Neoadjuvant Endocrine Treatment Research Articles

Abstract P1-07-01: HLA class I expression is associated with tumor-infiltrating lymphocytes and response and survival after neoadjuvant chemotherapy in hormone receptor-positive, HER2-negative breast cancer

Abstract Background: Interactions between cancer cells and the host immune system influence tumor biology, response to therapy and patient survival and their modulation offers promising new approaches for cancer therapy. The downregulation or loss of HLA class I expression in breast cancer cells might be an effective mechanism to evade the recognition by the immune system facilitating malignant behavior. Aim: To evaluate the association of tumor-infiltrating lymphocytes (TILs) with HLA class I expression and its theranostic value for therapy response and survival after neoadjuvant chemotherapy. Methods: HLA class I expression was evaluated by immunohistochemistry in a cohort of 732 pre-therapeutic core biopsies from breast cancer patients treated within the neoadjuvant GeparTrio trial. Patients received anthracycline- and taxane-based neoadjuvant therapy and adjuvant endocrine treatment if hormone receptor-positive (HR+). A publicly available microarray dataset of pre-therapeutic core biopsies from 508 breast cancer patients that received neoadjuvant chemotherapy and endocrine treatment if HR+ was used for validation of the results. The association of HLA class I expression with predefined genomic signatures for immune cell populations was evaluated in publicly available data from the cancer genome atlas. Results: HLA class I expression was associated with TILs (p < 0.001) and was predictive of better response to neoadjuvant chemotherapy in the subgroup of patients with HR+/HER2- breast cancer (14 % in tumors with high HLA vs. 7 % in tumors with low HLA, p = 0.029). Interestingly, high HLA was also predictive for shorter progression-free survival in univariate analysis (HR 1.590, 95 % CI 1.062—2.380; p = 0.024) and after adjustment to clinical and pathological parameters (HR 1.701, 95 % CI 1.105—2.618; p = 0.016). The results could be validated in the independent microarray-based dataset (HR 1.521, 95% CI 1.088 – 2.129; p = 0.0142). HLA class I was not associated with therapy response or survival in hormone receptor-negative breast cancer. HLA class I was associated with a predefined signature for T-cells and cytotoxic T- cells in the cancer genome atlas dataset (rho = 0.546). Conclusion: HLA class I expression is associated with better response but shorter progression-free survival in HR+/HER2- breast cancer following neoadjuvant chemotherapy. The underlying mechanisms warrant further investigation. Citation Format: Sinn BV, Weber K, Denkert C, Fasching PA, Schmitt WD, Thomas K, Ingold-Heppner B, van Mackelenbergh M, Symmans WF, Marmé F, Taube E, Müller V, Kunze CA, Schem C, Pfitzner BM, Stickeler E, von Minckwitz G, Loibl S. HLA class I expression is associated with tumor-infiltrating lymphocytes and response and survival after neoadjuvant chemotherapy in hormone receptor-positive, HER2-negative 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 P1-07-01.

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.

Neoadjuvant letrozole for postmenopausal estrogen receptor-positive, HER2-negative breast cancer patients, a study from the Danish Breast Cancer Cooperative Group (DBCG)

Introduction: Neoadjuvant endocrine treatment (NET) is a low-toxicity approach to achieve operability in locally advanced breast cancer, and to facilitate breast conservation in early breast cancer, particular in patients with highly estrogen receptor (ER) positive and HER2-negative disease. Here, we report the results obtained by neoadjuvant letrozole in patients with early breast cancer in a phase-II design.Material and methods: A total of 119 postmenopausal women with ER-positive, HER2-negative operable breast cancer were assigned to four months of neoadjuvant letrozole before definitive surgery. Sentinel node or diagnostic fine needle aspiration cytology procedure was performed prior to treatment and the women were assessed prior, at two months, and before surgery with clinical examination, mammography and ultrasonography. Surgical specimens were examined for pathological response. Primary outcome was pathological and clinical response.Results: The per protocol population consisted of 112 patients. Clinical response was evaluated in 109 patients and pathological response in 108. Overall a mean decrease in tumor size was 15% (p ≤ .0001). One patient had complete pathological response and 55% of patients had partial pathological response. ER at 100%, ductal subtype, tumor size below 2 cm and lymph node–negative status was significantly associated with a better response to NET and malignancy grade 3 with a poorer response to NET. One patient progressed during treatment and received neoadjuvant chemotherapy. Eight patients received adjuvant chemotherapy due to lack of response.Conclusion: Neoadjuvant aromatase inhibitor therapy is an acceptable strategy in selected postmenopausal patients with ER-rich and HER2-negative early breast cancer with ductal histology and should be considered when chemotherapy either isn’t indicated or feasible.

