjuvant chemotherapy, a high EP score was associated with a higher probability of chemotherapy response and the low EP risk group outlined a group of women with very poor tumor response to NCT(NPV 100%). In summary, EP low risk is associated with tumor response to endocrine treatment and predicts resistance in the chemotherapy group. NCT, especially to attain breast conservation in ER+/HER2-/EP low risk should be reconsidered. Citation Format: Dubsky PC, Fesl C, Singer CF, Pfeiler G, Kronenwett R, Hubalek M, Bartsch R, Stoeger H, Pichler A, Petru E, Bjelic-Radisic V, Greil R, Rudas M, Tea M-KM, Wette V, Petzner AL, Sevelda P, Egle D, Fitzal F, Exner R, Jakesz R, Balic M, Tinchon C, Bago-Horvath Z, Lax S, Regitnig P, Gnant M, Filipits M. The EndoPredict score predicts residual cancer burden after neoadjuvant chemotherapy and after neoendocrince therapy in HR+/HER2- breast cancer patients from ABCSG 34 [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 GS6-04.

Abstract GS5-05: Primary endocrine therapy for ER-positive ductal carcinoma in situ (DCIS) CALGB 40903 (Alliance)

Abstract Background: Standard treatment for ductal carcinoma in situ (DCIS) consists of surgery, often followed by adjuvant radiation therapy or endocrine therapy. This current approach is thought to represent overtreatment for some patients. This study was undertaken to determine whether an alternate approach of primary endocrine therapy alone could result in measurable radiographic changes in unresected estrogen receptor (ER)-positive DCIS. Methods: A phase II open-label single arm multi-center cooperative group trial (CALGB 40903) was conducted for postmenopausal patients diagnosed with ER-positive DCIS. All eligible patients underwent baseline mammography and MRI, followed by 6 months of preoperative therapy with letrozole. Follow up breast MRI was obtained at 3 and 6 months of treatment. The primary endpoint was change in total MRI volume of DCIS enhancement from baseline to 3 months and from baseline to 6 months. Secondary endpoints were change in MRI maximum diameter over baseline and change in mammographic extent of disease over baseline. Endpoints were analyzed via 2-sided paired t-tests (a=0.05). Results: From 8/1/12 to 2/1/16 108 patients were enrolled; Of the 77 patients who completed letrozole treatment per protocol, 66 patients were assessable. 2 additional patients who did not complete treatment per protocol were considered assessable and thus included in the analysis for a total of 68 patients. Median age of the cohort was 62.7 years. DCIS nuclear grade was low in 10% of patients, intermediate in 49%, and high in 40%. 82% of patients had ER-positive, PR-positive DCIS. The total mean MRI volume decreased from baseline to 3 months by 1.93 cm3 (p&amp;lt;0.001) and from baseline to 6 months by 1.82 cm3 (p&amp;lt;0.001). There was no significant difference in tumor volume between 3 and 6 months. Mean total mammographic tumor diameter decreased from baseline to 6 months by 3.31 mm2 (p=0.078). Conclusions: In a cohort of postmenopausal women treated with 6 months of preoperative endocrine therapy for ER-positive DCIS, MRI volume decreased markedly by 3 months, while mammographic extent of disease was not altered significantly. Correlation of imaging changes with pathology and baseline biomarkers will be conducted. These results will help determine whether MRI could be an effective modality for monitoring treatment response in some patients treated with primary endocrine therapy for ER-positive DCIS. Citation Format: Hwang ES, Duong S, Bedrosian I, Allred J, Wisner D, Hyslop T, Caudle A, Guenther J, Hudis C, Winer E, Esserman L, Hylton N. Primary endocrine therapy for ER-positive ductal carcinoma in situ (DCIS) CALGB 40903 (Alliance) [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 GS5-05.

ISY11-3 - Preoperative endocrine therapy as a predictive biomarker of adjuvant chemotherapy

