Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy.

Abstract

INTRODUCTION:

Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy).

METHODS:

We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test.

RESULTS:

Three independent SNPs in TGFBR2 and IL12B were associated with OS (P <10⁻³) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with TGFBR2 rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 × 10⁻⁴) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction <10-3). Two SNPs in IL12B (r² = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 × 10⁻⁴), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 × 10⁻⁴). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 × 10⁻⁵) without study heterogeneity.

CONCLUSIONS:

TGFBR2 variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.

• Authors: Jieping Lei, Anja Rudolph, Kirsten B Moysich, Sajjad Rafiq, Sabine Behrens, Ellen L Goode, Paul P D Pharoah, Petra Seibold, Peter A Fasching, Irene L Andrulis, Vessela N Kristensen, Fergus J Couch, Ute Hamann, Maartje J Hooning, Heli Nevanlinna, Ursula Eilber, Manjeet K Bolla, Joe Dennis, Qin Wang, Annika Lindblom, Arto Mannermaa, Diether Lambrechts, Montserrat García-Closas, Per Hall, Georgia Chenevix-Trench, Mitul Shah, Robert Luben, Lothar Haeberle, Arif B Ekici, Matthias W Beckmann, Julia A Knight, Gord Glendon, Sandrine Tchatchou, Grethe I Grenaker Alnæs, Anne-Lise Borresen-Dale, Silje Nord, Janet E Olson, Emily Hallberg, Celine Vachon, Diana Torres, Hans-Ulrich Ulmer, Thomas Rüdiger, Agnes Jager, Carolien H M van Deurzen, Madeleine M A Tilanus-Linthorst, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Sara Margolin, Veli-Matti Kosma, Jaana M Hartikainen, Vesa Kataja, Sigrid Hatse, Hans Wildiers, Ann Smeets, Jonine Figueroa, Stephen J Chanock, Jolanta Lissowska, Jingmei Li, Keith Humphreys, Kelly-Anne Phillips, kConFab Investigators, Sabine Linn, Sten Cornelissen, Sandra Alexandra J van den Broek, Daehee Kang, Ji-Yeob Choi, Sue K Park, Keun-Young Yoo, Chia-Ni Hsiung, Pei-Ei Wu, Ming-Feng Hou, Chen-Yang Shen, Soo Hwang Teo, Nur Aishah Mohd Taib, Cheng Har Yip, Gwo Fuang Ho, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Kazuo Tajima, Alison M Dunning, Javier Benitez, Kamila Czene, Lara E Sucheston, Tom Maishman, William J Tapper, Diana Eccles, Douglas F Easton, Marjanka K Schmidt, Jenny Chang-Claude
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 17 Pg. 18 (Feb 10 2015) ISSN: 1465-542X [Electronic] England
• PMID: 25849327 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Biomarkers, Tumor
• IL12B protein, human
• Interleukin-12 Subunit p40
• Receptors, Estrogen
• Receptors, Transforming Growth Factor beta
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type II

Topics

• Adult
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (genetics, metabolism)
• Breast Neoplasms (diagnosis, drug therapy, genetics, immunology, mortality)
• Female
• Genomics
• Humans
• Immunomodulation (genetics)
• Interleukin-12 Subunit p40 (genetics)
• Kaplan-Meier Estimate
• Middle Aged
• Neoplasm Grading
• Neoplasm Staging
• Polymorphism, Single Nucleotide
• Prognosis
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Receptor, Transforming Growth Factor-beta Type II
• Receptors, Estrogen (genetics, metabolism)
• Receptors, Transforming Growth Factor beta (genetics, metabolism)
• Signal Transduction
• Treatment Outcome
• Tumor Burden