Chemohormonal Therapy Research Articles

Predicting response to neoadjuvant chemotherapy in nonmetastatic hormone receptor-positive breast cancer using 21-gene Breast Recurrence Score test.

e12093 Background: The Recurrence Score (RS) result based on the 21-gene Oncotype DX Breast Recurrence Score assay is standard of care in deciding adjuvant chemo-hormonal therapy versus hormone therapy alone in hormone-receptor positive (HR+), HER 2 negative, node–negative breast cancer. This study explores the role of RS result in predicting the response to neoadjuvant chemotherapy (NACT). Methods: In this retrospective single institution cohort study, electronic medical records of 148 women with HR+, HER 2 negative, non-metastatic breast cancer who received NACT from 2006 onward were screened. 38 patients were excluded due to lack of tissue for testing. Pretreatment biopsy blocks were sent to Genomic Health, Inc. for Oncotype Dx testing. Low RS result was defined as ≤25. Pathologic complete response (pCR) was defined as no residual tumor. Partial response (PR) was residual tumor with > 25% decrease in the largest dimension. No response (NR) was defined as < 25% decrease in the tumor post NACT. Progression (PD) was defined as increase in size of original tumor or new site(s) of disease. Results: Of the 110 patients studied, 58% were postmenopausal women. Fifty percent were African American, 12% were Caucasian and 27% were Hispanic. Invasive ductal carcinoma was the predominant histology (86%). Most patients had > T2 disease (97%) with 73% being clinically node positive. Adriamycin based NACT regimen was used in treating 86.3% of the women. Forty patients (36.4%) had tumor with RS≤25. NR/PD was significantly higher in tumors with RS≤25 (27/40) vs RS > 25 (13/70) (OR: 9.1, 95% CI: 3.7-22.2, P< 0.001). pCR was seen in 16% with RS > 25 and 0% with RS ≤25. Response to NACT (pCR/PR) was 32.5% in RS≤25 vs 81.4% in RS > 25. In tumors with response, RS > 25 was associated with a greater percent decrease in the tumor size compared to RS≤25 (median decrease of 71% vs 52%, P= 0.033). Conclusions: HR+, HER 2 negative, RS≤25 breast cancer is associated with increased rates of NR/PD and is unlikely to respond to NACT. Recurrence Score result determination in pretreatment breast cancer biopsy samples can be an effective tool to select patients with non-metastatic breast cancer for NACT. Studies are needed to determine novel neoadjuvant therapeutic approaches in patients who are candidates for neoadjuvant therapy but are unlikely to benefit from NACT.

Cabazitaxel with abiraterone versus abiraterone alone randomized trial for extensive disease following docetaxel: the CHAARTED 2 Trial: A trial of the ECOG-ACRIN Cancer Research Group (EA8153).

TPS5094 Background: The E3805 CHAARTED trial showed a significant survival benefit from early treatment with docetaxel in patients (pts) with high-volume metastatic hormone-sensitive prostate cancer (HSPC). However, eventually all these patient will develop castration-resistant disease (CRPC) and it is currently unknown what is the optimal treatment in that setting. We hypothesize that treatment with a second round of chemohormonal therapy –this time in the CRPC setting- will improve outcomes. Methods: This is a prospective randomized phase II open label trial led by ECOG-ACRIN. Pts (N = 210) with metastatic CRPC who have previously received docetaxel for HSPC will be randomized to 2 treatment arms (1:1): abiraterone/prednisone plus cabazitaxel for up to 6 cycles versus abiraterone/prednisone alone. Stratification factors include ECOG performance status, time from initiation of ADT to development of CRPC and visceral versus bone only metastases. The primary objective is to evaluate the efficacy of abiraterone/prednisone plus cabazitaxel versus abiraterone/prednisone alone. The primary endpoint of the trial is progression-free survival (PFS), defined clinically or radiographically. Secondary endpoints include PSA response, radiographic response, time to PSA progression, overall survival and safety. Exploratory objectives include response assessment based on AR-V7 status as well as by NaF PET/CT imaging. Key inclusion criteria include: metastatic CRPC, prior treatment with at least 3 cycles of docetaxel for metastatic HSPC, no prior treatment for CRPC (radium-223 or sipuleucel-T excluded), ECOG performance status of 0-2 and peripheral neuropathy of less than 2. The study was activated on 02/08/2018. As of 01/21/2019, 28/210 pts have been enrolled. Support: CA180820, CA180794, CA180799, CA180802; and Genzyme Corporation, a subsidiary of Sanofi S.A. Clinical trial information: NCT03419234.

