#34 Background: Activating mutations of PI3 kinase (PIK3CA) and PTEN loss may be associated with trastuzumab resistance. Trastuzumab, a HER2 humanized monoclonal antibody, and lapatinib, an EGFR/HER2 tyrosine kinase inhibitor are both established treatments. Greater understanding of the cellular response to trastuzumab or lapatinib is needed to tailor targeted therapy for individual patients and identify those less likely to benefit. Material and Methods: We performed two sequential neoadjuvant clinical trials in HER-2 overexpressing LABC: 40 patients received weekly trastuzumab at standard doses given initially as a single agent for the first 3 weeks, then in combination with 3-weekly docetaxel for 12 weeks (T), while 49 patients received lapatinib as a single agent (1,500 mg daily, orally) for 6weeks then the combination of 3-weekly trastuzumab/docetaxel for 12 weeks, before primary surgery (L). Sequential core biopsies of the primary breast tumors were taken at initial, weeks 1 and 3 after the first dose of trastuzumab, and at initial, weeks 2, 4, and 6 after lapatinib. Apoptosis, Ki67 proliferation rate, and PTEN were assessed by immunohistochemistry. Low PTEN was defined as Allred score of <3. Genomic DNA (10-100ng) was sequenced using the BigDye Terminator Cycle Sequencing Kit (Applied Biosystems) and an ABI 3730 automated capillary sequencer. Two sample and paired sample comparisons were performed using nonparametric tests. Results: There was a significant decrease in clinical tumor size after three weeks of trastuzumab (n=35, median=-20%), and six weeks of lapatinib (n=49, median=-74%) compared to pre-therapy (p<0.001). At surgery, pathologic complete response was observed in 38% in patients on upfront T and 70% patient on L. There was a significant increase in apoptosis (median=3.5% to 4.7%, p=0.006) within one week after trastuzumab, with no significant change in Ki67 at any of the time point. Lapatinib was associated with a no significant increase in apoptosis but a significant decrease in Ki67 at week 2, 4, and 6 of therapy (p<0.001). Cases with low PTEN or PIK3CA mutations were significantly less likely to have a pathologic complete response to T (p<0.005). Howver, low PTEN or PIK3CA mutations was not significantly associated with pathologic resistance to L. Conclusions: Activation of PI3 kinase pathway is associated with trastuzumab but not lapatinib resistance. Lapatinib may affect signalling through the Ras/Raf/MAPK/ERK pathway, inhibiting cell division. Low PTEN expression was not associated with lapatinib resistance, and may explain the clinical efficacy of lapatinib in trastuzumab-resistant patients, supporting clinical trials for the combination of both agents. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 34.

#4115 Background: Sunitinib (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, FLT3, and CSF-1R, with proven single-agent activity in pts with advanced BC. Trastuzumab (T) is indicated as both monotherapy for second-line treatment and in combination with taxane-based therapies for first-line treatment of metastatic BC. This study investigates the activity and safety/tolerability of SU administered in combination with T in pts with advanced, HER2+ BC.
 Materials and methods: Eligible pts have unresectable, locally recurrent or metastatic HER2+ BC. Pts received SU at a starting dose of 37.5 mg/d po continuous daily dosing (CDD). T was administered iv wkly (loading 4 mg/kg then wkly 2 mg/kg) or q3w (loading 8 mg/kg then 6 mg/kg q3w). Due to changes in standard of care, the trial was amended from a randomized, placebo controlled design, to a single-arm study, and eligibility criteria were changed to allow inclusion of pts who had previously received CT in the first-line setting. Previous treatment with T (± lapatinib) was also permitted. The planned sample size is 53 pts and the primary endpoint is ORR.
 Results: In this ongoing trial, a total of 49 pts have been enrolled to date (6 pts under the original protocol and 43 under the amendment). All 43 pts enrolled under the amendment were evaluable for safety/tolerability, and antitumor activity, measured by RECIST. As of May 2008, 25 pts continue on study and 18 have discontinued, 4 due to AEs. Pts started a total of 167 cycles of treatment with a median of 4 cycles/pt (range: 1–8). The planned dose of SU (37.5 mg/d) was maintained in 31/43 pts (72%). It was reduced to 25 mg/d in 12/43 pts (28%). One pt achieved a CR and 10 a PR. SD occurred in 20 pts and PD in 6 pts. This translated into an ORR of 26% (95% CI, 13.5–41.2) and a clinical benefit rate of 35% (95% CI, 21.0–50.9). Median PFS was 25.3 wks (95% CI, 19.3–32.0). The most common treatment-related AEs were diarrhea (55.8%), asthenia (48.8%) and hypertension (37.2%) of which most were G1 or 2. The most frequent G3 AEs were neutropenia (14%) and asthenia (11.6%). There were 2 treatment-related G4 events: thrombocytopenia (2.3%) and LVEF decline (2.3%). There was 1 treatment-related G5 AE (cardiogenic shock).
 Conclusions: SU 37.5 mg/d on a CDD schedule in combination with T (wkly or q3w) appears to have a manageable safety profile and antitumor activity in pts previously treated for advanced HER2+ BC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4115.

