Taxane-based Combination Research Articles

Abstract P4-02-26: Quantitative estrogen receptor expression affects pathologic complete response to neoadjuvant chemotherapy in patients with early-stage breast cancer with low expression of HER2

Abstract BACKGROUND Recent pooled analysis of four major clinical trials of neoadjuvant chemotherapy (NAC) indicated that tumors with low expression of HER2 (HER2-low) as defined by immunohistochemistry (IHC) could be a new subgroup of breast cancer, distinct from HER2-negative tumors. In estrogen receptor (ER)-positive/HER2-negative breast cancer, we previously reported that 9.5% ER expression by IHC was the most appropriate cutoff to predict survival outcomes. However, little is known about the effect of quantitative ER expression on NAC outcomes in patients with HER2-low breast cancer. The present study aimed to elucidate the role of quantitative ER expression as a predictive and prognostic biomarker in the newly established HER2-low subgroup. MATERIALS AND METHODS We retrospectively reviewed the charts of 2,016 patients with newly diagnosed ER- and/or progesterone receptor (PR)-positive breast cancer between January 1982 and January 2019 in an extensive clinical database at The University of Texas MD Anderson Cancer Center. Our analysis included patients whose ER%, PR%, and HER2 IHC (0 to 2+) data were available. HER2-low was defined as IHC 1+ and 2+/situ hybridization (ISH)-negative. All patients had stage II or III disease at presentation and received NAC with anthracycline and a taxane-based combination regimen. Those with ER-positive tumors also received adjuvant endocrine therapy. The primary outcome measure was pathologic complete response (pCR) rate, compared between groups using logistic regression. Secondary outcomes were progression-free survival and overall survival after NAC completion, compared using Kaplan-Meier analysis and the log-rank test. The cutoff value for ER and PR positivity was 10% in the main analysis, identified by recursive partitioning and regression trees. RESULTS Among the 2,016 patients, 1134 (56%) had cStage II and 882 (44%) had cStage III disease. For IHC HER2 levels, 739 patients had 0 (37%), 926 had 1+ (46%), and 351 had 2+ (17%). For the primary outcome, 123 patients (6%) achieved pCR. The median follow-up period was 6.78 years. During the follow-up, 571 (28%) had distant metastasis. Mean ER expression (%) increased with HER2 IHC (HER2 IHC 0: 74.2%, 1+: 76.7%, 2+: 78.2%). In the multivariate logistic model, ER-negative (p< 0.0001), PR-negative (p < 0.0001), and high nuclear grade (p< 0.05) disease were associated with higher pCR rates. Although pCR rate did not differ among HER2 IHC groups (0 = 6.09%, 1+ = 6.26%, 2+ = 5.7%; p=0.93), significantly higher pCR rates were observed in the HER2 IHC=0/1+ and 1%≤ER< 10% group (p=0.0013) than in the HER2 IHC=0/1+ and ER≥10%, and HER2 IHC=2+ and ER≥10% groups. Kaplan-Meier curves showed that patients in the ER≥10% group had marginally improved PFS (p=0.046) and significantly longer OS (p=0.004) regardless of HER2 IHC status. Multivariable analysis showed that HER IHC status did not affect survival outcomes. Exploratory analysis showed that the patients with 70% or less in ER expression and HER2 IHC 1+/2+ tumor had higher pCR rate (12.3%) compared to those with ER>70% (4.1%). CONCLUSIONS Patients with ≥10% ER expression had better survival outcomes than those with ER< 10% regardless of HER2 expression level. The degree of HER2 expression in the HER2-low subgroup was not an independent predictive and prognostic factor for NAC response. The cutoff for ER expression for its predictive effect on pCR needs further validation in large external datasets. Citation Format: Toshiaki Iwase, Takeo Fujii, Clinton Yam, Wenli Dong, Yu Shen, Debu Tripathy, Naoto T. Ueno. Quantitative estrogen receptor expression affects pathologic complete response to neoadjuvant chemotherapy in patients with early-stage breast cancer with low expression of HER2 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-26.

Upregulation of the Long Noncoding RNA CASC10 Promotes Cisplatin Resistance in High-Grade Serous Ovarian Cancer.