Going towards a precise definition of the therapeutic management of de-novo metastatic castration sensitive prostate cancer patients: How prognostic classification impact treatment decisions

De-novo metastatic castration sensitive prostate cancer (mCSPC) is a subgroup of prostate cancer associated with poor prognosis. Recently, the treatment of mCSPC has been enriched by new life-prolonging options, including the combination of docetaxel or abiraterone acetate with androgen deprivation therapy (ADT). Of note, the advantage of chemohormonal therapy was more relevant in the subgroup of high-volume disease compared to low-volume, while the survival prolongation of abiraterone was observed only in high-risk patients. Choosing the most appropriate therapy is one of the most debated issues. This review describes the latest news on de-novo mCSPC to better outline patients' management. At the ESMO 2018 Congress two novel studies focused on this setting have been presented, trying to define the role of radiotherapy to the primary tumour and the efficacy of abiraterone acetate in the subset of low-risk patients. We have analysed these results in light of the evidence already available.

Targeting Metastatic Hormone Sensitive Prostate Cancer: Chemohormonal Therapy and New Combinatorial Approaches.

Androgen deprivation therapy alone has been the standard of care for metastatic hormone sensitive prostate cancer for the last 75 years. This review focuses on recent trials and mechanisms which highlight the new paradigm of combining androgen deprivation therapy with other agents, changing the treatment of patients with prostate cancer who have advanced disease. We searched the peer reviewed literature on the PubMed® and Web of Science® databases through January 2018 using the key words, "metastatic hormone sensitive prostate cancer," "metastatic castration sensitive prostate cancer," "docetaxel," "abiraterone" and "senescence in cancer." ClinicalTrials.gov was queried for ongoing studies. Relevant data recently presented at major urology and medical oncology meetings were also evaluated. Recently published, phase III trials using androgen deprivation therapy combinations for metastatic hormone sensitive prostate cancer can be broadly grouped into chemohormonal studies (docetaxel) or trials of androgen signaling inhibitors. The CHAARTED (Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) and STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) studies showed a survival advantage when combining androgen deprivation therapy with chemotherapy, as well as increased time to progression to castration resistant status. The abiraterone arm of the STAMPEDE and LATITUDE trials, which analyzed combining androgen deprivation therapy with abiraterone, revealed improved overall and progression-free survival. Androgen deprivation therapy generates a number of phenotypes in resistant cancer cells, including quiescence, autophagy and cellular senescence. Senescent cells represent a metabolic target for synergistic lethality with drugs such as metformin. Ongoing trials are under way to examine the effect of combining newer antiandrogens and novel drugs with androgen deprivation therapy in patients with metastatic hormone sensitive prostate cancer. Combination therapy has evolved as the standard of care for metastatic hormone sensitive prostate cancer. The ideal combination is tailored to patients after individualized counseling taking into account general health and comorbid illness status.

NEOADJUVANT FOR PATIENTS WITH HIGH AND VERY HIGH RISK PROSTATE CANCER

Objective: to assess safety, pathological response rate, and long-term oncologic outcomes of radical prostatectomy (RP) after neoadjuvant chemotherapy using docetaxel in prostate cancer (PCa) patients of high and very high risk groups. Materials and methods: 86 patients with high and very high risk PCa (PSA>20 ng/ml, Gleason score 8 and more, or clinical stage cT2c and more) were included, among them 46 received neoadjuvant (NCGT/RP group) treatment followed by RP and 40 patients received RP only. with a median follow-up of 11.4 years after RP. Neoadjuvant treatment included 3-weekly docetaxel (75 mg/m2 for up to 6 cycles) with concomitant degarelix (6 monthly injections). Results: NCGT cycle was started in 39 patients and completed in full dose and planned regimen in 34 (87.2%) patients. Toxicities were moderate. A statistically significant reduction of PSA>50% post-chemohormonal therapy was observed in all 39 cases. Among patients with completed neoadjuvant treatment RP was performed in 33 (97.1%) patients. Lower postoperative stage was noticed in 38.5% in NCGT/RP group compared with 2.7% in RP group. Similarly, positive surgical margin rate was higher in group without neoadjuvant therapy - 43.2% and 25.6% (RP group). Adjuvant or deferred treatment received 25 (67.6%) and 13 (39.4%) in RP and NCGT/RP group, respectively. Conclusion: The use of neoadjuvant chemohormonal therapy before the RP in selected regimen and dose represents a safe strategy resulting in benefit in early oncological results. Given the limitations of the study this concept should be evaluated in large prospective controlled studies.

Expected Monetary Impact of Oncotype DX Score-Concordant Systemic Breast Cancer Therapy Based on the TAILORx Trial.

TAILORx demonstrated that women with node-negative, hormone receptor-positive, HER2-negative breast cancers and Oncotype DX recurrence scores (RS) of 0-25 had similar 9-year outcomes with endocrine vs chemo-endocrine therapy; evidence for women aged 50 years and younger and RS 16-25 was less clear. We estimated how expected changes in practice following the trial might affect US costs in the initial 12 months of care (initial costs). Data from Surveillance, Epidemiology, and End Results (SEER), SEER-Medicare, and SEER-Genomic Health Inc datasets were used to estimate Oncotype DX testing and chemotherapy rates and mean initial costs pre- and post-TAILORx (in 2018 dollars), assuming all women received Oncotype DX testing and score-suggested therapy posttrial. Sensitivity analyses tested the impact on costs of assumptions about compliance with testing and score-suggested treatment and estimation methods. Pretrial mean initial costs were $2.816 billion. Posttrial, Oncotype DX testing costs were projected to increase from $115 to $231 million and chemotherapy use to decrease from 25% to 17%, resulting in initial care costs of $2.766 billion, or a net savings of $49 million (1.8% decrease). A small net savings was seen under most assumptions. The one exception was if all women aged 50 years and younger with tumors with RS 16-25 elected to receive chemotherapy, initial care costs could increase by $105 million (4% increase). Personalizing breast cancer treatment based on tumor genetic profiles could result in small cost decreases in the initial 12 months of care. Studies are needed to evaluate the long-term costs and nonmonetary benefits of personalized cancer care.

