Preoperative Endocrine Therapy Research Articles

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.

Immunohistochemical Ki67 after short-term hormone therapy identifies low-risk breast cancers as reliably as genomic markers.

BackgroundThe purpose of this study was to test whether immunohistochemical (IHC) Ki67 levels after short-term preoperative hormone therapy (post-Ki67) predict similar numbers of patients with favorable prognoses as genomic markers.ResultsThirty paired cases (60 samples) were enrolled in this study. Post-Ki67 levels were significantly lower than pre-treatment Ki67 levels (P < 0.001). Post-Ki67 predicted more low-risk cases (83.3%, 25/30) than pre-genomic surrogate signature(GSS) (66.7%: 20/30), but the difference in predictive power was not significant (P = 0.233). Proliferation (MKI67, STK15, Survivin, CCNB1, and MYBL2) and estrogen (ER, PGR, BCL2, and SCUBE2) related signatures were significantly downregulated after therapy (P < 0.001 and 0.041, respectively).Materials and MethodsCore needle biopsy specimens of primary breast cancer were collected at Okayama University Hospital from hormone receptor-positive and human epidermal growth factor 2-negative patients that subsequently received two weeks of neoadjuvant hormone therapy. Paired post-treatment specimens from surgical samples were also collected. IHC Ki67 levels and GSS were compared between pre- and post-hormone treatment samples. Changes of gene expression pattern in short-term hormone therapy were also assessed.ConclusionsIHC based post-Ki67 levels may have distinct predictive power compared with the naïve IHC Ki67. Future studies with larger cohorts and longer follow-up periods may be needed to validate our results.

Postoperative early ultrasensitive prostate-specific antigen identifies patients at risk for biochemical recurrence in margin positive prostate cancers: a single-center study.

To identify predictors for biochemical recurrence among patients with positive surgical margins (RM1) after radical prostatectomy and to examine the effect of ultrasensitive prostate-specific antigen measured early after prostatectomy on biochemical recurrence. We identified 705 patients with prostate cancer who were treated with radical prostatectomy without preoperative hormonal therapy at our institution between 2000 and 2014. The patients with RM1 who had a postoperative prostate-specific antigen <0.2 ng/ml without lymph node metastasis were evaluated for biochemical recurrence-free survival. Survival rates were calculated using the Kaplan-Meier method. The Cox regression model was used for multivariate analysis. The prediction of biochemical recurrence was assessed using area under the curve of the receiver operating characteristic. Among the 705 patients, 190 (27%) had RM1. Biochemical recurrence was evaluated in 164 patients, excluding 26 patients who underwent adjuvant therapy with or without lymph node metastasis. With a median follow-up of 55 months, the biochemical recurrence-free survival rate of the entire RM1 cohort was 78% at 2 years and 64% at 4 years. The multivariate analysis revealed that postoperative early ultrasensitive prostate-specific antigen >0.02 ng/ml was the significant risk factor for biochemical recurrence (hazard ratio 13.10). Meanwhile, the patients with postoperative early ultrasensitive prostate-specific antigen <0.01 ng/ml had a significantly lower risk for biochemical recurrence (hazard ratio 0.12). Area under the curve for the postoperative early ultrasensitive prostate-specific antigen value to predict biochemical recurrence was 0.789. The ultrasensitive prostate-specific antigen value measured early after prostatectomy was the potent predictor of biochemical recurrence among the patients with RM1.

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.

Personalization of loco-regional care for primary breast cancer patients (part 2).

Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the second of a two part conference scene, consensus recommendations for radiation treatment, primary systemic therapies and management of genetic predisposition are reported and focus on the following topics: influence of both clinical response to PST and stage at presentation on recommendations for postmastectomy radiotherapy; use of regional nodal irradiation in selected node-positive patients and those with adverse pathological factors; extent of surgical resection following downstaging of tumors with PST; use of preoperative hormonal therapy in premenopausal women with larger, node-negative luminal A-like tumors and managing increasing demands for contralateral prophylactic mastectomy in patients with a unilateral sporadic breast cancer.

Personalization of loco-regional care for primary breast cancer patients (part 1).