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.

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.

Abstract P3-13-05: Multicentre observational study evaluating why mastectomies are advised by UK multi-disciplinary teams

Abstract Background: Marked variation in mastectomy rates exists across the UK. Identification of variation in practice is a key step towards standardisation of service. The rationale for advising mastectomy by multi-disciplinary teams (MDTs) has not been previously explored in the UK. The main aim of this multicentre observational study was to describe current practice in MDT decision-making for patients undergoing mastectomy. A secondary aim was to determine utilisation of neoadjuvant therapies. Methods: A multicentre, protocol-driven, prospective cohort study, led by trainees of the West Midlands Research Collaborative was performed during July and September 2015. Data was collected securely using Research Electronic Data Capture. Inclusion criteria were: women &amp;gt;18 years undergoing mastectomy for in situ/invasive disease; presenting with symptomatic or screen detected disease; performed as a primary procedure or following failure of breast conserving surgery (BCS); with or without immediate breast reconstruction (IR). Results: A total of 1776 patients (1823 mastectomies; 47 bilateral procedures) from 68 units were included. Median age was 63 years (range 20-99). In total 481 (26%) IRs were performed; median IR rate was 22% (range 0-67%). Mastectomy was advised by the MDT in 1402 (77%) cases. Reasons for advising mastectomy are shown in Table 1. Table 1. MDT rationale for advising mastectomyRationaleNumber of mastectomiesProportion (%)Large tumour to breast size ratio making BCS unsuitable53029.1Multi-centric disease on imaging37220.4Extensive malignant microcalcification1799.8Previous radiotherapy (Breast/Mantle)1638.9Requiring further surgery for positive margins following BCS1588.7Central tumour1136.2Large primary tumour, patient not suitable for neoadjuvant endocrine or chemotherapy treatment1126.1Neoadjuvant therapy failed to downsize tumour to allow BCS884.8Neoadjuvant therapy apparently successful but mastectomy advised anyway794.3Family History-High Risk512.8 In total 153 patients with oestrogen receptor positive (ER+) tumours were offered neoadjuvant endocrine treatment (NET); 131 (86%) received treatment. A total of 293 post-menopausal women with uni-focal, ER+ tumours, &amp;gt;20mm were not offered NET; mastectomy was advised by MDTs in 202 patients and the rationale for advising mastectomy in 173 patients (86%) was large tumour to breast size ratio. In total 104 patients with Human Epidermal Growth Factor Receptor 2 over-expressing (HER2+) tumours were offered neoadjuvant chemotherapy and trastuzumab (NACT); 89 (86%) received treatment. A total of 88 women &amp;lt;70 years old with HER2+ tumours, &amp;gt;20mm were not offered NACT; mastectomy was advised by MDTs in 75 patients and rationale for advising mastectomy in 45 women (60%) was large tumour to breast size ratio. Conclusions: Although most mastectomies are advised for large tumour to breast size ratio, there is inconsistency in the utilisation of neoadjuvant therapies with many potentially eligible patients with large tumours not being given the opportunity to be downsized. Application of standardised recommendations for neoadjuvant treatment resulting in increased and appropriate use of neoadjuvant therapies could reduce the number of mastectomies advised by MDTs. Citation Format: Singh JK, McEvoy K, Marla S, Wilcox M, Rea D, Hallissey MT, Francis A, West Midlands Research Collaborative. Multicentre observational study evaluating why mastectomies are advised by UK multi-disciplinary teams [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 P3-13-05.

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.

Phase III study of ribociclib (LEE011) plus fulvestrant for the treatment of postmenopausal patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (aBC) who have received no or only one line of prior endocrine treatment (ET): MONALEESA-3.