4-Hydroxytamoxifen enhances sensitivity of estrogen receptor α-positive breast cancer to docetaxel in an estrogen and ZNF423 SNP-dependent fashion.

In early stage, ERα-positive breast cancer, concurrent use of endocrine therapy and chemotherapy has not been shown to be superior to sequential use. We hypothesized that genetic biomarkers can aid in selecting patients who would benefit from chemo-endocrine therapy. Our previous studies revealed that ZNF423 is a transcription factor for BRCA1 and an intronic single nucleotide polymorphism (SNP) in ZNF423, rs9940645, determines tamoxifen response. Here, we identified mitosis-related genes that are regulated by ZNF423 which led us to investigate taxane response in a rs9940645 SNP- and tamoxifen-dependent fashion. The Cancer Genome Atlas (TCGA) breast cancer dataset was used to identify genes correlated with ZNF423. Quantitative reverse transcription PCR, chromatin immunoprecipitation, and luciferase reporter assays were used to validate the gene regulation. We used CRISPR/Cas9 to engineer paired ZR-75-1 cells which differ only in ZNF423 rs9940645 SNP genotype to test SNP-dependent phenotypes including cell cycle and cell viability. We validated our findings in an additional two breast cancer cell lines, Hs578T-ERα and HCC1500. Mitosis-related genes VRK1 and PBK, which encode histone H3 kinases, were experimentally validated to be regulated by ZNF423. ZNF423 knockdown decreased VRK1 and PBK expression and activity. Additionally, ZNF423 knockdown enhanced docetaxel-induced G2/M arrest and cytotoxicity through VRK1 or PBK regulation. Lastly, cells carrying the rs9940645 variant genotype had increased G2/M arrest and decreased cell viability when treated with docetaxel in combination with estradiol and 4-OH-TAM. We identified ZNF423 regulated genes involved in the G2/M phase of the cell cycle. 4-OH-TAM sensitized ERα-positive breast cancer cells to docetaxel in a ZNF423 SNP-dependent manner. Our findings suggest that patients with rs9940645 variant genotype may benefit from concurrent tamoxifen and docetaxel. This would impact a substantial proportion of patients because this SNP has a minor allele frequency of 0.47.

LBA-12 CALGB 90203 (ALLIANCE): RADICAL PROSTATECTOMY WITH OR WITHOUT NEOADJUVANT CHEMOHORMONAL THERAPY IN MEN WITH CLINICALLY LOCALIZED, HIGH RISK PROSTATE CANCER

INTRODUCTION AND OBJECTIVES:Radical prostatectomy (RP) is a mainstay of treatment for men with clinically localized, high risk prostate cancer (CLHRPC). We assessed whether chemohormonal therapy wi...

Taxane-based chemohormonal therapy for metastatic hormone-sensitive prostate cancer: a Cochrane Review.

To provide a precis of the Cochrane Collaboration Review of taxane-based chemohormonal therapy for metastatic hormone-sensitive prostate cancer by Sathianathen NJ, Philippou YA, Kuntz GM etal. Cochrane Database of Systematic Reviews 2018, Issue 10. Art. No.: CD012816. https://doi.org/10.1002/14651858.cd012816.pub2.

Concurrent neoadjuvant chemotherapy and estrogen deprivation in patients with estrogen receptor–positive, human epidermal growth factor receptor 2–negative breast cancer (CBCSG‐036): A randomized, controlled, multicenter trial

The current randomized, controlled, multicenter clinical trial was conducted to investigate the efficacy of concurrent neoadjuvant chemotherapy (NCT) and estrogen deprivation in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Eligible patients with AJCC stage IIB to stage IIIC, ER-positive, HER2-negative breast cancer were enrolled and randomly assigned to receive NCT with or without estrogen deprivation. The primary endpoint was the objective response rate (ORR). A total of 249 patients were assigned to either neoadjuvant chemoendocrine therapy (NCET) (125 patients) or the NCT group (124 patients). In the intention-to-treat analysis, the ORR was found to be significantly higher in the NCET group compared with the NCT group (84.8% vs 72.6%; odds ratio, 2.11 [95% CI, 1.13-3.95; P=.02). The efficacy of NCET was more prominent in tumors with a higher Ki-67 index (>20%), with an ORR of 91.2% reported in the NCET group versus 68.7% in the NCT group (P=.001). The pathologic complete response and pathological response rates did not differ significantly between the 2 groups. Although there was no significant difference with regard to progression-free survival (PFS) between the 2 groups (P=.188), patients with a higher baseline Ki-67 index appeared to derive a greater PFS benefit from NCET (2-year PFS rate of 91.5% in the NCET group vs 76.5% in the NCT group; P=.058). Adding endocrine agents to NCT did not result in significant differences in adverse events (grade 3 or 4; graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) between the 2 groups. The addition of estrogen deprivation to NCT appears to improve the clinical response in patients with ER-positive, HER2-negative breast cancer, especially for those individuals with a higher Ki-67 index. Patients with a higher Ki-67 index might derive more PFS benefit from concurrent neoadjuvant treatment.