Patients with early breast cancer (stage I¯IIIA) usually receive adjuvant systemic therapy due to prevent recurrence after surgery. Treatment strategies are determined based on molecular subtypes and baseline risk. In practice, investigators provide the best strategy for individual patients based on risk benefit balance according to clinical, pathological factors and multigene signature. However the appropriateness of chemotherapy for luminal breast cancer has been an important clinical issue during ten years and we don't have clear answer. We conducted randomized phase III trials as called New primary Endocrine therapy Origination Study (NEOS) in luminal breast cancer patients about ten years ago. NEOS has been performed at multicenter in Japan since Jun 2008. NEOS is evaluated with or without chemotherapy in patients with postmenopausal breast cancer that has responded to preoperative endocrine therapy. The aims of this trial are to| define patients who might not require chemotherapy by using their response to preoperative endocrine therapy| analyze the relationship between preoperative endocrine therapy and long-term prognosis| and analyze the correlation between clinical and pathologic response to preoperative endocrine therapy with additional adjuvant chemotherapy. Multigene profiling kits such as Oncotype DX® and MammaPrint® have been used in trials (TAILORx in North America and MINDACT in Euro, respectively) conducted outside of Japan in an attempt to prospectively identify patients likely or unlikely to benefit from adjuvant chemotherapy. Already some parts of TAILORx and MINDACT trial data were published Nov 2015 and Aug 2016 respectively. However these gene screening kits are not widely used because of high cost without health insurance covered in Japan. Therefore, response to preoperative endocrine therapy may become a very useful tool in practice if it can help to determine the appropriate postoperative treatment regimen.

Tumor-infiltrating lymphocytes and molecular response after neoadjuvant therapy for HR+/HER2-breast cancer: results from two prospective trials.

The aim was to evaluate the role of tumor-infiltrating lymphocytes (TIL) in predicting molecular response after preoperative endocrine or cytotoxic treatment for HR+/HER2- patients who do not achieve a pathological complete response. Stromal (Str) TIL were centrally evaluated on samples from diagnostic core-biopsies of HR+/HER2- patients included in two prospective randomized trials: the LETLOB trial (neoadjuvant endocrine-based treatment) and the GIOB trial (neoadjuvant chemotherapy-based treatment). Pre- and post-treatment Ki67 was centrally assessed. StrTIL were evaluable in 111 cases (n=73 from the LETLOB trial and n=38 from the GIOB trial). Median StrTIL was 2%. Patients with high StrTIL (StrTIL ≥10%, n=28) had more frequently breast cancer of ductal histology (p=0.02), high grade (p=0.049), and high Ki67 (p=0.02). After neoadjuvant endocrine treatment (LETLOB cohort), a significant Ki67 suppression (p<0.01) from pre- to post-treatment was observed in both the low and high StrTIL groups. High StrTIL patients achieve more frequently a relative Ki67 suppression ≥50% from baseline as compared to low StrTIL patients (55 vs. 35%, p non significant). After neoadjuvant chemotherapy (GIOB cohort), a significant Ki67 suppression was observed only for low StrTIL patients (Wilcoxon p=0.001) and not in the high StrTIL group (p=0.612). In this cohort, the rate of patients achieving a relative Ki67 suppression ≥50% from baseline was significantly higher in the low vs high StrTIL group (64% vs 10%, p = 0.003). Geometric mean Ki67 suppression was evaluated in each cohort according to StrTIL: the lowest value (-41%) was observed for high StrTIL cases treated with chemotherapy. This hypothesis-generating study suggests that in HR+/HER2- breast cancer StrTIL at baseline may influence the achievement of a molecular response after neoadjuvant treatment. Further evaluation in large studies is needed, and interaction with the type of treatment warrants to be explored.

WS-2-2 - Preoperative therapy for luminal breast cancer-chemotherapy

Preoperative therapy for breast cancer is an established standard therapy. For luminal cancer, whether chemotherapy or endocrine therapy should be used is to be determined. A report by Semiglazov showed that the response rate and the rate of breast conserving surgery were similar in postmenopausal patients with breast cancer. On the other hand, a report by Alba (GEICAM study) which explored in both premenopausal and postmenopausal patients showed superior response rate with chemotherapy; although the response rate was similar in postmenopausal subset. These data suggest that preoperative endocrine therapy is active to some extent. However, the objective of preoperative therapy is to improve relapse free survival or overall survival. From this point of view, preoperative chemotherapy is proven to be equal to the postoperative chemotherapy; however preoperative endocrine therapy lacks such evidence. Therefore the standard preoperative therapy is considered to be chemotherapy so far. Endocrine therapy is one of the alternative options with low toxicity and similar response rate and the rate of breast conserving surgery compared to chemotherapy.

The Japanese Breast Cancer Society Clinical Practice Guideline for systemic treatment of breast cancer

1. For operable, postmenopausal, hormone receptorpositive, HER2-negative breast cancer, preoperative endocrine therapy may be considered for the purpose of breast conservation (Grade C1). 2. Preoperative endocrine therapy improves the breast conservation rate in premenopausal breast cancer as well as postmenopausal breast cancer. However, it is not generally recommended since evidence is scarce (Grade C2).