TPS624Background: Inhibition of the cyclin D–cyclin dependent kinase (CDK)4/6–retinoblastoma pathway may overcome ET resistance and enhance the efficacy of existing ET regimens in HR+, HER2– aBC. Combination of the CDK4/6 inhibitor ribociclib (LEE) with fulvestrant (FUL) has demonstrated potent tumor regressions in preclinical HR+ breast cancer (BC) models (O’Brien et al. Cancer Res 2014;74:Abstr 4756). Methods: In this phase III, double-blind study (NCT02422615), postmenopausal patients with HR+, HER2– aBC (N≈660) will be randomized 2:1 to oral LEE (600 mg QD on Days 1–21 of each 28-day cycle) + FUL (500 mg intramuscularly on Days 1 and 15 of Cycle 1 and Day 1 of each cycle thereafter; Arm A) or placebo + FUL (Arm B). Randomization is stratified by presence of lung or liver metastases and prior ET. Patients may have newly diagnosed aBC that is treatment-naive, relapsed BC that has progressed at any time during/after (neo)adjuvant ET with no treatment for metastatic disease, relapsed BC that has progresse...

Invasive papillary carcinoma treated with neoadjuvant endocrine therapy in which pathological complete response was achieved

BackgroundInvasive papillary carcinoma is a rare type of invasive ductal carcinoma. Neoadjuvant endocrine therapy is now considered as an optional therapy for postmenopausal women with hormone receptor-positive breast cancers, including invasive papillary carcinoma.Case presentationWe discuss the case of an 83-year-old postmenopausal Japanese female with hormone receptor-positive invasive papillary carcinoma who started treatment with an aromatase inhibitor and achieved pathological complete response after 12 months of endocrine treatment.ConclusionAppropriate drugs and durations of neoadjuvant endocrine treatment have yet to be established. Continuing therapy with an aromatase inhibitor until the best clinical response is achieved may represent one of the best strategies in neoadjuvant endocrine therapy.

Neoadjuvant endocrine therapy: Patient selection, treatment duration and surrogate endpoints

Neoadjuvant endocrine treatment has become of increasing interest for downstaging primary ER+ breast cancers as it has become clear that the pathologic complete response rate of luminal tumours to chemotherapy is much lower than that of non-luminal and differs little from that to endocrine therapy. There is much more experience in postmenopausal than premenopausal women. Aromatase inhibitors are generally the agent of choice. Responses are lower in those with the low levels of ER. While duration of endocrine treatment in clinical trials has usually been standardized at around three to four months it is clear that volume reductions continue to occur beyond that time in a large proportion of cases and routine clinical practice is often to treat to maximum response. This relatively slow emergence of downstaging relates to the absence of any increase in apoptosis with endocrine therapy and dependence of responses on the antiproliferative effects of oestrogen withdrawal: apoptosis occurs but at a slightly lower rate such that cell loss is attritional. The dependence of responses on the reduced proliferation underpins the value of Ki67 as an intermediate end-point for treatment benefit with multiple studies having found that relative effects on proliferation by different drugs in neoadjuvant trials match their relative impact on recurrence. While change in Ki67 is now accepted as a validated endpoint for comparing endocrine agents in the neoadjuvant scenario, on-treatment levels of Ki67 are related to long-term prognosis more closely than pretreatment Ki67. The Preoperative Endocrine Prognostic Index (PEPI) that combines residual Ki67 score with measures of on-treatment ER and other clinicopathologic factors has also found application in clinical trials. The potential to make longitudinal assessments of both clinical and biomarker responses has encouraged the development of novel clinical trial designs for assessing the impact of agents that aim to enhance response beyond that of endocrine agents alone. Such strategies include the early measurement of residual Ki67 levels after challenge with an endocrine agent alone and evaluation of the impact of the added agent on Ki67 or other agent-specific end-points.

P027. An evaluation of breast cancer response to neoadjuvant endocrine treatment with letrazole and the requirement for subsequent surgical management and re-operation

P027. An evaluation of breast cancer response to neoadjuvant endocrine treatment with letrazole and the requirement for subsequent surgical management and re-operation

Neoadjuvant endocrine treatment in breast cancer: analysis of daily practice in large cancer center to facilitate decision making