Clinical validation of an immunohistochemistry-based CanAssist-Breast test for distant recurrence prediction in hormone receptor-positive breast cancer patients.

CanAssist‐Breast (CAB) is an immunohistochemistry (IHC)‐based prognostic test for early‐stage Hormone Receptor (HR+)‐positive breast cancer patients. CAB uses a Support Vector Machine (SVM) trained algorithm which utilizes expression levels of five biomarkers (CD44, ABCC4, ABCC11, N‐Cadherin, and Pan‐Cadherin) and three clinical parameters such as tumor size, grade, and node status as inputs to generate a risk score and categorizes patients as low‐ or high‐risk for distant recurrence within 5 years of diagnosis. In this study, we present clinical validation of CAB. CAB was validated using a retrospective cohort of 857 patients. All patients were treated either with endocrine therapy or chemoendocrine therapy. Risk categorization by CAB was analyzed by calculating Distant Metastasis‐Free Survival (DMFS) and recurrence rates using Kaplan‐Meier survival curves. Multivariate analysis was performed to calculate Hazard ratios (HR) for CAB high‐risk vs low‐risk patients. The results showed that Distant Metastasis‐Free Survival (DMFS) was significantly different (P‐0.002) between low‐ (DMFS: 95%) and high‐risk (DMFS: 80%) categories in the endocrine therapy treated alone subgroup (n = 195) as well as in the total cohort (n = 857, low‐risk DMFS: 95%, high‐risk DMFS: 84%, P < 0.0001). In addition, the segregation of the risk categories was significant (P = 0.0005) in node‐positive patients, with a difference in DMFS of 12%. In multivariate analysis, CAB risk score was the most significant predictor of distant recurrence with hazard ratio of 3.2048 (P < 0.0001). CAB stratified patients into discrete risk categories with high statistical significance compared to Ki‐67 and IHC4 score‐based stratification. CAB stratified a higher percentage of the cohort (82%) as low‐risk than IHC4 score (41.6%) and could re‐stratify >74% of high Ki‐67 and IHC4 score intermediate‐risk zone patients into low‐risk category. Overall the data suggest that CAB can effectively predict risk of distant recurrence with clear dichotomous high‐ or low‐risk categorization.

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

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

Abstract GS6-03: Symptoms and health-related quality of life on endocrine therapy alone (E) versus chemoendocrine therapy (C+E): TAILORx patient-reported outcomes results