Despite initial responses to first-line treatment with platinum and taxane-based combination chemotherapy, most high-grade serous ovarian carcinoma (HGSOC) patients will relapse and eventually develop a cisplatin-resistant fatal disease. Due to the lethality of this disease, there is an urgent need to develop improved targeted therapies against HGSOC. Herein, we identified CASC10, a long noncoding RNA upregulated in cisplatin-resistant ovarian cancer cells and ovarian cancer patients. We performed RNA sequencing (RNA-seq) in total RNA isolated from the HGSOC cell lines OVCAR3 and OV-90 and their cisplatin-resistant counterparts. Thousands of RNA transcripts were differentially abundant in cisplatin-sensitive vs. cisplatin-resistant HGSOC cells. Further data filtering unveiled CASC10 as one of the top RNA transcripts significantly increased in cisplatin-resistant compared with cisplatin-sensitive cells. Thus, we focused our studies on CASC10, a gene not previously studied in ovarian cancer. SiRNA-mediated CASC10 knockdown significantly reduced cell proliferation and invasion; and sensitized cells to cisplatin treatment. SiRNA-mediated CASC10 knockdown also induced apoptosis, cell cycle arrest, and altered the expression of several CASC10 downstream effectors. Multiple injections of liposomal CASC10-siRNA reduced tumor growth and metastasis in an ovarian cancer mouse model. Our results demonstrated that CASC10 levels mediate the susceptibility of HGSOC cells to cisplatin treatment. Thus, combining siRNA-mediated CASC10 knockdown with cisplatin may represent a plausible therapeutic strategy against HGSOC.

FER regulates endosomal recycling and is a predictor for adjuvant taxane benefit in breast cancer.

Elevated expression of non-receptor tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/triple-negative breast cancer (TNBC) patients. Here, we show that high FER levels are also associated with improved outcomes after adjuvant taxane-based combination chemotherapy in high-risk, HER2-negative patients. In TNBC cells, we observe a causal relation between high FER levels and sensitivity to taxanes. Proteomics and mechanistic studies demonstrate that FER regulates endosomal recycling, a microtubule-dependent process that underpins breast cancer cell invasion. Using chemical genetics, we identify DCTN2 as a FER substrate. Our work indicates that the DCTN2 tyrosine 6 is essential for the development of tubular recycling domains in early endosomes and subsequent propagation of TNBC cell invasion in 3D. In conclusion, we show that high FER expression promotes endosomal recycling and represents a candidate predictive marker for the benefit of adjuvant taxane-containing chemotherapy in high-risk patients, including TNBC patients.

Abstract LB203: FER regulates endosomal recycling and is a candidate predictor for taxane benefit in breast cancer

Abstract To this day, targeted treatment options for patients with triple negative metastatic breast cancer (TNBC) are still virtually absent. Previously, we showed that elevated expression of the tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/TNBC patients. Here, we show that high FER levels are also associated with improved outcome after adjuvant taxane-based combination chemotherapy, in high-risk, HER2-negative patients. In TNBC cells, we observed a causal relation between high FER levels and sensitivity to taxanes. Our proteomics and mechanistic studies demonstrated that FER regulates endosomal recycling, a microtubule-dependent process that underpins breast cancer cell invasion. Using chemical genetics, we identified DCTN2 as a novel FER substrate. Our work indicates that the DCTN2 tyrosine 6 is essential for tubular recycling domains development in early endosomes and subsequent propagation of TNBC cell invasion in 3D. In conclusion, we show that high FER expression promotes endosomal recycling and represents a candidate predictive marker for benefit of adjuvant taxane-containing chemotherapy in high-risk patients, including TNBC patients. Citation Format: Sandra Tavares, Nalan Liv, Milena Pasolli, Mark Opdam, Max Ratze, Manuel Saornil, Lilian Sluimer, Rutger Hengeveld, Robert van Es, Erik van Werkhoven, Harmjan Vos, Holger Rehmann, Boudewijn Burgering, Hendrika Oosterkamp, Susanne Lens, Judith Klumperman, Sabine Linn, Patrick Derksen. FER regulates endosomal recycling and is a candidate predictor for taxane benefit in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB203.

Insights Into the Impacts of BRCA Mutations on Clinicopathology and Management of Early-Onset Triple-Negative Breast Cancer.

BackgroundLittle is known regarding the clinicopathologic characteristics, oncologic outcomes, and treatment strategies that could be ascribed to BRCA mutation in early-onset triple-negative breast cancer (eTNBC).MethodseTNBC patients who underwent BRCA genetic testing were derived from our clinical database between 2012 and 2018. Differences in clinical features and pathologic characteristics were examined in groups divided by BRCA mutation status, and the contribution of germline mutations in conjunction with treatment modalities to survival outcomes was determined.ResultsOf the 355 qualifying eTNBC patients, 67 (18.87%) were BRCA mutated and 288 (81.13%) were BRCA wild. Overall, median age at diagnosis was 34 years (range, 24–40 years) in the BRCA mutated subgroup and 35 years (range, 21–40 years) in BRCA wild. The majority of clinicopathologic parameters were parallel; however, tumor size (P = 0.07) and nuclear grade (P =0.08) tend to be more aggressive in the BRCA mutated subgroup. Compared with BRCA wild patients, BRCA mutated patients had a higher likelihood of receiving anthracyclines and taxane-based combination chemotherapy (P = 0.04) and tend to be lower tumor burden (P =0.01). After approximately 5-year median follow-up, the overall survival (OS) (P = 0.021) and breast cancer-specific survival (BCSS) (P = 0.004) in BRCA mutated patients were superior to those in their BRCA wild counterparts. Intriguingly, the clinical outcomes were comparable in patients with breast conserving surgery (BCS) regardless of BRCA mutations and in patients with BRCA mutations in spite of surgical schedules.ConclusionsThese results suggest that eTNBC patients with BRCA mutations are prone to better OS and BCSS, which might be largely attributed to more benefit from anthracyclines and taxane-based chemotherapy. The BCS procedure could be a safe alternative surgical option for eTNBC patients with BRCA mutations. Future studies with substantial numbers of participants are urgently needed to validate whether BRCA mutation eTNBC patients are more sensitive to chemotherapy.