ABSTRACT Kyoto Breast Cancer Consensus Conference, Kyoto, Japan, 18-20 February 2014 The loco-regional management of breast cancer is increasingly complex with application of primary systemic therapies, oncoplastic techniques and genetic testing for breast cancer susceptibility. Personalization of loco-regional treatment is integral to optimization of breast cancer care. Clinical and pathological tumor stage, biological features and host factors influence loco-regional treatment strategies and extent of surgical procedures. Key issues including axillary staging, axillary treatment, radiation therapy, primary systemic therapy (PST), preoperative hormonal therapy and genetic predisposition were identified and discussed at the Kyoto Breast Cancer Consensus Conference (KBCCC2014). In the first of a two part conference scene, consensus recommendations for axillary management are presented and focus on the following topics: indications for completion axillary lymph node dissection in primary surgical patients with ≤2 macrometastases or any sentinel nodal deposits after PST; the timing of sentinel lymph node biopsy in the context of PST; use of axillary irradiation as a component of primary treatment plans and the role of intraoperative node assessment in the post-Z0011 era.

Meta-analysis of Androgen Insensitivity in Preoperative Hormone Therapy in Hypospadias

To define androgen insensitivity prevalence in hypospadias patients treated with preoperative hormone therapy. We searched databases that were published in English and Chinese up to September 10, 2014 for our studies. Eligibility criteria were pre-established. Title, abstract, and full-text screenings were conducted by 2 authors independently. Discrepancies were resolved by consensus. Quality assessment of included studies was completed. Meta-analysis was done when appropriate using R, version 3.1.1 for Windows. Heterogeneity among individual studies was tested using the Cochran chi-square Q test and quantified by calculating the I(2) index. Thirteen of 1278 publications met inclusion criteria and were incorporated into this study. Of 306 patients with preoperative hormone therapy, 25 displayed androgen resistance. Meta-analysis demonstrated that the random-effects model generates a pooled estimate of 7.14% (95% confidence interval [CI], 3.16%-15.31%), whereas the fixed-effect model provides an estimate of 14.61% (95% CI, 10.00%-20.85%). Heterogeneity among included studies was found above medium (I(2) = 67.1% [95% CI, 41.2%-81.6%]; P = .0003]. After exclusion of the heterogeneity, both random-effects and fixed-effect models produce a consistent pooled estimate of 6.95% (95% CI, 0%-47.8%). We have defined that the prevalence of androgen resistance in hypospadias is 7.14% (95% CI, 3.16%-15.31%). To distinguish isolated hypospadias from patients with androgen insensitivity syndrome, we recommend that androgen-resistant patients should be specifically targeted by molecularly focused diagnosis. Management strategies should include identification of mutations in the androgen receptor gene, timely surgery to repair hypospadias, and long-term follow-up of sexual function and fertility later in life.

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).

Microdissection testicular sperm extraction for non-mosaic klinefelter syndrome patients

OBJECTIVE: Fertilization and pregnancies can be obtained with spermatozoa recovered not only from the ejaculate, but seminiferous tubules (testicular sperm extraction, TESE). Microdissection (Micro)TESE, in combination with intracytoplasmic sperm injection (ICSI), presently is used to treat infertility in cases of NOA including Klinefelter syndrome (KS). KS is the most common sex-chromosome disorder among infertile males, with a prevalence of 1 in 660 men and is a frequent cause of hypogonadism and infertility. The aim of this study is to assess the prevalence and the significance including sperm retrieval rate (SRR) by micro-TESE in non-obstructive azoospermic patients including KS. DESIGN: Retrospective clinical analysis. MATERIALSANDMETHODS: The records were retrospectively evaluated for 1028 NOA patients (including 123 non-mosaic KS patients) who were underwent micro-TESE. Chromosomal analysis was performed on all patients on cultured lymphocytes from peripheral blood. Micro-TESE was used in which seminiferous tubule are directly examined throughout the testicle using an operating microscope and selectively biopsied for all of the NOA patients in modified Schlegel’s method. We did not undergo preoperative hormonal therapy for KS patients. In our study, KS patients did not have microdeletion of Y chromosomes. RESULTS: Testicular sperm were successfully retrieved by microTESE in 69 of 123 (56.1%) non-mosaic KS and 380 of 905 (42.0%) not KS NOA patients. Of these, 48 (69.6%) KS and 344 (90.5%) not KS NOA patinets had sperm identified through the initial wide incision alone. For patients with KS, the chance of sperm retrieval on the contralateral side after a negative unilateral microdissection was 28.0% (21/75) and significant higher than not KS NOA patients (36/5611⁄46.4%) (p <0.001). In almost all patients in whom micro-TESE was successful we could identify focal spermatogenesis in dilated and opaque seminiferous tubules surrounded by shrunken tubules or fibrous tissue. No correlation was found between serum FSH, LH, and T level with the success of sperm retrieval. Testicular volume also did not affect the SRR for micro-TESE. Patient age in successful micro-TESE for cases of KS is significantly younger (33.5 4.2 years) than that in failed cases (37.4 3.9 years) (p <0.05). CONCLUSION: Micro-TESE is particularly helpful for successful sperm retrieval in KS cases. In NOA, the absence of uniformity in testicular tissue is a critical key to succeed and rationale in microTESE.

