Abstract P2-05-02: Preliminary translational results from PROMIX, a phase II trial of preoperative chemotherapy with the addition of bevacizumab in large operable and locally advanced HER2-negative breast cancer
Authors: Loman Niklas , Johansson Ida , Bjöhle Judith , Frisell Jan , Lekberg Tobias , Rydén Lisa , von Wachenfeldt Anna , Bergh Jonas , Hatschek Thomas , Hedenfalk Ingrid 
Published: May 2015

Abstract
Background: Preoperative chemotherapy in breast cancer (bc) provides unique possibilities to evaluate effects of therapy by studying response and changes in the tumor during the course of treatment. A pathologic complete response (pCR) correlates positively with long term prognosis in high-proliferating bc. In triple negative bc (TNBC) the prognosis was still relatively serious in cases with pCR in one large meta-analysis (Cortazar Lancet 2014).
Methods: 150 cases were included in this multicenter study, and treated with six cycles of epirubicin and docetaxel, adding bevacizumab from cycle 3, before surgery. Core needle biopsies were collected at free hand or with ultrasound (US) guidance and snap frozen at base-line and after cycle 2, tissue was also collected at surgery. Subtyping was performed using immunohistochemistry (IHC) of ER, Ki67 and HER2 according to modified St Gallen criteria; and using bead array gene expression profiling (GEX) according to PAM50.
Results: Biopsies were successfully retrieved from 145/150 pts at baseline, 138 after cycle 2 and 139 at surgery. The mRNA yield was adequate for GEX from 123/145 (85%) at baseline, 82/138 (59%) at cycle 2 and 71/139 (51%) at surgery, the decrease being a result of tumor shrinkage during treatment.
Initial PAM50 subtypes were as follows: luminal A (LA) 20%, luminal B (LB) 45%, HER2 5 %, basal like (BL) 22% and normal like (NL) 8%. PAM50 at baseline differed compared to IHC subtypes. Among IHC defined LA-like cases 15/33 (45%) were classified as LB by PAM50. Similarly, among IHC LB-like 22/57 (39%) were classified as non-LB (6 basal, 8 LA, 3 HER2 and 5 NL), while among IHC TNBC 7/28 (25%) were classified as non-BL subtypes (1 LA, 3 HER2 and 3 NL).
Of the pts with a baseline GEX analysis, 17 (14%) achieved a pCR. The observed pCR rates among PAM50 subtypes were: LA 8%, LB 5%, HER2 17%, BL 53% and NL 20%. For non-pCR cases, 39/52 (75%) of the tumors changed PAM50 subtype between baseline and surgery. The majority changed to the NL subtype. 33% of the LB tumors changed to the LA subtype.
Currently, after 2.2 years of follow-up, 16 pts are deceased due to bc. Among BL cases, 6/9 pts with a pCR at surgery remain alive; while 3/9 have died from bc. Exploratory analyses using functional gene modules (Desmedt Clin Cancer Res 2008) suggest that patients with BL tumors who have died have higher scores for PLAU/invasion and lower scores for STAT1/immune response compared with those who are still alive. Tumor size at baseline did not obviously correlate with outcome.
Conclusion: We show that biological material can be retrieved from a substantial fraction of cases treated within a multicenter study of preoperative chemotherapy. The success rate may be ameliorated by routine use of US guidance. The distribution of subtypes differs between modified IHC St Gallen criteria and PAM50, especially within the luminal subtypes. The pCR rate is highest among cases with a BL tumor at baseline. Shift of the gene signature between different subtypes during the course of treatment is frequent. In this set of relatively large tumors, the prognosis among BL bc appears to be adverse in spite of a pCR.
Citation Format: Niklas Loman, Ida Johansson, Judith Bjöhle, Jan Frisell, Tobias Lekberg, Lisa Rydén, Anna von Wachenfeldt, Jonas Bergh, Thomas Hatschek, Ingrid Hedenfalk. Preliminary translational results from PROMIX, a phase II trial of preoperative chemotherapy with the addition of bevacizumab in large operable and locally advanced HER2-negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-05-02.