Background: Nivo is an inhibitory antibody against programmed death receptor-1 (PD-1), a regulator of antitumor immunity. Nivo is approved for treatment of unresectable or metastatic melanoma and disease progression (PD) following ipilimumab or, in BRAF V600 mutation–positive melanoma, following a BRAF inhibitor, and for metastatic squamous non-small cell lung cancer (NSCLC) following PD during or after platinum-based chemotherapy. Nivo and other immune checkpoint inhibitors are also being investigated in other tumor-types. nab-P is a novel taxane formulation and does not require prophylaxis with immunosuppressive steroids. It has demonstrated superior efficacy over control regimens in phase III studies of MBC, pancreatic cancer, and NSCLC. This open-label, 6-arm, multicenter phase I trial will evaluate the safety of Nivo with nab-P in 3 cancer types (2 arms/disease): MBC, advanced NSCLC (+ carboplatin), and advanced pancreatic cancer (± gemcitabine). The study design for the MBC portion is described below. Methods: Eligibility criteria include histologically/cytologically confirmed HER2-negative MBC; 1 prior chemotherapy for MBC, including an anthracycline unless clinically contraindicated; no relapse < 12 months after taxane adjuvant therapy; measurable disease by RECIST v1.1; ECOG performance status 0-1; adequate organ function; and preexisting peripheral neuropathy grade < 2. Patients (pts) with MBC will be treated in 2 arms: nab-P 100 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus Nivo 3 mg/kg on days 1 and 15 starting at cycle 3 or nab-P 260 mg/m2 on day 1 of each 21-day cycle plus Nivo 5 mg/kg on day 15 starting at cycle 3. Pts will be treated until PD or allowed to continue treatment beyond RECIST v1.1–defined PD if they continue to meet study eligibility; do not have rapid PD or clinical deterioration or unacceptable toxicities; and can benefit from continuation of study treatment in the treating physician's opinion and will not delay an imminent intervention to prevent serious complications of PD. The primary endpoints of the study are the number of pts with dose-limiting toxicities (DLTs) in each treatment arm (part 1) and the percentage of pts with grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to a TEAE (parts 1 and 2). Part 1 of the study will assess whether the starting dose of Nivo is deemed safe (≤ 1 DLT in 6 pts); otherwise, the Nivo dose will be de-escalated and assessed in a new cohort at the next lower dose level. The Nivo dose in combination with nab-P deemed safe in a treatment arm may be further assessed in part 2 of the study, with enrollment expanded to an additional ∼ 14 pts/arm (total of 20 Nivo-treated pts/arm). Secondary study endpoints include TEAEs leading to dose reduction, delay, interruption, or treatment discontinuation; progression-free survival; overall survival; disease control rate; overall response rate; and duration of response (per RECIST v1.1). Exploratory endpoints include tumor-associated PD-L1 expression, modulation of immune activation in the tumor and peripheral blood in response to Nivo treatment, Nivo serum levels, and development of anti-globulin antibodies. ClinicalTrials.gov identifier NCT02309177. Citation Format: Waterhouse D, Gutierrez M, Bekaii-Saab T, DeRosa W, Wainberg Z, George B, Duval Fraser C, Ko A, Pierce DW, Stergiopoulos S, Soliman H. nab-paclitaxel (nab-P) plus nivolumab (Nivo) in human epidermal growth factor receptor 2 (HER2)–negative recurrent metastatic breast cancer (MBC). [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 OT1-01-07.

Background HER2+ status is associated with poor prognosis and a high incidence of brain metastases (BM) in breast cancer (BC). Addition of HER2−targeted therapies to conventional chemotherapy has significantly improved survival in HER2+ patients (pts). Management of BM implies a multidisciplinary therapeutic approach involving medical oncology, radiation oncology and neurosurgery teams. Nevertheless available data evaluating health resources use and associated costs are limited. Our objective was to describe treatment patterns and healthcare costs associated with HER2+ BMBC patients. Patients and methods An observational retrospective study was conducted on 207 HER2+ BC pts, newly diagnosed with BM as first site of relapse or as secondary metastases between January 2006 and December 2008. Pts were recruited in 10 hospitals, all funded by a prospective payment system based on Diagnosis Related Groups (DRG). Individual data concerning initial diagnosis, distant and BM relapses, treatments, complications and hospitalization stays were collected during a 2 year — follow-up. DRGs 2007 official tariffs (per-case payment basis) and 2007 expensive innovative drugs tariffs (drugs paid to hospitals by Health Insurance in addition to per-case payments) were used to estimate direct medical costs from the Health Insurance perspective. Survival was estimated using Kaplan Meier method. In the presence of cost-censored data, a partitioned estimator was used to adjust censoring costs (Bang and Tsiatis, Biometrics, 2002). Results 91.8% (190/207) of BMBC pts received radiation therapy, 84.5% (175/207) received chemotherapy including HER2 targeted treatments and 12.6% (26/207) were treated by neurosurgery. 72.5% (150/207) of pts were hospitalized at least once during the follow-up period. Pts had on average 2.90 hospital stays (range 1–8). The median duration of stay was 9 days (1-221). Complications leading to re-hospitalization were recorded in 45.9% (95/207) of pts. The median overall survival from the diagnosis of BM was 13 m. Hospital healthcare costs were concentrated on the 6 first months following BM diagnosis. Mean cost of BMBC management was 18,480€/patient within the 6 first months and decreased to 16,306€ from 7–12 months, 15,844€ from 13–18 months, and 15,225€ from 19–24 months. The proportion of costs attributed to inpatient hospitalizations stay (treatments and complications) was similar to the one attributed to drugs whatever the period of follow-up. Pts with BM as first site of relapse consumed more healthcare resources compared to pts with secondary BM (38,813€/pt vs 32,253€/pt after one year of follow-up, respectively). Conclusions Healthcare resources spending is mainly concentrated at the beginning of metastatic disease management, especially for patients with BM as first site of relapse. These results illustrate the use of expensive treatments in the first months following BM diagnosis. Individual data derived from this observational study allowed us to gather more specifically treatment patterns for HER2+ BMBC in order to estimate the costs more accurately. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-10-02.

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