A case of ectopic breast carcinoma of the right axilla treated with neoadjuvant endocrine therapy

We herein report a case of an ectopic breast carcinoma of the right axilla treated with preoperative endocrine therapy. A 65-year-old female presented with an ulcerated mass in the right axilla. The tumor was 1.7 cm in diameter. The clinical and pathological diagnosis based on the findings of a core needle biopsy (ER-positive and PR-positive) was ectopic breast carcinoma of the axilla. The tumor was widely spread in the right axilla. We were concerned that an extensive scar that would result from surgery would restrict the range of motion of the right upper extremity. The estrogen receptor was highly expressed in the tumor, therefore, neoadjuvant endocrine therapy was started. Letrozole, an aromatase inhibitor, was administrated for 6 months before surgery, and the tumor was reduced in size and became easily resectable. The clinicopathological effect was a partial response. The resection of the right axilla and axillary lymph node dissection were performed. The defect of the right axilla was small, and no contracture occurred. Adjuvant endocrine therapy was continued after surgery. To the best of our knowledge, this is the first report of a case of ectopic breast carcinoma of the axilla successfully treated with neoadjuvant endocrine therapy. This case is considered to be a valuable case, and we have added some bibliographic considerations to further increase the value of this report.

Oncotype DX and proliferation response to short-term preoperative endocrine therapy for chemotherapy decision in early breast cancer: Biomarker data from the prospective multicenter phase II/III WSG-ADAPT trial.

524^ Background: WSG-ADAPT aims to optimize early breast cancer therapy within a genomically classified (by OncotypeDX) intermediate-risk group using individual endocrine sensitivity. Methods: WSG-ADAPT HR+/HER2- analyzes biomarker changes after 3 weeks of preoperative ET [aromatase inhibitors (AI) in postmenopausal, tamoxifen (Tam) in premenopausal women]. Overall, n=1760 patients (HR+/HER2-, pN0-1) with Recurrence Score (RS) 0-11 or RS 12-25 and post-Tx Ki-67<10% are treated by ET alone. Other RS 12-25 and all RS ≥26 patients are included in phase III CTx design (n=2200). Results: 1118 patients from 61 centers have been enrolled (01/2014); run-in phase analysis included 383 patients (median age 54 years, 175 Tam, 208 AI). RS distribution (≤11/12-25/≥26) was 23%/57%/20%; median relative Ki-67 decreases were 0.67/0.60/0.40 by RS groups (p=0.017). Median relative Ki-67 decrease was more pronounced in post- vs. premenopausal patients (75% vs. 38%; p<0.001). Mean PR (not ER) expression changes were also more...

Health-related quality of life and psychological distress during neoadjuvant endocrine therapy with letrozole to determine endocrine responsiveness in postmenopausal breast cancer

Trials of adjuvant endocrine therapy for breast cancer have shown that aromatase inhibitors have little impact on global health-related quality of life (HRQoL), but have significant effects on patient-reported endocrine symptoms (ESs). There are few studies of HRQoL and psychological distress during preoperative endocrine therapy performed to determine endocrine responsiveness. The NEOS trial is a multicenter, phase 3 randomized controlled trial in postmenopausal women with hormone receptor-positive breast cancer. The primary aim of the trial was to evaluate the need for adjuvant chemotherapy in patients with clinical T1c-T2N0M0, hormone receptor-positive tumors who responded to neoadjuvant letrozole (LET) administered for 24-28 weeks before surgery. The primary endpoint was disease-free survival and the secondary endpoints included adverse events, HRQoL, and cost-effectiveness. In a HRQoL sub-study, subjects were assessed at baseline and 4 and 16 weeks after starting neoadjuvant LET, using the functional assessment of cancer therapy-breast and its ES subscale, and the hospital anxiety and depression scale. HRQoL and psychosocial distress were analyzed in the uncontrolled phase during 24-28 weeks of neoadjuvant LET therapy in the NEOS trial. From May 16, 2008, to December 14, 2011, 503 patients were recruited into the HRQoL sub-study. The full analysis set included 497 patients with a mean age of 63-years old. The questionnaire response rates at enrollment and 4 and 16 weeks were 94.4, 90.7, and 89.1 %, respectively. There were no significant changes in the FACT-G or B-trial outcome index over time, but the social and family well-being score and the ES subscale deteriorated significantly, and the number of patients with clinically significant hot flush increased significantly. Anxiety, depression, and emotional well-being improved significantly after neoadjuvant LET. Neoadjuvant endocrine therapy with LET had no impact on global HRQoL, but did influence endocrine-related symptoms such as hot flush. This study is registered as UMIN000001090.