Abstract Background: TAILORx patient-reported outcomes (PRO) quantify symptoms and health-related quality of life (HRQL) from C+E beyond E alone from the patient's perspective, thus can inform decision-making for women in the intermediate risk group for whom chemotherapy may still be considered. Methods: TAILORx participants with OncoType DX Recurrence Scores 11-25 were randomly assigned to E or C+E. All TAILORx participants enrolled 1/2010-10/2010 (N=612) completed PROs measuring fatigue, endocrine symptoms, cognitive impairments (PCI), and fear of recurrence at baseline, 3, 6, 12, 24 and 36 months. HRQL was assessed at baseline, 12, and 36 months. Linear regression (LR) examined PRO scores among the per-protocol sample. Results: Overall, participants reported significantly more fatigue, endocrine symptoms and PCI at 3, 6, 12, 24 and 36 months compared to baseline and those randomized to C+E reported a greater magnitude of change baseline-3 months compared to those randomized to E alone (Table 1). Overall, by 12 months symptoms were comparable between groups. Pre-menopausal women had comparable symptoms at 24 and 36 months. Post-menopausal women randomized to C+E had greater endocrine symptoms at 24 and 36 months and greater fatigue at 6 and 24 months. Fear of recurrence was comparable between arms during treatment and follow-up. Multiple linear regression identified increased fatigue (LR slope β=0.67), endocrine symptoms (β =0.14), and PCI (β=0.11) as significant predictors of decreased HRQL across arms (p&amp;lt; 0.001). HRQL was comparable between E and C+E at 12- and 36-months. Mean PRO change scores from baseline by treatment arm and menopausal status in per protocol population Months 36122436N=Overall454469458384343n=Pre-menopausal153151150118103n=Post-menopausal301318308266240FACIT-Fatigue Overall sample C+E-8.77-4.37-4.01-4.27-3.67E-2.48-1.97-2.14-1.49-1.83LMED-5.32***-1.55-1.01-1.76-0.90Pre-M C+E-8.01-3.26-2.99-2.45-1.60E-3.87-1.66-1.32-2.52-2.11LMED-3.11-0.82-1.121.021.46Post-M C+E-9.22-4.97-4.55-5.14-4.67E-1.87-2.10-2.52-1.09-1.71LMED-6.42***-1.99*-1.16-3.02*-2.01FACT-Endocrine Symptoms Overall sample C+E-5.56-5.63-6.96-6.81-7.14E-3.61-4.24-5.62-5.31-5.17LMED-1.62*-0.97-1.08-1.05-1.69Pre-M C+E-7.62-8.34-7.94-8.29-8.96E-5.96-6.19-8.95-10.39-10.84LMED-1.44-1.631.062.272.18Post-M C+E-4.39-4.19-6.45-6.10-6.28E-2.55-3.41-4.10-3.23-2.87LMED-1.49-0.45-2.04-2.39*-3.17**Significance between mean change scores *p&amp;lt;0.05;**p&amp;lt;0.01;***p&amp;lt;0.001. LMED=estimated tx difference using linear model regressing score on baseline value and tx Conclusions: TAILORx is the first trial to examine patient-reported fatigue, endocrine symptoms, PCI and HRQL among breast cancer patients randomized to endocrine therapy alone vs chemoendocrine therapy, thus allowing us to quantify acute and long-term symptoms uniquely attributable to chemotherapy. As expected, chemotherapy is associated with greater fatigue, endocrine symptoms and PCI acutely during treatment, and for post-menopausal women with greater long-term endocrine symptoms. Increased symptoms were associated with poorer HRQL. Long-term HRQL was comparable between groups. Citation Format: Wagner LI, Gray RJ, Garcia S, Whelan TJ, Tevarweerk A, Yanez B, Carlos R, Gareen I, McCaskill-Stevens W, Cella D, Sparano JA, Sledge, Jr. GW, On behalf of the TAILORx Study Team. Symptoms and health-related quality of life on endocrine therapy alone (E) versus chemoendocrine therapy (C+E): TAILORx patient-reported outcomes results [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS6-03.

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

Abstract Aim To investigate the efficacy and safety of initial neoadjuvant endocrine therapy with exemestane (EXE) alone followed by tailored treatment: continued EXE monotherapy for responders or EXE plus docetaxel–cyclophosphamide (TC) combination therapy for non-responders. Methods This open-label phase II study enrolled postmenopausal patients with primary invasive estrogen receptor (ER)-positive, HER2-negative, stage I–IIIA (T1c–T3 N0–2 M0) breast cancer and Ki67 index ≤30%. Patients first received EXE 25 mg/day for 12 weeks. Based on clinical response and change in Ki67 index, responders were defined as patients who achieved complete response (CR), partial response (PR) with Ki67 index ≤5% after treatment, or stable disease (SD) with Ki67 index ≤5% both before and after treatment. Non-responders were defined as patients with PR and Ki67 index &amp;gt;5% after treatment, or SD and Ki67 index &amp;gt;5% before or after treatment. For the subsequent 12 weeks, responders continued EXE monotherapy (continued EXE group) and non-responders received EXE plus 4 cycles of TC (docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks) (EXE+TC group). Primary endpoint was clinical response (CR and PR) at week 24. Results A total of 58 patients (median age 60 years, range 53–67 years) were enrolled between December 2010 and May 2016. Five patients discontinued treatment in the initial 12-week EXE monotherapy period; therefore 53 received the subsequent treatment. After 8–12 weeks of initial EXE monotherapy, 15 patients were classified as responders (8 with PR and Ki67 index ≤5% after treatment, 7 with SD and Ki67 index ≤5% before and after treatment) and 38 as non-responders (5 with PR and Ki67 index &amp;gt;5% after treatment, 33 with SD and Ki67 index &amp;gt;5% before or after treatment). Clinical response rates at weeks 12 and 24 were 71% (10/14, 95%CI 41.9–91.6%) and 57% (8/14, 95%CI 28.9–82.3%), respectively, in the continued EXE group, and 16% (4/25, 95%CI 4.5–36.1%) and 56% (14/25, 95%CI 34.9–75.6%), respectively, in the EXE+TC group. At week 24, no significant difference was found in median Ki67 index between the continued EXE and EXE+TC groups (1.4% and 2.0%, respectively). The proportion of patients with preoperative endocrine prognostic index (PEPI) 0 was higher in the continued EXE than in the EXE+TC group (60% vs 29%), but not significantly so (P=0.058, Fisher's exact test). The breast-conserving surgery rate was 93% and 56% (continued EXE and EXE+TC groups, respectively). Adverse events (AEs) ≥grade 3 were reported in 40% (21/53) of patients (continued EXE group 8%, 1/15; EXE+TC group 53%, 20/38). The most common AEs were leukopenia (37%, 14/38), neutropenia (32%, 12/38), and febrile neutropenia (16%, 6/38) during chemotherapy (EXE+TC group). Conclusion Tailored treatment maintained the favorable clinical response to EXE alone in responders and improved subsequent clinical response in non-responders. EXE+TC was associated with higher incidence of hematological AEs, but these were manageable. The results show the effectiveness of tailored neoadjuvant endocrine and chemoendocrine therapy in postmenopausal ER-positive breast cancer patients. (JBCRG-11TC; UMIN000004752) Citation Format: Yasojima H, Sato N, Masuda N, Morimoto T, Ueno T, Kanbayashi C, Kaneko K, Saji S, Sasano H, Morita S, Ohno S, Toi M. Neoadjuvant exemestane or exemestane plus docetaxel and cyclophosphamide tailored by clinicopathological response to 8–12 weeks' exemestane exposure for ER+/HER2– postmenopausal breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-07.

