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Background: The randomized phase II SNAP trial assessed three alternative reduced maintenance chemotherapy regimens using nab-Paclitaxel after a short term induction phase at conventional doses as first line treatment in patients (pts) with metastatic breast cancer (MBC). For all three regimens median progression-free survival was greater than achieved with full dose docetaxel (historical reference). Symptom palliation and quality of life (QoL) are important when deciding on therapeutic agents and schedules in MBC pts. Methods: Of the 258 pts with MBC enrolled from April 2013 to August 2015 in the SNAP trial, 255 were included in the QoL analysis. Pts were randomized to three arms, each receiving the same induction chemotherapy based on 3 cycles of nab-Paclitaxel 150 mg/m2 dd 1, 8, 15 Q28, which was reduced to 125 mg/m2 after a safety review. The schedules of nab-Paclitaxel in maintenance therapy differed in each arm: Arm A) 150 mg/m2 dd 1,15 Q28; Arm B) 100 mg/m2 dd 1,8,15 Q28; Arm C) 75 mg/m2 dd 1,8,15,22 Q28. Pts completed a QoL form to assess global and symptom-specific indicators (range 0-100) at baseline, and at day 1 of every cycle for the first 12 cycles on treatment, or until treatment discontinuation. Changes in QoL scores during induction (day 1 cycle 4 − baseline) and maintenance (day 1 cycle 12 – day 1 cycle 4) therapy were summarized descriptively per arm. Treatment effects on changes in QoL during maintenance therapy were analyzed by repeated measurement models including timepoints (from day 1 of cycle 4 to day 1 of cycle 12), induction start dose, age, and treatment arms as covariates. Results: During induction therapy, mean changes [SD] in hair loss (Arm A:−70.2 [41.9]; Arm B: −77.3 [34.5]; Arm C: −72.6 [32.8]), sensory neuropathy (Arm A: −19.0 [25.2]; Arm B: −20.6 [22.7]; Arm C: −18.8 [23.8]), and treatment burden (Arm A: −12.9 [33.4]; Arm B: −13.4 [33.5]; Arm C: −11.4 [34.8]) showed the most pronounced worsening. During maintenance therapy, scores for sensory neuropathy remained impaired without worsening. No significant differences in changes for sensory neuropathy or the other symptoms were seen between arms, except for hair loss, with pts in arm C (mean difference 10.91; 95% CI [0.35, 21.48]; p=0.04) ] and B (mean difference 18.55; 95% CI [7.52, 29.59]; p=0.001) reporting a greater improvement compared to those in arm A. Pts in arm C reported a significantly greater improvement in mood compared to arm A (mean difference 13.34; 95% CI [6.08, 20.60]; p Conclusion: The effectiveness of alternative maintenance chemotherapy schedules with reduced doses after a short term induction phase at conventional doses must be weighed against a substantial worsening in sensory neuropathy during induction therapy, and scores continuing to be impaired without worsening with prolonged administration. During maintenance therapy, improvements were seen in the perception of hair loss and in mood, particularly in Arm B and C, with a similar tendency seen for some other QoL domains. A more frequent administration of reduced dose chemotherapy agents is favorable with respect to QoL in this setting. Citation Format: Ribi K, Sun Z, Jerusalem G, Hasler-Strub U, Colleoni M, von Moos R, Cortés J, Vidal M, Hennessy B, Walshe J, Amillano Parraga K, Morales Muriilo S, Pagani O, Barbeaux A, Bortsnar S, Maibach R, Regan MM, Gennari A, Bernhard J. Nab-Paclitaxel-based therapy in the first line treatment of metastatic breast cancer (IBCSG 42-12/BIG 2-12 SNAP): Impact of different schedules on quality of life [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 P5-18-02.