Abstract P6-05-11: Run-in phase of prospective WSG-ADAPT HR+/HER2- trial demonstrates feasibility of early endocrine sensitivity prediction by recurrence score and conventional parameters in clinical routine

Abstract Background: Despite promising evidence regarding outcome prediction, endocrine sensitivity, as determined by proliferation response to short-term preoperative endocrine therapy, is currently not included in adjuvant chemotherapy decisions in early HR+/HER2- breast cancer (BC). Methods: The prospective WSG-ADAPT HR+/HER2- trial includes early BC patients with 0-3 positive LN who are candidates for adjuvant chemotherapy based on clinical-pathological criteria alone; it aims to spare chemotherapy in a substantial proportion utilizing a combination of genomic assessment by Oncotype DX and endocrine sensitivity testing. All patients received 3-week preoperative endocrine induction therapy (ET): aromatase inhibitors (AI) if postmenopausal, tamoxifen if premenopausal. Patients with low (0-11) Recurrence Score (RS) or intermediate RS (12-25) and ET response (centrally tested, post-therapy Ki-67 &amp;lt;10%) are recommended to forego adjuvant chemotherapy (“low-risk” patients). Distribution of RS, responder percentages in each group, and impacts of RS, ET regimen, and initial Ki-67 on post-therapy Ki-67 are reported here. Results: As of 6/2013, 380 patients from 30 study centers had been enrolled in the ADAPT HR+/HER2- trial. Median age was 54 years. At first pre-planned analysis (5/2013), paired Ki-67 measurements (pre-/post-therapy) were available in 241 patients; RS was available in 208 cases (201 with paired Ki-67). RS was low in 21.6%, intermediate in 57.7%, and high in 20.7%; the respective risk group responder percentages (post-treatment Ki 67 &amp;lt;10%) were 84.1%, 73.9%, and 40.0% (p&amp;lt;0.001 when comparing low/intermediate vs. high, chi-square). In particular, these percentages support the pre-trial estimate of &amp;gt;70% endocrine responders in the intermediate genomic risk group, who could potentially be spared adjuvant chemotherapy. Median Ki 67 level decreases (as percentage of pre-treatment value) were 25% in premenopausal patients (tamoxifen, n = 101) vs. 75% in postmenopausal patients (AI, n = 115) (p&amp;lt;0.001, Mann-Whitney); median decreases by RS group were similar, 61% (low), 53% (intermediate) and 56% (high), respectively (p = 0.81, Kruskal-Wallis). In linear regression, pre-treatment Ki-67, endocrine regimen/menopausal status, and RS were all independent predictors for post-treatment Ki 67. Final run-in-phase analysis and validation will be presented after completion of endocrine induction therapy in 400 patients. Conclusions: The Run-In Phase of the WSG ADAPT HR+/HER2- trial confirms trial design estimates of RS and proliferation response to induction ET. It indicates that the multicenter prospective ADAPT concept combining static and dynamic biomarker assessment for individualized therapy decisions in early BC is feasible. Proliferation response was strongly associated with therapy group (AI/post-menopausal vs. tamoxifen/pre-menopausal). Survival non-inferiority of intermediate Recurrence Score proliferation responders vs. low Recurrence Score patients (active control) will be tested in the ADAPT main phase to determine if adjuvant chemotherapy can be spared in 70% of patients with 0-3 positive LN classified as “intermediate risk” by conventional factors. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-11.

Abstract OT3-2-02: PreOperative window of endocrine therapy provides information to increase compliance: POWER PIINC: A feasibility study