Abstract P2-08-24: The average modified Magee score can be helpful in predicting an Oncotype DX recurrence score ≤ 25

Abstract Introduction: The recent TAILORx results suggests that adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone–positive, HER2-negative, axillary node–negative breast cancer who had an Oncotype Dx recurrence score (ODXRS) between 11 and 25. These findings, along with updated results that patients with an ODXRS &amp;lt; 11 have a 9-year recurrence rate of only 3%, suggest that certain populations of patients with an ODXRS ≤ 25 may not benefit from additional systemic chemotherapy. Oncotype Dx is an expensive test (current list price of $4,650.00), and cost has been an impediment to its adoption in many centers throughout the United States, and internationally. The test can be performed only at a commercial specialized laboratory. Based on a modification of the new Magee equations (Klein ME, et al. Mod Pathol. 2013;26(5):658–664) we published an algorithm based on 283 patients with ODXRS's (Turner BM, et al. Mod Pathol. 28(7):921-31) that suggested our algorithm offered a less expensive alternative to Oncotype DX testing. We have validated this algorithm in a multi-institutional study on an additional 619 patients with ODXRS's (in preparation for publication). Our validation data, and our data from the original study, also suggests that the average modified Magee equation can reliably predict patients who will have an ODXRS ≤ 25. Methods: 903 cases with an available ODXRS (2006-2018) were identified from the pathology files at the University of Rochester Medical Center (n = 752) and the University of Louisville (n = 151). Information required to calculate the average modified Magee score, which includes estrogen receptor (ER) and progesterone receptor (PR) status, Her-2 status, Nottingham score, tumor size, and Ki-67 were also extracted from the medical record. 78 patients did not have an available Ki-67, leaving 825 patients for inclusion in this study. Results: 478/488 (98%) patients with an average Modified Magee score ≤ 18 had an ODXRS ≤ 25 (only 2% had an ODXRS &amp;gt; 25 - Table 1). 125/337 (37%) patients with an average Modified Magee score &amp;gt;18 had an ODXRS &amp;gt; 25 (Table 1) . Conclusions: The average Modified Magee Score can be helpful in predicting an ODXRS ≤ 25. Patients with an average Modified Magee score ≤ 18 may not need to be sent out for Oncotype Dx testing. The potential cost savings to the health care system would be enormous. Table 1:Average Modified Magee score and risk of an Oncotype Dx recurrence score (ODXRS) &amp;gt; 25Magee scorenAverage ODXRSMinimum ODXRS valueMaximum ODXRS valueCases with ODXRS &amp;gt; 25 [n (%)]≤ 91811.02190 (0)102110.90261 (4.8)113712.10250 (0)126012.00281 (1.7)136412.00230 (0)147012.90271 (1.4)156513.61313 (4.6)165614.12292 (3.6)175214.50272 (3.8)184514.30250 (0)195418.96379 (16.7)204319.30348 (18.6)215921.193715 (25.4)223819.32496 (15.8)232523.383811 (44)242920.83329 (31)252325.0144011 (47.8)&amp;gt; 25-272729.2174620 (74.1)&amp;gt; 27-301634.9225113 (81.3)&amp;gt; 302345.7317823 (100)≤ 1848812.903110 (2)&amp;gt; 1833723.7078125 (37) Citation Format: Turner BM, Sanders MA, Breaux A, Soukiazian A, Soukiazian N, Hicks DG. The average modified Magee score can be helpful in predicting an Oncotype DX recurrence score ≤ 25 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-24.