Background Longer chemotherapy (CT) duration is associated with a significant improvement in progression-free survival (PFS) and a moderate, but significant improvement in overall survival (OS) in MBC patients (pts). Prolonged CT administration, however, must be weighed against the side effects of continuous CT delivery. The SNAP trial was designed to improve the tolerability of prolonged CT by studying alternative treatment schedules. Methods The SNAP trial enrolled 258 women from April 2013 to Aug 2015. Eligibility criteria included HER2- MBC, no prior CT for advanced disease, measurable and/or non-measurable disease. All eligible pts were randomized to one of three arms. Pts received the same induction chemotherapy consisting of 3 cycles of nab-Paclitaxel given days 1,8,15 Q28, followed by one of the three maintenance therapy schedules. Originally, the dose of the induction chemotherapy was 150 mg/m2, but this was reduced to 125 mg/m2 following the first safety review of 48 treated pts. The three schedules of nab-Paclitaxel used as maintenance therapy were (Arm A) nab-Paclitaxel 150 mg/m2 d 1,15 Q28; (Arm B) nab-Paclitaxel 100 mg/m2 d 1,8,15 Q28; (Arm C) nab-Paclitaxel 75 mg/m2 d 1,8,15,22 Q28. The primary objective is to evaluate the efficacy of three nab-Paclitaxel regimens as measured by progression-free survival (PFS), using the historical reference of PFS (based on AVADO study) of docetaxel for first-line treatment of metastatic breast cancer. Each of the three regimens is compared to the historic 7-month median PFS to determine whether any of the three regimens are worthy of further investigation. Secondary endpoints include tolerability, feasibility, response rate, OS and QoL. Results Two-hundred-fifty-eight pts have been randomised and 255 are available for primary endpoint evaluation. At 18.2 months' median follow-up, 182 PFS events and 85 deaths have been observed. Median PFS was 7.9 months (90%CI 6.8-8.4) in Arm A, 9.0 months (90%CI 8.1-10.9) in Arm B and 8.5 (90%CI 6.7-9.5) in Arm C. PFS in Arm B was significantly longer than the historic PFS of first-line docetaxel (one-sided log-rank p=0.03). As expected, neurotoxicity was the most frequent adverse event. In the induction phase, grade≥2 sensory neuropathy was reported in 14.8% of pts at the starting dose of 150 mg/m2 and 7.5% at the starting dose of 125 mg/m2; grade≥3 sensory neuropathy occurred in 2.5% and 0% of the pts, respectively. In the maintenance phase, grade≥2 sensory neuropathy was reported in 37.9% of pts in Arm A, 36.1% in Arm B and 31.2% in Arm C; grade≥3 sensory neuropathy occurred in 9.1%, 5.6% and 6.6% of the pts, respectively. 199 pts started the maintenance phase. The median number of maintenance cycles was 3, 4, and 5, respectively. Stopping maintenance for reasons other than objective progression occurred in 41%, 58%, and 53%, respectively. Conclusion The SNAP trial indicates that alternative maintenance chemotherapy schedules with reduced doses after a short term induction phase at conventional doses are feasible and significantly more active than the historical PFS of docetaxel in the first line treatment of advanced breast cancer. Citation Format: Gennari A, Sun Z, Hasler-Strub U, Colleoni M, Kennedy J, von Moos R, Cortes J, Vidal M, Hennessy B, Walshe J, Amillano Parraga K, Morales Murrillo S, Pagani O, Barbeaux A, Borstnar S, Rabaglio M, Maibach R, Regan MM, Jerusalem G. Randomized phase II study evaluating different schedules of nab-paclitaxel in metastatic breast cancer (MBC): Results of the SNAP study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-15-05.

Background: To explore the patterns of breast cancer (BC) relapse according to BC subtypes in a lower risk (lymph node (LN)-negative) population we classified pts from two trials according to a molecular classification using IHC surrogates. IBCSG Trial VIII randomized 1109 premenopausal pts with LN-negative BC to sequential treatment with six cycles of CMF followed by 18 months of goserelin, six courses of CMF alone, or 24 months of goserelin alone. The IBCSG Trial IX randomized 1669 postmenopausal pts with LN-negative BC to sequential treatment with 3 courses of CMF followed by tamoxifen for 57 months or tamoxifen alone for 5 years. Retrospective central pathology evaluation including ER, PgR, HER2 and Ki67 was used to define a molecular classification. Patients & Methods: Of the 2778 pts enrolled in both trials the present analysis includes 2033 (824 from trial VIII and 1209 from trial IX) who also had centrally-reviewed pathology data. The BC molecular subtypes were defined as following: Luminal-A (ER and/or PR-present, HER2-negative and Ki67 Results: In the population analyzed (N = 2033), 25.9% had luminal-A (LA) tumors, 40.3% had luminal B (LB) tumors, 17.7% had HER2-positive tumors, and 16.0% had basal tumors. At 12.7 years median follow-up, a total of 699 (34.4%) pts had BC recurrence or non-BC events (secondary malignancy or death): LA = 152 (28.8%), LB = 291 (35.5%), HER2- positive = 134 (37.2%), and Basal = 122 (37.4%). Among 2033 pts, no significant differences were observed among the molecular subtypes for time to local recurrence (LA 6.1%, LB 6.7%, HER2 7.8%, basal 6.7%, p = 0.98), contralateral BC (LA 3.4%, LB 4.1%, HER2 2.5%, basal 4.9%; p = 0.36), and non-BC events (LA 12%, LB 10%, HER2 8.3%, basal 7.7%; p=0.39). Patients with LB disease had more bone recurrences (LB 5.5%, LA 2.5%, HER2 3.3%, basal 1.8%; p=0.004). The patterns over time of soft tissue nodes and visceral recurrence varied according to the adjuvant treatment received (interaction tests P Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-13-01.