Therapeutic Considerations for Docetaxel and Paclitaxel in Metastatic Breast Cancer

Breast cancer is the main source of death among women. Currently, 77% of women diagnosed with breast cancer are age 50 and older; however, it is projected that approximately 66% of the new cases diagnosed will occur in women younger than 65. Several clinical trials have assessed the wellbeing and adequacy of taxanes along with their tolerability in patients with metastatic cancer (MBC) The overview of these Paclitaxel and Docetaxel, the mechanism of action, pharmacokinetics and pharmacodynamics, dose and administration, adverse effects, clinical potency, and sufferable profiles combination therapies, the pathological complete response of these taxanes are included. The different novel formulations of taxanes are formulated from nanoparticles, polyglutamate, liposomes to improve the wellbeing and adequacy taxanes to reduce their toxicities. Single-agent research located with docetaxel and paclitaxel in metastatic breast most cancers show clinically huge antitumor motion even in the advanced stage, heavily pretreated, safe, as properly as in refractory diseases. This action is likewise clear with taxane-based combination regimens. Serious hematologic and nonhematologic toxicities are incompatible, with different toxicities noted dependent on the portion and weekly regimen selected. Weekly docetaxel and paclitaxel regimens speak to important helpful treatment options for women suffering from metastatic breast cancer and have entered assessment as a major aspect of adjuvant treatment for this disease Toxicity associated with taxanes chemotherapy are based totally on the dose schedules and weekly regimen selected and the most frequent toxicities related with these marketers include myalgia, peripheral neuropathy, neutropenia, etc Docetaxel retains in tumor cells for longer duration when compared to paclitaxel because of its slow efflux and large amounts of uptake into the cell which explains its more benefits when compared to paclitaxel. Clinical studies conducted so far suggested a more benefit to risk ratio for docetaxel when compared to paclitaxel. This article reviews mainly different actions exhibited by taxanes in the therapy of metastatic breast cancer and others on stages of cancer along with the toxicities associated with these agents.

Abstract P1-19-33: Real-world efficacy of ribociclib + aromatase inhibitor, or endocrine monotherapy, or chemotherapy as first-line treatment in postmenopausal women with HR-positive, HER2-negative locally advanced or metastatic breast cancer: Second interim analysis from the RIBANNA study