Abstract Background: The addition of systemic therapy to the surgical treatment of breast cancer has improved survival of patients. A mainstay of systemic therapy in the setting of hormone receptor positive breast cancer is endocrine therapy. Despite the known advantages, the compliance with short and long term systemic endocrine therapy is less than ideal. Several studies report significant rates of non-compliance with endocrine therapy, either in patients never starting the medication or not completing the recommended multi-year course. It is estimated that as many as 10% of patients per year discontinue their therapy. We wondered why women would forgo such an important part of their treatment and how we might intervene to improve compliance. Using information gleaned from POWER PIINC, we hope to design a behavioral intervention study to see if the patient knowing her tumor's preoperative response to endocrine therapy will improve long term compliance. In order to do such a study we would need to define the minimal length of preoperative endocrine therapy needed to detect measurable changes in the tumor. After 14 days of endocrine therapy, significant decreases in Ki67 can be seen in most hormone sensitive breast cancers. In fact two current studies are using this information (POETIC and ADAPT trials). Both of these trials are being conducted outside of the U.S. where operative therapy does not typically occur within a week or two of seeing the surgeon. POWER PIINC is a feasibility study to determine if we can detect changes in Ki67 with only 7 days of therapy. The results of POWER PIINC will inform the behavioral intervention trial. Trial Design: This is a prospective, single-arm feasibility study. Participants take tamoxifen for 7 days prior to surgery. Ki67 is measured pre (core biopsy) and post (surgical specimen) tamoxifen. Eligibility critieria: Non-pregnant women age 18 or older with a hormone positive (&amp;gt;1% ER or PR) clinical Stage 1 or 2 breast cancer who are candidates for surgical therapy of their breast cancer. No concurrent CYP2D6 inhibitors or other contraindications to tamoxifen. Specific Aims: Primary Objective: Demonstrate a significant reduction in Ki67 expression in tumors with 7 days of pre-surgical tamoxifen. Secondary Objectives: - Evaluate symptom patterns from baseline through 18 months of follow-up (presence, severity, and bother) -Evaluate 18-month endocrine therapy adherence -Evaluate change in attitude regarding endocrine therapy -Evaluate correlation between changes in Ki67 expression and symptom scores -Evaluate additional changes in proliferative markers (subset of PAM 50) Statistical Methods: A one-sample t-test will be applied to the log-ratio of Ki67 at resection to pre therapy. If this ratio is not normally distributed we will use a non-parametric Wilcoxon test. Secondary objectives will be analyzed using a variety of appropriate statistical tests. Accrual: Target accrual is 52 patients over 18 months. We opened this study in August of 2012. To date (9 months) we have accrued 23 patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-2-02.

Neoadjuvant endocrine treatment for breast cancer: from bedside to bench and back again?

In recent years, considerable attention has been paid to the role of neoadjuvant chemotherapy as a pluripotential test bed for the treatment of breast cancer. Although traditionally reserved to render inoperable disease operable, neoadjuvant chemotherapy is increasingly being used to improve the chance for breast-conserving surgery, to gain information on pathologic response rates for a more rapid assessment of new chemotherapy-biologic regimens, and also to study in vivo tumour sensitivity or resistance to the agent being used. Similarly, use of neoadjuvant endocrine treatment was also traditionally restricted to elderly or frail patients who were felt to be unsuitable for chemotherapy. It is therefore not surprising that, given the increasing realization of the pivotal role of endocrine therapy in patient care, there is enhanced interest in neoadjuvant endocrine therapy not only as a less-toxic alternative to chemotherapy, but also to assess tumour sensitivity or resistance to endocrine agents. The availability of newer endocrine manipulations and increasing evidence that the benefits of chemotherapy are frequently marginal in many hormone-positive patients is making endocrine therapy increasingly important in the clinical setting. The hope is that, one day, instead of preoperative endocrine therapy being restricted to the infirm and the elderly, it will be used in the time between biopsy diagnosis and surgery to predict which patients will or will not benefit from chemotherapy in the adjuvant setting.

Phase II trial evaluating the use of 21-gene recurrence score (RS) to select preoperative therapy in hormone receptor (HR)-positive breast cancer.