Background Young breast cancer (BC) patients often face the disease before completing their family planning. The best available retrospective evidence suggests that pregnancy after BC does not negatively impact disease outcome in patients with endocrine sensitive BC and is safe for the offspring. However, given the need for prolonged adjuvant endocrine therapy for 5-10 years, it is not feasible to wait until completion of therapy in most of these women and thus there is a need to explore the safety of temporary interruption of endocrine therapy to allow pregnancy. To date, no definitive prospective study has been conducted in young women desiring future pregnancy. Trial Design Young patients with endocrine responsive early BC and pregnancy desire will interrupt endocrine treatment for up to 2 yrs to attempt pregnancy. As resumption of menses and conception depends on many factors, e.g. patient's age and adjuvant treatment received, the 2-yr interruption period is approximate, intended to include treatment wash-out (3 mos) conception (∼3-6 mos), delivery (∼9 mos), breast feeding (∼6 mos). Patients will be strongly advised to resume ET as soon as pregnancy attempts are concluded, and to complete 5-10 yrs ET at the local investigator discretion. Major Eligibility Criteria -Histologically-proven stage I-III endocrine-responsive BC. -Age ≥ 18 and ≤ 42 years at enrollment. -Adjuvant endocrine therapy (SERM alone, GnRH analogue plus SERM or AI) for ≥18 months but ≤30 months, stopped within 1 month prior to enrollment. -Patient wishes to become pregnant. -Premenopausal status at BC diagnosis. Specific Aim To assess the risk of BC relapse associated with temporary interruption of ET to permit pregnancy and to evaluate pregnancy success. Statistical Methods A true risk of BC recurrence of 2% per year is assumed for patients who do not interrupt endocrine treatment. With 500 patients enrolled in 4.0 yrs and an additional 1.6 yrs of follow up, there will be approximately 1600 patient-yrs of follow up and a median follow up of approximately 3 yrs at the time of the primary analysis, anticipated to occur 5.6 yrs after enrollment of the first patient. If the true risk of BC recurrence is 2% per yr, we anticipate 31 BC recurrences and an estimated 3-yr breast cancer free interval (BCFI) failure of 5.6% (95% CI 4.0% to 7.9%). Translational Research will investigate different ovarian function parameters; uterine evaluation; and circulating tumor DNA. FFPE tissue of the primary tumor will be collected to integrate different parameters related to biology of BC arising in young women. All material will be banked centrally. Psycho-oncological Companion Study on fertility concerns, psychological well-being and decisional conflicts is mandatory in the United States and open to interested centers elsewhere. Accrual: Target: 500; Actual: 4 (31 May 2015) Contact Information POSITIVE is conducted and sponsored by the International Breast Cancer Study Group. Alliance for Clinical Trials in Oncology is US sponsor for NCTN network. Contact Trial Coordinators at ibcsg48_positive@fstrf.org. Citation Format: Pagani O, Partridge A, Azim Jr HA, Peccatori FA, Ruggeri M, Sun Z. POSITIVE: A study evaluating pregnancy and disease outcome and safety of interrupting endocrine therapy for young women with endocrine responsive breast cancer who desire pregnancy (IBCSG 48-14/BIG 8-13). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-01-08.