Abstract Background: Ribociclib (RIB, a selective CDK4/6 inhibitor) plus an aromatase inhibitor (AI) or fulvestrant (FUL) is approved for the treatment of premenopausal and postmenopausal women with HR+/HER2- advanced breast cancer (aBC). Real-world evidence for the effectiveness, safety and tolerability of RIB + AI/FUL in routine clinical practice is needed to support the use of this combination. Methods: RIBANNA is a noninterventional study ongoing in Germany since October 2017. Premenopausal and postmenopausal patients (N=3020) treated with RIB + AI/FUL, or endocrine monotherapy (ET), or chemotherapy (CT) as first-line treatment for HR+/HER2- aBC in accordance with German guidelines were included. Data are being collected from clinical practice in all 3 cohorts. Further lines of treatment are noted to examine outcomes of sequential therapy. Results: For the first interim analysis, 461 patients were enrolled until October 9, 2018, while full analysis set comprised 282 patients (Table 1). The first-line mean daily dose of RIB was 382 mg including and 540 mg excluding dose interruptions, respectively. RIB was prescribed mainly in combination with letrozole (83%), anastrozole (8%), and exemestane (7%); ET included nonsteroidal AI (64%), selective estrogen receptor degrader (25%), selective estrogen receptor modulator (7%), and steroidal AI (5%); CT included taxane-based monotherapy (30%) or combination therapy (27%), other monotherapy (23%) or other combination therapy (13%), and anthracycline-based combination therapy (5%). Conclusion: RIBANNA study showed diverse population characteristics among patients who received RIB treatment in a real-world setting. Based on the baseline demographics data, RIB (CDK4/6 inhibitor) treatment was found to be very well adopted among premenopausal and postmenopausal patients with HR+/HER2- aBC. The second interim analysis is planned for October 2019. Updated baseline data of approximately 1200 to 1300 patients and information on safety and dose modification for first-line patients from all cohorts will be presented. Table 1. Baseline demographic characteristicsTotal (N = 282)RIB + AI (n = 216)Endocrine therapy (n = 26)Chemotherapy (n = 40)Mean age, years (SD)67 (11)67 (10)71 (12)62 (10)Mean time since initial diagnosis, years5.45.56.53.9T stage at initial diagnosis, n (%)T0+T161 (100)48 (79)6 (10)7 (11)T2-T4198 (100)149 (75)17 (9)32 (16)N stage at initial diagnosis, n (%)N0+N1186 (100)144 (77)16 (9)26 (14)N2+N364 (100)48 (75)5 (8)11 (17)M stage at initial diagnosis, n (%)M0156 (100)121 (78)14 (9)21 (13)M1101 (100)75 (74)9 (9)17 (17)Locally advanced, n (%)101 (100)73 (72)9 (9)19 (19)Metastatic, n (%)101 (100)75 (74)9 (9)17 (17)Metastatic location, n (%)CNS, liver, lungs119 (100)96 (81)1 (1)22 (18)Bone only84 (100)62 (74)17 (20)5 (6)Skin, lymph nodes, other52 (100)37 (71)6 (11)9 (17) Citation Format: Achim Wöckel, Pawel Basiora, Michael Bohlmann, Thomas Decker, Jörg Falbrede, Peter Fasching, Helmut Forstbauer, Tobias Hesse, Oliver Hoffmann, Christian Jackisch, Anna Kaczerowsky, Ralf Lorenz, Kerstin Lüdtke-Heckenkamp, Diana Lüftner, Frederik Marmé, Thomas Mueller, Christoph Mundhenke, Arnd Nusch, Volker Petersen, Gabriele Prange-Krex, Toralf Reimer, Thomas Resch, Christian Roos, Oliver Tomé, Anja Weishap. Real-world efficacy of ribociclib + aromatase inhibitor, or endocrine monotherapy, or chemotherapy as first-line treatment in postmenopausal women with HR-positive, HER2-negative locally advanced or metastatic breast cancer: Second interim analysis from the RIBANNA study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-33.

Should MMMT still be treated with adjuvant taxane-based combination chemotherapy?

BackgroundMalignant mixed Mullerian tumors of endometrial (MMMT-E) and ovarian (MMMT-O) origin are associated with poor prognosis. Suggestively epithelial-driven tumors, their treatment has shifted from anthracycline or ifosfamide-based towards taxane-based chemotherapy. It remains unclear whether this change associates with better outcomes.Patients and methodsA conjoined Australian and Swiss patient cohort of MMMT-E (N = 103) and MMMT-O (N = 17) was compared to patients with adenocarcinoma of the endometrium (EC, N = 172) and ovary (OC, N = 189). Clinicopathological characteristics, FIGO stage, first-line treatment, and patient outcomes were analyzed. The generated hypothesis was verified in an US-American cohort with high-grade serous ovarian cancer (HGSOC, N = 1290) and MMMT-O (N = 450) using immunohistochemistry and next-generation sequencing.ResultsEarly stage I/II MMMT-E showed a survival plateau after 2.5 years, with no recurrence or death observed afterwards. Relapse-free survival was significantly worse in MMMT-E treated with platinum/taxanes (P = 0.024) compared to non-taxane regimen. Hypothesizing that also MMMT-O might benefit from an adjuvant non-paclitaxel regimen, a second independent cohort of MMMT-O and HGSOC patients was examined. p53 mutations dominated in both cancers with comparable frequency. PI3KCA and KRAS mutations were less frequent: they were more frequent in MMMT-O than in HGSOC (P = 0.015 and P = 0.018, respectively). MMMT-O responded better to a combination of carboplatin with anthracyclines than with taxanes (73.9% vs. 39.4%).ConclusionEarly stage I/II MMMT-E patients have excellent prognosis if no recurrence has appeared within the first 2.5 years. In MMMT-E, platinum/anthracycline or ifosfamide regimen associated with better outcomes than platinum/taxanes regimens. This might also apply to MMMT-O.