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.

Long-term results of radical prostatectomy with immediate adjuvant androgen deprivation therapy for pT3N0 prostate cancer

BackgroundRadical prostatectomy is used to treat patients with clinically localized prostate cancer, but there have been few reports of its use in locally advanced disease. We evaluated the long-term results of radical prostatectomy and immediate adjuvant androgen deprivation therapy in Japanese patients with pT3N0M0 prostate cancer.MethodsWe retrospectively reviewed 128 patients with pT3N0M0 prostate cancer who underwent radical prostatectomy at our institute from 2000 to 2006. All pT3N0 patients were treated with adjuvant androgen deprivation therapy shortly after radical prostatectomy. Immediate adjuvant androgen deprivation therapy was continued for at least 5 years. Twenty-three were excluded because of preoperative hormonal therapy, missing data, or others. Death from any cause, death from prostate cancer, clinical recurrence and hormone-refractory biochemical progression were analyzed by Kaplan-Meier graphs. Relative risks of progression were estimated using Cox proportional hazards models with 95% confidence intervals.ResultsThe 10-year hormone-refractory biochemical progression-free survival rate was 88.3% and the cancer-specific survival rate was 96.3% after a median follow-up period of 8.2 years (range 25.6-155.6 months). Higher clinical stage (p = 0.013), higher Gleason score at biopsy (p = 0.001), seminal vesicle invasion (p = 0.003) and microlymphatic invasion (p = 0.006) were predictive factors for hormone-refractory biochemical progression by univariate analyses. Multivariate analyses identified Gleason score at biopsy (p = 0.027) and seminal vesicle invasion (p = 0.030) as independent prognostic factors for hormone-refractory biochemical progression. None of the patients with clinical T1 cancers (n = 20), negative surgical margin (n = 12), or negative perineural invasion (n = 11) experienced hormone-refractory biochemical progression.ConclusionsRadical prostatectomy with immediate adjuvant androgen deprivation therapy may be a valid treatment option for patients with pT3N0M0 prostate cancer.

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.

The Impact of Clinical Stage on Prostate Cancer Survival Following Radical Prostatectomy

Clinical stage has been incorporated into multiple risk stratification models for patients with newly diagnosed prostate cancer. However, the independent prognostic value of this variable remains open to debate. In this study we evaluated the association of clinical stage with death from prostate cancer in men who underwent radical prostatectomy and assessed for changes in its prognostic value over time. We reviewed the records of 14,842 consecutive patients who underwent radical prostatectomy at our institution between 1970 and 2008 without having received preoperative hormone or radiation therapy. Postoperative disease recurrence was estimated using the Kaplan-Meier method and compared using the log rank test. Multivariate Cox proportional hazard regression models were used to analyze the association of clinical stage with outcome. A total of 5,725 (38.6%) men were classified as having cT1 tumors, 8,160 (55.0%) cT2 tumors and 957 (6.4%) cT3 disease. On univariate analysis clinical stage was significantly associated with postoperative biochemical recurrence, systemic progression and death from prostate cancer (p <0.001 for each). Moreover on multivariate analysis clinical stage was significantly associated with death from cancer for patients treated before (1.45, p = 0.006) and those treated during (1.96, p <0.001) the prostate specific antigen era. Furthermore, the incorporation of clinical stage into contemporary risk stratification improved the prediction of cancer specific survival (c statistic 0.782 without and 0.802 with clinical stage). Clinical stage is significantly associated with systemic progression and death from prostate cancer. Inclusion of this variable in multivariate prediction models improves the prediction of systemic progression and cancer specific survival.