BackgroundTo examine outcomes of neoadjuvant endocrine therapy in daily practice to inform decision making. MethodsWe retrospectively selected 204 patients who received neoadjuvant endocrine therapy with T2 (≥30 mm) or T3 tumors, examining subsequent breast-sparing surgery and long-term outcomes. ResultsNeoadjuvant endocrine therapy was administered for 7.3 months (median) and breast-sparing surgery was achievable in 53% of patients. Smaller initial tumor size and modified version of the Scarff–Bloom and Richardson grades 1 to 2 were associated with breast-sparing surgery. Disease progression during treatment was 6.9%; actuarial risk of local relapse was 3% at 5 years and 15% at 10 years. Five- and 10-year metastasis relapse-free survival was 78% and 63%, respectively. Grade 3, negative progesterone receptors, and absence or slow response to neoadjuvant therapy were associated prognostic factors. ConclusionThese daily practice data provide important information about feasibility, efficacy, and long-term results of neoadjuvant endocrine therapy and can be used to inform patients for decision making between mastectomy and endocrine induction therapy.

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.

Neoadjuvant endocrine treatment of women with breast cancer

Neoadjuvant endocrine treatment of women with breast cancer

Neoadjuvant endocrine treatment of women with breast cancer

Neoadjuvant therapy has four goals in breast cancer: decrease tumor volume to operate tumors that initially were inoperable, increase the number of conservative surgeries, evaluate the chemosensitivity in vivo and analyze the management of micrometastases. Neoadjuvant treatment provides a unique setting in which we can monitor clinical, pathological, proliferative and molecular responses. Combining different strategies such us surgery, radiation therapy, chemotherapy, and endocrine therapy has contributed substantially to the survival improvement in breast cancer. Thirdgeneration aromatase inhibitors have proven to be superior to tamoxifen in the adjuvant and, more recently, the neoadjuvant treatment of postmenopausal patients. The need to define how to select the patients that will benefit the most from these therapies, the optimal duration of treatment, the bestmethod to evaluate the treatment response, the identification of predictive factors for response, and the superiority of certain endocrine agents over others have been reviewed. We have carried out a critical analysis of the current literature on the utilization of endocrine therapy in the neoadjuvant setting for breast cancer. This review discusses the current evidence regarding primary endocrine therapy and the current opinions on length of treatment and measurement of response prior to surgery.

Neoadjuvant endocrine treatment of women with breast cancer

Neoadjuvant therapy has four goals in breast cancer: decrease tumor volume to operate tumors that initially were inoperable, increase the number of conservative surgeries, evaluate the chemosensitivity in vivo and analyze the management of micrometastases. Neoadjuvant treatment provides a unique setting in which we can monitor clinical, pathological, proliferative and molecular responses. Combining different strategies such us surgery, radiation therapy, chemotherapy, and endocrine therapy has contributed substantially to the survival improvement in breast cancer. Thirdgeneration aromatase inhibitors have proven to be superior to tamoxifen in the adjuvant and, more recently, the neoadjuvant treatment of postmenopausal patients. The need to define how to select the patients that will benefit the most from these therapies, the optimal duration of treatment, the bestmethod to evaluate the treatment response, the identification of predictive factors for response, and the superiority of certain endocrine agents over others have been reviewed. We have carried out a critical analysis of the current literature on the utilization of endocrine therapy in the neoadjuvant setting for breast cancer. This review discusses the current evidence regarding primary endocrine therapy and the current opinions on length of treatment and measurement of response prior to surgery.

Neoadjuvant endocrine treatment of women with breast cancer

Neoadjuvant therapy has four goals in breast cancer: decrease tumor volume to operate tumors that initially were inoperable, increase the number of conservative surgeries, evaluate the chemosensitivity in vivo and analyze the management of micrometastases. Neoadjuvant treatment provides a unique setting in which we can monitor clinical, pathological, proliferative and molecular responses. Combining different strategies such us surgery, radiation therapy, chemotherapy, and endocrine therapy has contributed substantially to the survival improvement in breast cancer. Third-generation aromatase inhibitors have proven to be superior to tamoxifen in the adjuvant and, more recently, the neoadjuvant treatment of postmenopausal patients. The need to define how to select the patients that will benefit the most from these therapies, the optimal duration of treatment, the best method to evaluate the treatment response, the identification of predictive factors for response, and the superiority of certain endocrine agents over others have been reviewed. We have carried out a critical analysis of the current literature on the utilization of endocrine therapy in the neoadjuvant setting for breast cancer. This review discusses the current evidence regarding primary endocrine therapy and the current opinions on length of treatment and measurement of response prior to surgery.