Real-world effectiveness of ribociclib + aromatase inhibitor, or endocrine monotherapy, or chemotherapy as first-line treatment in postmenopausal women with HR-positive, HER2-negative locally advanced or metastatic breast cancer: Baseline data from the RIBANNA study.

e12520 Background: Ribociclib, a selective CDK4/6 inhibitor, in combination with an aromatase inhibitor (AI) is approved for the treatment of HR+/HER2- advanced breast cancer (aBC) (locally advanced or metastatic). Real-world evidence for the effectiveness, safety and tolerability of ribociclib + AI in routine clinical practice is needed to support its use. Methods: RIBANNA (CLEE011ADE03) is a non-interventional study running in Germany since October 2017 involving up to 3020 postmenopausal patients receiving ribociclib + AI, endocrine monotherapy (ET), or chemotherapy (CT) as first-line treatment for HR+/HER2- aBC, prescribed in line with German guidelines. Data are collected from clinical practice in all three cohorts. Further lines of treatment are documented to examine outcomes of sequential therapy. Results: 461 patients enrolled to October 9, 2018 (Table). First-line mean daily ribociclib dose was 382 mg including and 540 mg excluding dose interruptions; mean duration of exposure to ribociclib: 128 days. Ribociclib was given in combination with anastrozole (8%), exemestane (7%), and letrozole (83%); ET comprised a selective estrogen receptor degrader (25%), nonsteroidal AI (64%), steroidal AI (5%), and a selective estrogen receptor modulator (7%); CT included taxane-based monotherapy (30%) or combination therapy (27%), anthracycline-based combination therapy (5%), other monotherapy (23%) or other combination therapy (13%). Conclusions: Population characteristics from the RIBANNA study show a diverse group of patients from a real-world setting of ribociclib treatment. Baseline demographics and characteristics. Clinical trial information: CLEE011ADE03. [Table: see text]

Carcinosarcoma of ovary with long-term overall survival

Carcinosarcoma or mixed Mullerian malignant tumors are a rare entity representing 1% of all the malignant ovarian neoplasms. It has poor prognosis, and the survival outcome is worst. We report a case of carcinosarcoma of the ovary in a 68-year-old female. The patient was treated with cytoreductive surgery followed by platinum- and taxane-based combination chemotherapy regimen. Now, the patient is under regular follow-up with long-term overall survival for 76 months without any disease. Therefore, our case highlights the importance of cytoreductive surgery followed by adjuvant chemotherapy with platinum- and taxane-based combination regimen in the form of improved survival demanding a long-term follow-up for such cases.

Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Clinical Practice Guideline Focused Update.

Purpose To update key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer. Methods An Expert Panel conducted targeted systematic literature reviews guided by a signals approach to identify new, potentially practice-changing data that might translate to revised practice recommendations. Results The Expert Panel reviewed phase III trials that evaluated adjuvant capecitabine after completion of standard preoperative anthracycline- and taxane-based combination chemotherapy by patients with early-stage breast cancer HER2-negative breast cancer with residual invasive disease at surgery; the addition of 1 year of adjuvant pertuzumab to combination chemotherapy and trastuzumab for patients with early-stage, HER2-positive breast cancer; and the use of neratinib as extended adjuvant therapy for patients after combination chemotherapy and trastuzumab-based adjuvant therapy with early-stage, HER2-positive breast cancer. Recommendations Patients with early-stage HER2-negative breast cancer with pathologic, invasive residual disease at surgery following standard anthracycline- and taxane-based preoperative therapy may be offered up to six to eight cycles of adjuvant capecitabine. Clinicians may add 1 year of adjuvant pertuzumab to trastuzumab-based combination chemotherapy in patients with high-risk, early-stage, HER2-positive breast cancer. Clinicians may use extended adjuvant therapy with neratinib to follow trastuzumab in patients with early-stage, HER2-positive breast cancer. Neratinib causes substantial diarrhea, and diarrhea prophylaxis must be used. Additional information can be found at www.asco.org/breast-cancer-guidelines .

Taxane-based or platinum-based combination chemotherapy given concurrently with radiation followed by surgery resulting in high cure rates in esophageal cancer patients.

e16051Background: Preoperative chemoradiotherapy (CRT) is one standard option for localized esophageal or gastroesophageal junction (GEJ) cancer patients but an optimal concurrent chemotherapy comb...

Abstract P6-08-05: United States real-world drug utilization patterns and associated overall survival in Medicare patients with newly-diagnosed metastatic triple negative breast cancer using surveillance, epidemiology, and end results-Medicare data

