Abstract Background: The 21-gene Recurrence Score (RS) assay is prognostic among women with early-stage estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) negative breast cancer (BC) and is used to select patients for chemotherapy (CT). Young women (age <40) have represented a minority in studies evaluating gene expression assays, including TAILORx, and additional data in young women are needed. Methods: In the Young Women's Breast Cancer Study, a prospective cohort study of women diagnosed with BC at age <40 enrolling between 2006-2016 (N=1302), we identified those with stage I-III ER+/HER2- BC. Disease and treatment information were obtained through serial surveys and medical record review. The RS was performed on banked specimens for those not tested clinically. Distant recurrence free interval (DRFI), defined as distant recurrence or BC specific death, by risk group was assessed using Cox regression and Kaplan-Meier survival estimates. Outcomes by receipt of CT were explored in the RS 11-25 group, and due to small number of events, reported descriptively. Results: Among eligible women (N=577), 189 (33%) had undergone RS testing and 320 (56%) had banked specimens sufficient for testing. Median follow-up was 6 years. Median age at diagnosis was 37, most had N0 BC (300/509, 59%), and the majority had RS 11-25 (306/509, 60%). RS result was significantly associated with DRFI in N0 BC, with hazard ratio (HR) (95% CI) of 0.29 (0.07,1.30) and 0.21 (0.09,0.50) for RS<11 and RS 11-25, respectively, relative to RS>26 (and trended towards significance in N1 BC). Results were similar using conventional RS groups. Among women with N0 BC and RS 11-25, 44% received CT, with two events in the 86 receiving CT (2.3%) and 6 events in the 109 without CT (5.5%); 5/8 (63%) occurred in those with RS 20-25. Table 1 N0N1Total Cohort N%N%N% 3005916332509100Median Age37.137.537.2Tumor Stage T120869694229358T28227784817635T3103159357T4001151Grade I4716855711II16555794926652III8829754618536Not assessed 1 1 PR status by IHC Negative (<1%)2071710398Positive (>=1%)280931469047092Chemotherapy No1414712715430Yes159531519335570Ovarian Suppression No263881499145289Yes37121495711TAILORx RS Groups RS <1133111495411RS 11-2519565885430660RS >=267224613714929Conventional RS Groups RS <1812742543319939RS 18-3012542694221142RS >=31481640259919 Table 2 6-year freedom from distant recurrence or breast cancer deathDRFI HR (95% CI) N0N1N0N1TAILORx RS Groups RS <1194.4%92.3%0.29 (0.07,1.30)0.21 (0.03,1.61)RS 11-2596.9%85.2%0.21 (0.09, 0.50)0.55 (0.27,1.12)RS >=2685.1%71.3%RefRefConventional RS Groups RS <1897.5%85.9%0.19 (0.06,0.59)0.31 (0.13,0.74)RS 18-3093.1%87.3%0.39 (0.16,1.00)0.32 (0.14,0.73)RS >=3186.4%62.8%RefRef Conclusions: The RS is prognostic among young women with node-negative and node-positive BC, and is a valuable tool for risk stratification. Disease outcomes among young women with N0 disease and RS 11-25, a minority of whom received CT, are very good. Evaluation of the effect of ovarian suppression/CT-induced amenorrhea by RS/treatment strata is ongoing. Citation Format: Poorvu PD, Gelber SI, Rosenberg SM, Ruddy KJ, Tamimi RM, Collins LC, Peppercorn J, Schapira L, Borges VF, Come SE, Warner E, Jakubowski DM, Russell C, Winer EP, Partridge AH. Prognostic impact of the 21-gene recurrence score assay among young women with node-negative and node-positive ER+/HER2- breast cancer [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 P2-08-07.

Twenty-five women with advanced breast carcinoma refractory to first-line chemotherapy entered a phase II trial to evaluate the efficacy of ifosfamide and carboplatin. Additionally the trial assessed the clinical usefulness of oral 2-mercaptoethane sulfonate (mesna) for urothelial protection. Two partial remissions were observed (8%); toxicity was significant but acceptable, with no treatment-related deaths. The combination of ifosfamide and carboplatin had little activity as the second-line treatment in our population of patients with heavily pretreated metastatic breast cancer. Oral mesna was effective for urothelial protection, permitting outpatient administration of ifosfamide.

The epipodophyllotoxin derivatives etoposide and teniposide have been evaluated intermittently for possible use in the treatment of ovarian cancer. Conflicting studies suggest that variables such as dose and prior treatment have a major influence on outcome. Response rates ranged from 0% to 40% in five series with teniposide, and from less than a 10% overall response rate to greater than a 10% complete response rate in nine studies with etoposide. One study documented activity with oral etoposide. However, because all patients had received various prior chemotherapies, firm conclusions regarding the activity of etoposide could not be drawn. These results, and the expectation of synergy with etoposide and cisplatin, led to several studies that combined etoposide with platin compounds by the systemic and intraperitoneal (IP) routes. Various studies have used intravenous drug combinations of these agents in both previously treated and untreated patients. One study, which used carboplatin instead of cisplatin, reported only seven failures among 26 previously untreated patients. Conversely, the prominent toxicities reported by another study were discouraging, and responses did not exceed what might be expected from cisplatin alone. Studies of analogous combinations administered IP are ongoing. A favorable experience, which was initially reported by the University of California (San Diego group), is being confirmed by other investigators. This has prompted the incorporation of etoposide into first-line strategies. The pharmacologic advantage of etoposide by the IP route (related to its high protein binding) may provide appropriate dose intensity against IP disease while sparing systemic toxicities. Finally, systemic dose intensity with autologous bone marrow support indicates some promise for etoposide in combination with high-dose alkylating drugs.