Neoadjuvant Chemotherapy: Not the Best Option in Estrogen Receptor–Positive, HER2-Negative, Invasive Classical Lobular Carcinoma of the Breast?

In 1973, the European Institute of Oncology performed the first prospective neoadjuvant chemotherapy study in locally advanced, inoperable breast cancer. The original purpose was to downstage the primary tumor in order to achieve surgical resection. This approach has subsequently increased in popularity, and in the last 10 years, randomized controlled trials of neoadjuvant chemotherapy have been performed with a view to further downstage the primary tumor and lymph nodes in order to achieve greater rates of breast-conserving surgery and to test whether systemic therapy given earlier would confer a survival benefit. Although the net result of these trials did demonstrate a higher rate of breast conservation, no overall survival benefit was seen. However, in subgroup analysis, there was a significant survival benefit in patients in whom a complete pathologic response (pCR) was achieved. In the National Surgical Adjuvant Breast and Bowel Project B-18 trial of neoadjuvant chemotherapy, at 9 years median follow-up, the overall survival rate for patients achieving a pCR was 85% compared with 73% in those in whom residual cancer was detected on histopathologic examination. For disease-free survival, the respective rates were 75% and 58%. After adjustment for other prognostic factors, achievement of a pCR was associated with a 50% reduction in deaths compared with the group as a whole. Mauri et al evaluated nine randomized studies, with a total of 3,946 patients with breast cancer in whom neoadjuvant therapy was compared with adjuvant systemic therapy. They found no statistically or clinically significant difference between neoadjuvant therapy and adjuvant therapy arms with regard to overall survival, disease progression, or distant disease recurrence. However, they observed that neoadjuvant therapy was associated with an increased risk of locoregional disease recurrence compared with adjuvant therapy, especially in trials where more patients in the neoadjuvant arm received radiation therapy without surgery. In several retrospective studies, the pCR rates in invasive ductal breast carcinoma (no special type) have been shown to be approximately 15% or less, whereas the pCR rates in invasive lobular carcinoma have been shown to be 2% or less. Katz et al reviewed randomized trials of neoadjuvant chemotherapy and noted that the pCR rate was 1.7% in invasive lobular carcinoma and 11.6% in invasive ductal breast carcinoma (no special type). Regarding invasive lobular carcinoma, they concluded: “the benefit from systemic chemotherapy for individuals with this form of breast disease is unclear.” Similarly, two retrospective studies have demonstrated low rates of successful breast conservation for patients with lobular carcinoma who underwent neoadjuvant chemotherapy. In patients who received breast-conserving surgery after neoadjuvant therapy, Soucy et al found surgical margin involvement in 43% of patients with lobular carcinoma compared with 16% of patients with invasive ductal carcinoma (no special type). Another study, from the M. D. Anderson Cancer Center, of 284 consecutive patients diagnosed with pure invasive lobular carcinoma between 1998 and 2006 compared patients who received neoadjuvant chemotherapy with those who received primary surgery as first-line treatment and concluded that neoadjuvant chemotherapy did not increase the rates of breast conservation in this morphologic subtype. It should be noted that the above studies are retrospective, not randomized, trials. In the three randomized trials of neoadjuvant endocrine therapy (P024 conducted by the Letrozole Neoadjuvant Breast Cancer Study Group, IMPACT [Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen], and PROACT [Pre-Operative “Arimidex” Compared to Tamoxifen]) for women with estrogen receptor (ER) –positive disease, none of which carried out analysis of histological tumor type (ie, lobular v ductal [no special type]), a higher rate of breast conservation was observed in women who received preoperative endocrine treatment. The lack of subgroup analysis in these three studies does not allow one to draw conclusions regarding histologic type-specific effectiveness of neoadjuvant endocrine treatment, although classical lobular carcinoma is well recognized as more often being ER positive than ductal tumors (no special type). JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 28 NUMBER 22 AUGUST 1 2010

Tumor Ki67 Proliferation Index within 4 Weeks of Initiating Neoadjuvant Endocrine Therapy for Early Identification of Non-Responders.