Abstract P4-06-06: Comparison of the immunological and clinical effect of personalized peptide vaccination for patients with breast cancer

Abstract Background: Selected therapeutic personalized peptide vaccines (PPV) were effective for boosting anticancer immune response that was associated with the clinical outcome as a prognostic factor for metastatic recurrent breast cancer (mrBC) 1-2. In this study, we investigated the immunological and clinical effect of PPV as the prophylactic cancer vaccine for non-recurrent but high-risk BC (nrhrBC) patients (pts), and we compared it's features to those of the mrBC pts who had active cancers or became resistant to the standard therapies(TR-mrBC). Methods: Material and Patient eligibility criteria: The peptides were selected from the 31 PPVs according to the results of HLA typing and peptide-specific IgG titers. Pts with a histological diagnosis of BC and their HLA-A molecules should be each of -A2, A3, A11, A24, A26, A31 or A33. The clinical protocols were approved by the institutional review board. (UMIN000003081and 00000184400000). Treatment schedule: A maximum of 4 peptides was administrated as weekly for initial four vaccinations and as biweekly for further inoculations. The concomitant standard endocrine therapy and the chemo-endocrine therapy were available for nrhrBC pts after finishing the standard adjuvant chemotherapy, and for mrBC pts concurrently. Immune and clinical response assessment: Specific T-cell responses, IgG titers and cytokines were evaluated using by interferon (IFN)-γ ELISPOT, Luminex assay and ELISA system in every 6-8 vaccinations. Toxicity, clinical response and correlation with the immune responses were investigated. Results: 16 pts with nrhrBC, 41 pts with mrBC and 79 pts with TR-mrBC received median 18, 16 and 14 vaccines, respectively. After PPV therapies, peptide-specific IgG and CTLs increased significantly in a total of 47 (77%) and 37(60%) in nrhrBC pts, 102 (63%) and 98 (61%) in mrBC pts, and 150(53%) and 100 (42%) in TR-mrBC pts. Pts experienced Grade 1-3 skin reaction at injection site, no other grade 3 or 4 SAEs were associated with PPV but with the disease progression or combination therapy. The median time to progression (TTP) and overall survival (OS) were not reached in nrhrBC pts, 7.8 and 29 months in mrBC pts, and were 7.5 and 15.9 months in TR-mrBC pts, respectively. The peptide specific CTL response was correlated significantly with OS in nrhrBC pts and the IgG levels were associated with the better OS in either non TR-mrBC pts or TR-mrBC pts. High levels of IL-6, GM-CSF, IFN-g, IL-2 receptor, BAFF were associated with worse prognosis for pts with TR-mrBC. And high levels of GM-CSF and BAFF were associated with worse prognosis for pts with nrhrBC and mrBC, respectively. In contrast, High levels of IL-2 were associated with the better prognosis for pts with mrBC. Conclusion: This study indicated that immunological features of these three groups were different from each other with most potent PPV-induced immune boosting for nrhrBC pts. Pts with mrBC who had lower immune-suppressive cytokine levels had the better prognosis. These results suggested the PPV therapy could be effective for postoperative prophylactic vaccination in patients with nrhrBC.

Abstract P3-11-02: Breast cancer-specific mortality (BCSM) in patients (pts) with node-negative (N0) and node-positive (N+) breast cancer (BC) guided by the 21-gene assay: A SEER-genomic population-based study

Abstract Introduction: The 21-gene Breast Recurrence Score® (RS) in the randomized NSABP B-20, SWOG S8814, and TAILORx studies predicted chemotherapy (CT) benefit for pts with N0 and N+ disease. Endocrine therapy was not inferior to chemoendocrine therapy in 6,711 randomized TAILORx pts with RS 11-25 and N0 disease. We characterized BCSM for the TAILORx-defined RS groups (0-10, 11-15, 16-20, 21-25, and 26-100) in the large population-based SEER study of pts treated based on RS results. Methods: RS results were provided electronically to SEER registries per their linkage methods (Petkov npj Breast Cancer 2016). Eligible pts were diagnosed Jan 2004 - Dec 2014 with N0 and N+(N1mic, 1-3 positive nodes[N1]), HR+, HER2-negative BC, and had no prior malignancy or multiple tumors, with follow-up information through Dec 2015. BCSM estimates by reported CT use yes vs. no/unknown were computed, and must be interpreted cautiously given lack of randomization. Results: There were 80,605 pts with RS results; 70,087 with N0 disease, 4,336 with N1mic, and 6,182 with N1. Median follow-up was 49 months, with 20,151 pts followed &amp;gt;76 months. 1,020 pts had experienced breast cancer death. There was a significant positive association between higher RS results and increased BCSM (p&amp;lt;0.001) without and with adjustment for nodal status, age, tumor size, and grade. Reported CT use increased with increasing RS result (Table). 9-y BCSM was &amp;lt;4% without CT for pts with RS 0-25 and N0 disease and for pts with RS 0-20 and N1 disease. For RS 26-100, 9-y BCSM was lower with CT use than without (Table). Similar results were seen in the 4,336 pts with N1mic disease. Pts treated with CT for every RS group, as expected, tended to have higher risk features (age, tumor size and grade), and multivariable models and adjustment by propensity scores will be presented to allow for more definitive conclusions. Table N0; CT Use No (N=55726)N0; CT Use Yes (N=14361)N1; CT Use No (N=3810)N1; CT Use Yes (N=2372)RS 0-10n139823891005283 9-y BCSM1.4% (1.0%, 2.1%)2.1% (0.7%, 5.9%)2.2% (1.0%, 4.8%)1.4% (0.4%, 4.6%)RS 11-15n1675810661193453 9-y BCSM2.0% (1.5%, 2.6%)2.7% (1.3%, 5.4%)1.5% (0.8%, 3.1%)4.4% (1.4%, 13.6%)RS 16-20n144842719992587 9-y BCSM2.2% (1.7%, 2.8%)1.9% (1.1%, 3.0%)3.8% (1.6%, 8.5%)4.2% (1.6%, 10.9%)RS 21-25n67043544397431 9-y BCSM3.9% (3.0%, 5.0%)3.4% (2.6%, 4.6%)7.1% (4.1%, 12.1%)5.7% (2.9%, 11.2%)RS 26-100n37986643223618 9-y BCSM8.8% (7.4%, 10.4%)7.0% (5.9%, 8.4%)15.2% (8.7%, 25.9%)10.8% (7.2%, 16.2%) Conclusion: In both N0 and N+ disease (up to 3 positive nodes), low RS results identify more than 70% of BC patients with excellent long-term outcomes and no apparent CT benefit, and high RS results (26-100) identifies an important minority of patients where CT reduces BCSM. Real-world evidence from SEER reconfirms that the 21-gene assay is prognostic and strongly suggests it is predictive of CT benefit, irrespective of nodal status. Citation Format: Hortobagyi GN, Shak S, Sledge, Jr. GW, Winer EP, Albain KS, Mamounas EP, Jakubowski DM, Petkov VI, Wolmark N. Breast cancer-specific mortality (BCSM) in patients (pts) with node-negative (N0) and node-positive (N+) breast cancer (BC) guided by the 21-gene assay: A SEER-genomic population-based study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-11-02.