Abstract Background: Limited information is available about treatment patterns for elderly patients (pts) with metastatic triple negative breast cancer (mTNBC). This analysis characterized real-world drug utilization patterns and associated overall survival (OS) for Medicare mTNBC pts. Methods: Pts ≥66 years of age who were newly diagnosed with mTNBC between 2004 and 2011 were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Triple negative status was obtained from the SEER registry, except for HER2 that was unavailable from 2004-2009 during which we assumed that pts who had a claim for a HER2 test followed by absence of hormonal therapy to be presumed HER2 negative. Pts were followed from diagnosis to death, Medicare disenrollment, HMO enrollment, or 12/31/2013 (whichever occurred first) to characterize the sequence of chemotherapy received – first regimen (1R), second regimen (2R), and third regimen (3R) and median (interquartile, IQR) duration of and between regimens. OS estimates were reported using the Kaplan-Meier method. Results: Among 694 mTNBC pts, 69 died within 30 days of diagnosis and were excluded. In the remaining 625 pts observed from 2004 through 2013 (median age: 75 years; Charlson comorbidity index (CCI) ≥2: 21%; and median follow-up: 11.4 months), 317 (51%) received chemotherapy. Of the 317 pts, 161 got only 1R, 88 got only 2R, and 68 got 3R+. Compared to pts on 1R, pts on 2R were significantly younger (median age: 2R, 72; 1R, 75 years), married (2R, 40%; 1R, 30%), had fewer comorbidities (CCI≥2: 2R, 16%; 1R, 23%). The top 2 most commonly prescribed single agents in 1R, 2R, and 3R were: 1R, paclitaxel followed by capecitabine; 2R, capecitabine followed by paclitaxel; 3R, gemcitabine followed by capecitabine. The most common combination regimen given was taxane-based in 1R (57%) and 2R (70%). Drug utilization patterns First Regimen (n=317)Second Regimen (n=156)Third Regimen (n=68)Single Agent205 (65%)74 (47%)40 (59%)Microtubule inhibitors80 (39%)23 (31%)NRPaclitaxel72 (35%)18 (24%)NRAnthracyclines29 (14%)13 (18%)NRDoxorubicin27 (13%)13 (18%)NRAntimetabolites/Others96 (47%)38 (51%)27 (73%)Capecitabine51 (25%)20 (27%)NRGemcitabineNRNR13 (35%)OthersNRNRNRCombination Regimens112 (35%)82 (53%)28 (41%)Taxane-based64 (57%)57 (70%)NRNR, not reported per DUA with NCI. %, col. % relative to single/comb. category Median (IQR) durations of 1R, 2R, and 3R were 2.7 (1.4-4.4), 3.1 (1.6-5.0), and 2.3 (0.9-4.5) months, respectively. Median time from diagnosis to start of 1R was 1.6 (0.9-2.8) months. Median time to start of 2R and 3R after the end of the previous regimen was 4.6 (2.1-8.1), and 6.2 (3.3-11.0) months, respectively. The median (12-month) OS was 7 months (34%) for all pts and ranged from 3.5 (17%) in the untreated to 25.3 (88%) months in 3R+ pts. Conclusions: About half of Medicare mTNBC pts do not receive chemotherapy in the real world. Paclitaxel and capecitabine were the most commonly used single agents and taxane-based combination therapy was the most commonly used combination. Citation Format: Aly A, Shah R, Hill K, Waldeck AR, Botteman M. United States real-world drug utilization patterns and associated overall survival in Medicare patients with newly-diagnosed metastatic triple negative breast cancer using surveillance, epidemiology, and end results-Medicare data [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 P6-08-05.

Safety and efficacy of bevacizumab in combination with first-line chemotherapy in advanced breast cancer: data from the Italian cohort of the ATHENA trial.

The ATHENA international study investigated the safety and efficacy of bevacizumab plus first-line chemotherapy in locally recurrent/metastatic breast cancer in routine oncology practice. The present paper focuses on the outcomes of the Italian cohort of the study. A subgroup analysis was carried out to report on the safety (primary endpoint) and efficacy (secondary endpoint) outcomes of patients recruited from Italian Centers. A total of 278 patients were included. Median age was 57 years (range, 26-85), and ECOG performance status was 0 or 1 in 96% of the patients. Bevacizumab was predominantly combined with a taxane monotherapy: paclitaxel (41.4%), docetaxel (21.9%), or a taxane-based combination therapy (12.2%). The most frequent grade ≥3 adverse events previously associated with bevacizumab were hypertension (3.2%), proteinuria (2.9%), and cardiac disorders (0.7%). Median time to progression was 10.9 months. Median overall survival was 29.9 months, and 1-year survival probability was 85%. Objective responses were observed in 62.6% of the patients, and an additional 30% achieved stable disease. Results from the study support the safety and efficacy of bevacizumab in combination with chemotherapy for the treatment of locally recurrent/metastatic breast cancer in the context of routine oncology practice in Italy.