Abstract Background: The Preoperative Endocrine Prognostic Index (PEPI) scores the independent prognostic effects of tumor pathologic staging and expression levels of ER and the “proliferation” marker Ki67 in the surgical sample to predict long term outcomes after completion of neoadjuvant endocrine treatment (Ellis et al JNCI 100:1380, 2008). A limitation of the PEPI is that the prognostic information becomes available only after 4 months of treatment. We therefore evaluated the value of an early assessment of the Ki67 level in a tumor biopsy sample taken two to four weeks after initiating treatment in two neoadjuvant endocrine therapy trials for the purposes of the early identification of non- respondersMethods: A Ki67 cut point of greater than 10% for poor outcome in ER+ breast cancer was derived by comparing the PAM50 intrinsic subtype profile using a qRT-PCR assay with Ki67 data in a 700+ sample data set. A baseline level of 10% or less correlated most closely with a PAM50-based definition of LumA breast cancer and above 10% LumB breast cancer. We subsequently applied the 10% cut point to the baseline and early on-treatment Ki67 data in two trials, POL (Olson et al JACS 208:906, 2009) and IMPACT (Smith et al JCO: 23, 5108, 2005).Results: At baseline the dichotomized Ki67 definition was not significantly predictive for surgical Ki67 level, PEPI score or RFS in this modest size sample set. In contrast, in a result that emphasizes the enhaced prognostic properties of the on-treatment Ki67 approach, the one month POL sample Ki67 values (62 patients) predicted a higher level of Ki67 in the surgical samples at four months after treatment initiation (P=.01), a poorer PEPI score (P=0.01), a smaller number of patients in the PEPI risk point zero group (P=0.08) and worse relapse free survival (P=0.003). The IMPACT data (153 patients) confirmed that a two week Ki67 &amp;gt;10% predicted higher Ki67 in the surgical specimen (P=0.001), a poorer PEPI score (P=0.001), smaller numbers of patients in the PEPI 0 risk point group (P= 0.004) and worse relapse free survival (P=0.008).Ki67 and OutcomePOL 4W Ki67% PEPI 0RFS (events)10%&amp;gt;1/19 (5%)5/21 (23%)10%≤10/36 (28%)1/41 (2.4%)P ValueP=0.08 (Fisher)P=0.003 (log rank)IMPACT 2W Ki67% PEPI 0RFS (events)10%&amp;gt;0/32 (0%)9/35 (26%)10%≤21/101 (21%)13/118 (11%)P ValueP=0.004 (Fisher)P=0.008 (log rank) Conclusions: A tumor Ki67 assessment taken a short time (2 to 4 week window) after the initiation of neoadjuvant AI identifies patients with poor outcome ER+ disease. Amendment 6 of the neoadjuvant endocrine therapy protocol ACOSOG Z1031 will triage patients with an “on treatment” Ki67 value above 10% to chemotherapy in order to assess the pathological response rate to cytotoxic therapy in this important tumor subset.Supported by R01 CA095614, Avon PFP award 3P50 CA68438-07S2, U01 CA114722, ACOSOG U10 CA 76001, Breakthrough Cancer UK and AstraZenica (IMPACT trial). Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 78.

Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer

Mutations in the alpha catalytic subunit of phosphoinositol-3-kinase (PIK3CA) occur in approximately 30% of ER positive breast cancers. We therefore sought to determine the impact of PIK3CA mutation on response to neoadjuvant endocrine therapy. Exons 9 (helical domain) and 20 (kinase domain-KD) mutations in PIK3CA were determined samples from four neoadjuvant endocrine therapy trials.Interactions with clinical, pathological, and biomarker response parameters were examined. A weak negative interaction between PIK3CA mutation status and clinical response to neoadjuvant endocrine treatment was detected(N = 235 P < or = 0.05), but not with treatment-induced changes in Ki67-based proliferation index (N = 418). Despite these findings, PIK3CA KD mutation was a favorable prognostic factor for relapse-free survival (RFS log-rank P = 0.02) in the P024 trial (N = 153). The favorable prognostic effect was maintained in a multivariable analysis(N = 125) that included the preoperative endocrine prognostic index, an approach to predicting RFS based on post neoadjuvant endocrine therapy pathological stage, ER, and Ki67 levels (HR for no PIK3CA KD mutation, 14, CI 1.9-105 P = 0.01). PIK3CA mutation status did not strongly interact with neoadjuvant endocrine therapy responsiveness in estrogen receptor-positive breast cancer. Nonetheless, as with other recent studies, a favorable interaction between PIK3CA KD mutation and prognosis was detected. The mechanism for the favorable prognostic impact of PIK3CA mutation status therefore remains unexplained.