Late Stage Prostate Cancer

Prostate cancer remains the second leading cause of cancer death in men and encapsulates a wide spectrum of disease. This review describes recent advances in genomic sciences and summarizes the impact of emerging molecular profiling–based clinical applications in the diagnosis and management of early and advanced prostate cancer. It addresses the controversial guidelines surrounding prostate-specific antigen–based screening for prostate cancer and summarizes the recommendations from six different agencies. This review highlights landmark clinical trials in metastatic prostate cancer, focusing on developments within the last 5 years. It also summarizes the rationale for earlier use of chemotherapy for newly diagnosed prostate cancer (chemohormonal therapy) and gives an overview of ongoing research into the development of novel genome-based therapeutics. This review contains 4 figures, 7 tables, and 53 references. Key words: castration resistant, molecular profiling, prostate cancer, screening guidelines, treatment options

Late Stage Prostate Cancer

Prostate cancer remains the second leading cause of cancer death in men and encapsulates a wide spectrum of disease. This review describes recent advances in genomic sciences and summarizes the impact of emerging molecular profiling–based clinical applications in the diagnosis and management of early and advanced prostate cancer. It addresses the controversial guidelines surrounding prostate-specific antigen–based screening for prostate cancer and summarizes the recommendations from six different agencies. This review highlights landmark clinical trials in metastatic prostate cancer, focusing on developments within the last 5 years. It also summarizes the rationale for earlier use of chemotherapy for newly diagnosed prostate cancer (chemohormonal therapy) and gives an overview of ongoing research into the development of novel genome-based therapeutics. This review contains 4 figures, 7 tables, and 53 references. Key words: castration resistant, molecular profiling, prostate cancer, screening guidelines, treatment options

Combination of Aromatase Inhibitors with Metronomic Capecitabine: A New Chemoendocrine Treatment for Advanced Breast Cancer

Purpose: Endocrine therapy is one of the main treatment options for hormone receptor (HR)-positive advanced breast cancer (ABC). However, whether the combination of endocrine therapy with chemotherapy is practicable and more effective than endocrine therapy alone remains unknown. The aim of this study was to investigate the clinical efficacy of the aromatase inhibitors (AIs) combined with metronomic capecitabine to provide the clinical evidence for further research in patients with HR-positive ABC. Methods: Data from 407 patients with HR-positive ABC were retrospectively analyzed. A total of 305 patients were given AIs alone, and 102 patients were given AIs plus capecitabine as first-line treatment. Progression-free survival (PFS) was the primary endpoint. Results: The median follow-up for all patients was 47.0 months (range, 3 - 119 months). The median overall survival (OS) and PFS were 52.0 months and 24.2 months, respectively. The median PFS in the combination group was significantly longer than that in the AIs group (22.0 months vs. 14.0 months, p = 0.002). Additionally, patients in the combination group had significantly longer OS than patients in the AI group (66.0 months vs. 49.0 months, p = 0.003). Multivariate analysis showed that combination therapy was a significant favorable predictor for PFS and OS. Furthermore, young age ( 24 months) improved the benefit from combination therapy. Conclusions: AIs plus metronomic capecitabine significantly improves PFS and OS in patients with HR-positive ABC. Thus, chemo-endocrine therapy should be further explored.