Elevated circulating monocyte chemoattractant protein 1 (MCP-1/CCL-2) level may be an unfavorable predictive factor to platinum- and taxane-based combination chemotherapy in patients with gastric cancer

Monocyte chemoattractant protein 1 (MCP-1/CCL-2) is a member of the CC chemokine family and a potent chemotactic factor for monocytes that regulate migration and infiltration of monocytes and macrophages. It plays an important role in the pathogenesis of multiple malignancies, and its expression strongly also affects the outcomes of cancer patients. The objective of this study was to determine the clinical significance of the serum levels of MCP-1/CCL-2 in gastric cancer patients. A total of 78 patients diagnosed with gastric cancer were enrolled in this study. Serum MCP-1/CCL-2 concentrations were determined by the solid-phase sandwich ELISA method. Age- and sex-matched 30 healthy controls were included in the analysis. The median age at diagnosis was 60 years, range 21–84 years. The baseline serum MCP-1/CCL-2 concentrations of the gastric cancer patients were significantly higher than of healthy subjects (p < 0.001). The known clinical variables including gender, age, site of lesion, histopathology, tumor size, lymph node involvement, and stage of disease were not found to be correlated with serum MCP-1/CCL-2 concentrations (p > 0.05). However, a significant relationship was shown between serum MCP-1/CCL-2 levels and response to chemotherapy (p = 0.05). Chemotherapy non-responsive patients had higher serum MCP-1/CCL-2 concentrations. Serum MCP-1/CCL-2 concentrations were not associated with prognosis on both progression-free and overall survival (p = 0.53 and p = 0.39, respectively). Elevated circulating MCP-1/CCL-2 level may be an unfavorable predictive factor to chemotherapy based on platinum and taxane in patients with gastric cancer. However, serum MCP-1/CCL-2 concentrations were not associated with prognosis on both progression-free and overall survival.

Long-term outcomes and failure patterns of patients with nasopharyngeal carcinoma staged by magnetic resonance imaging in intensity-modulated radiotherapy era: The Zhejiang Cancer Hospital's experience.

To study and report the clinical outcomes and patterns of failure in the patients with nasopharyngeal carcinoma (NPC) staged by magnetic resonance imaging (MRI) and treated with intensity-modulated radiotherapy (IMRT). From January 2007 to December 2011, 720 NPC patients without metastasis staged by MRI were treated with definitive IMRT at Zhejiang Cancer Hospital. The IMRT prescribed dose was 69 Gy to planning target volume (PTV) of gross disease in nasopharynx and 67.5 Gy to PTV of positive lymph nodes in 30 fractions, high risk, and low risk region PTV was 60 and 54 Gy in 30 fractions, respectively. The treatment outcomes and patterns of failure were observed. Using the 7th edition of the American Joint Committee on Cancer staging system for NPC, the proportions of the 720 patients with Stages I, II, III, and IVa-b disease were 2.1% (15/720), 17.8% (128/720), 51.7% (372/720), and 28.5% (205/720), respectively. After the median follow-up period of 48 months (range: 3-89 months), a total of 146/720 (20.3%) patients had experienced failure: 37 (5.1%) at primary sites, 17 (2.4%) at regional sites, 79 (11.0%) at distant sites, and 13 (1.8%) at multiple sites. The 5-year overall survival, cancer-specific survival, disease-free survival, local relapse-free survival (LRFS), regional relapse-free survival, and distant metastasis (DM) free survival were 86.1%, 88.1%, 76.6%, 90.8%, 93.6%, and 87.2%, respectively. LRFS of T1 to T3 was all >90% and has no significant difference. In addition to N stage, T category, and neoadjuvant chemotherapy were independent predictors for DM in multivariate analysis. Our long-term outcome of large NPC series supports the effectiveness of IMRT for excellent local-regional control though up to 20% patients would develop DM, which becomes the main pattern of failure. T4 disease remained difficult to be cured not only for local recurrence but distant failure. A taxane-based combination chemotherapy might be useful to reduce DM in the induction setting and worth further studying.

Treatment patterns among elderly patients with stage IV breast cancer treated with HER-2-targeted therapy.

To evaluate treatment patterns among elderly, newly diagnosed stage IV breast cancer patients receiving HER-2-targeted therapy. Women aged 65+ with an incident diagnosis of stage IV breast cancer (index) and no history of other cancer were identified from 2006 to 2010 linked Surveillance, Epidemiology and End RESULTS and Medicare data. Continuous enrollment from 1 year preindex (baseline) through disenrollment, death or the end of the data (follow-up) was required. Patients were required to receive HER-2-targeted therapy (trastuzumab or lapatinib) during follow-up. Treatment therapies during follow-up were evaluated, as was the distribution of treatment combinations. Initial treatment regimens were evaluated based on the treatment(s) received after index. A 42-day gap in therapy or the addition of a biologic therapy was used as a marker for a subsequent regimen. A total of 173 patients were identified (mean [standard deviation] age: 73.9 [6.7] years). The majority received trastuzumab (>93%) during follow-up (mean [standard deviation] duration: 24.3 [11.3] months), with 9.8% receiving lapatinib. Most received chemotherapy (83.2%), approximately half received surgery (55.5%), over 40% received hormonal therapy and a third received radiation (35.3%). Trastuzumab + chemotherapy was the most common initial treatment regimen (43.9%); less common therapies include trastuzumab alone (17.3%), and trastuzumab + chemotherapy + hormonal (13.3%). Among patients receiving chemotherapy, the majority received a taxane-based chemotherapy. The average treatment duration for any treatment regimen was just less than a year (44.9-52.5 weeks). Among this population, the majority received taxane-based combination chemotherapy, consistent with National Comprehensive Cancer Network guidelines.