562 Background: Hormone receptor (HR)- positive breast cancer patients (pts) typically have lower pathological responses to pre-operative chemotherapy than HR-negative breast cancers. Objective: We evaluated the pathologic and radiologic response rates to pre-operative endocrine therapy or chemotherapy, as directed by RS, in pts with HR-positive resectable breast cancers. Methods: Pts with HR-positive breast cancers had RS performed on the initial diagnostic biopsy. Pts were treated pre-operatively as follows based on RS: ≤10, exemestane +/- goserelin for 6 to 12 months (ET); 11 to 25 randomized to ET or docetaxel-cyclophosphamide (TC) for 6 cycles (CT); ≥ 26, CT. Results: From 4/2009 to 12/2012, 66 pts signed consent for RS testing and 46 are evaluable for efficacy analysis. Median age is 57 (40 to 78); one-third of pts are African-American; 41% have clinically node positive disease. RS ranged from 2 to 57. 28 pts received CT: Pathologic complete response (PCR) rate was 10% and 60% of cancers were down-staged based on initial T-stage. Radiologic response is available for 20 pts: complete radiologic response (CRR) 15%, partial RR (PRR) 40%, progressive disease (PD) 5%. In 11 pts with RS 11 to 25: PCR 0%, down-staged 45%, up-staged 18%, radiologic responses: CRR 17%, PRR 50%, PD 17%. In 17 pts with RS ≥ 26: PCR 18%, down-staged 71%, up-staged 0%, radiologic responses: CRR 14%, PRR 36%, PD 0%. 18 pts received ET for between 6 to 22 months, 5 remain on study and have not had surgery: PCR 0%; down-staged 38%; up-staged 15%; radiologic responses: CRR 13%, PRR 40%, PD 0%. There was no correlation between RS and efficacy of ET. To date, 3 pts have relapsed, all of whom received CT. Conclusions: This is the first prospective use of the 21-gene RS to select pre-operative therapy for pts with HR-positive breast cancer. Pre-operative CT results in tumor down-staging in the majority of cancers with RS ≥ 11, though it appears to be more effective with RS ≥ 26. ET was moderately effective in down-staging cancers with RS ≤ 25. Updated results will be presented. Clinical trial information: NCT00941330, NCT00832338.

Use of the neo-adjuvant exemestane in post-menopausal estrogen receptor-positive breast cancer: A randomized phase II trial (PTEX46) to investigate the optimal duration of preoperative endocrine therapy

PurposeThe optimal treatment duration time and the causal relationship between neoadjuvant endocrine therapy and clinical response are not clear. Therefore, we conducted the present study to investigate the potential benefits of neoadjuvant exemestane therapy with the goal of identifying the optimal treatment duration. MethodsThis study was conducted at three hospitals, as a multicenter, randomized phase II trial(UMIN000005668) of pre-operative exemestane treatment in post-menopausal women with untreated primary breast cancer. Fifty-one post-menopausal women with ER-positive and/or PgR-positive invasive breast cancer were randomly assigned to exemestane for 4 months or 6 months. Clinical response, pathological response, and decisions regarding breast-conserving surgery were the main outcome measures. ResultsOf the 52 patients that enrolled, 51 patients underwent surgery. Of those, 26 and 25 patients had been treated with exemestane for 4 and 6 months, respectively. Treatments were performedat 3 hospitals in Japan between April 2008 and August 2010. The response rates as assessed by clinical examination were 42.3% and 48.0% for 4 and 6 months of treatment, respectively. Pathological responses (minimal response or better) were observed in 19.2% and 32.0% of patients, and breast-conserving surgery was performed on 50.0% and 48.0% of patients from the 4 and 6 month treatment groups, respectively. ConclusionThe results of this study demonstrate that responses were equal to 4 or 6 months of exemestane treatment. Therefore, we propose that the rates of breast-conserving surgery could be maximized by 4 months of treatment. Furthermore, in addition to using exemestane as a preoperative treatment in post-menopausal women with ER-positive breast cancer, we envision administering the drug over the long term under careful clinical supervision.

Preoperative endocrine therapy with goserelin acetate and tamoxifen in hormone receptor-positive premenopausal breast cancer patients

The use of preoperative endocrine therapy for breast cancer has increased during the last decade. Although several studies have reported favorable response rates in postmenopausal women, its effectiveness in premenopausal women remains unknown. This study therefore aimed to evaluate the potential benefits of preoperative endocrine therapy in premenopausal women. Fifty-three patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative invasive breast cancer were included in this study. Preoperative endocrine therapy with goserelin acetate and tamoxifen was administered for 3months. Clinical evaluations were performed by ultrasonography before and after endocrine therapy. Pathological evaluations were performed using core biopsy and surgical specimens. Immunohistochemical evaluations of ER, progesterone receptor (PgR), HER2, and Ki-67 were performed before and after endocrine therapy. Partial response (PR) was observed in 23% (12/53) and progressive disease (PD) in 2% (2/53) of patients. Significant suppression of Ki-67 was observed following endocrine therapy in 90% (47/52) of patients (P<0.0001). Significant downregulation of PgR was observed after endocrine therapy (P=0.0002), which tended to be correlated with clinical response (P=0.058). Three months of preoperative endocrine therapy with goserelin acetate and tamoxifen was safe and effective in premenopausal patients with invasive breast cancer, with a 23% PR rate. Changes in PgR and Ki-67 expression might be promising markers for endocrine responsiveness.