Neoadjuvant Taxane-Based Combination Chemotherapy in Patients With Advanced Penile Cancer

Introduction/BackgroundNeoadjuvant taxane-based combination chemotherapy has shown promising results in unresectable squamous cell carcinoma of the head and neck area, and the penis. Our primary aim was to assess the objective response in penile cancer patients neoadjuvantly treated with taxane-based combination chemotherapy. Secondary outcomes were progression-free survival (PFS), disease-specific survival (DSS), and toxicity. Patients and MethodsTwenty-six patients were treated within the framework of a nonrandomized institutional registration study with 4 courses of TPF (docetaxel, cisplatin, and 5-fluorouracil) for advanced penile cancer between 2008 and 2012. Response was measured using computed tomography (CT) and/or fluorodeoxyglucose positron emission tomography/CT according to Response Evaluation Criteria in Solid Tumours 1.1 criteria and European Organisation for Research and Treatment of Cancer recommendations, respectively. Toxicity, PFS, and DSS were analyzed using either the Common Toxicity Criteria of Adverse Events version 4.0 or the Kaplan-Meier methods. To analyze possible association with survival, univariable and multivariable Cox regression analyses were performed for tumor differentiation, N-category, recurrent disease, tumor margins, and administration of radiotherapy. ResultsDuring a median follow-up of 30 months, an imaging-based response was obtained in 60% (95% confidence interval [CI], 39%-79%) (15/25) of patients. However, pathologic complete response was observed in 1 of 25 evaluable patients (4%; 95% CI, 0%-20%). Toxicity was considerable with registered toxicity in every patient. The 2-year PFS and DSS probability were 12% and 28%, respectively. Patients responsive to chemotherapy had significantly better survival than nonresponsive patients. ConclusionDespite a fairly good response percentage, TPF chemotherapy was poorly tolerated with disappointing survival rates. Therefore, other treatment options should be considered.

58 Neoadjuvant taxane-based combination chemotherapy in patients with advanced penile cancer

58 Neoadjuvant taxane-based combination chemotherapy in patients with advanced penile cancer

Abstract 3475: Progranulin as a prognostic biomarker of advanced epithelial ovarian cancer.

Abstract Late diagnosis and early recurrence make epithelial ovarian cancer (EOC) the leading cause of gynecologic cancer death in the US. Indicators of early relapse may allow triage of high-risk patients to earlier therapy. Progranulin (PGRN) is a growth and survival factor overexpressed in EOC. We hypothesize that elevated serum (s)PGRN concentrations after clinical complete response (CCR) to primary platinum and taxane-based combination chemotherapy prognosticates disease recurrence and decreased survival in advanced EOC patients. We previously demonstrated high plasma (p)PGRN concentration (cutoff 59ng/ml) at first CCR distinguished early from late recurrence and predicted long-term survival (ROC AUC=0.944; sensitivity 93%; specificity 100%). In multivariate analysis, high pPGRN concentration predicted early recurrence (HR=23.5; 95%CI: 2.49-221; P&amp;lt;0.006). As PGRN is cleaved into proinflammatory granulins by neutrophil elastase, we wished to investigate the reliability of sPGRN as a biomarker. We compared PRGN concentrations in ten blinded, paired serum and plasma samples, using commercial PRGN ELISA assays; paired two-tailed t-test demonstrated comparability (P=0.90, R2= 0.002). A cohort of 35 blinded serum samples from a different institution was analyzed using the ELISA. The optimal dichotomization concentration of sPGRN, 49.5ng/ml, was determined by ROC statistics at a specificity of 90%, and applied to outcome analyses using Cox proportional hazards and Kaplan-Meier modeling. This PGRN cutoff significantly differentiated progression-free survival (PFS; P=0.0013). Subjects with low sPGRN had 100% survival (OS) at 2 years (N=11; range 2-12). Further validation of PGRN's discriminatory value could lead to its clinical investigation as a prognostic biomarker to stratify those at high risk for recurrence to closer monitoring or maintenance therapy, as well as its examination as a predictive biomarker for response to initial therapy. Citation Format: Sharon Fitzgerald, Minshu Yu, John Hays, Nicola Di Santo, Laura Havrilesky, Elise Kohn. Progranulin as a prognostic biomarker of advanced epithelial ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3475. doi:10.1158/1538-7445.AM2013-3475