Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2015

01-11-2015 | Epidemiology

Comprehensive genomic profiling of inflammatory breast cancer cases reveals a high frequency of clinically relevant genomic alterations

Authors: Jeffrey S. Ross, Siraj M. Ali, Kai Wang, Depinder Khaira, Norma A. Palma, Juliann Chmielecki, Gary A. Palmer, Deborah Morosini, Julia A. Elvin, Sandra V. Fernandez, Vincent A. Miller, Philip J. Stephens, Massimo Cristofanilli

Published in: Breast Cancer Research and Treatment | Issue 1/2015

Login to get access

Abstract

Inflammatory breast cancer (IBC) is a distinct clinicopathologic entity that carries a worse prognosis relative to non-IBC breast cancer even when matched for standard biomarkers (ER/PR/HER2). The objective of this study was to identify opportunities for benefit from targeted therapy, which are not currently identifiable in the standard workup for advanced breast cancer. Comprehensive genomic profiling on 53 IBC formalin-fixed paraffin-embedded specimens (mean, 800× + coverage) using the hybrid capture-based FoundationOne assay. Academic and community oncology clinics. From a series of 2208 clinical cases of advanced/refractory invasive breast cancers, 53 cases with IBC were identified. The presence of clinically relevant genomic alterations (CRGA) in IBC and responses to targeted therapies. CRGA were defined as genomic alterations (GA) associated with on label targeted therapies and targeted therapies in mechanism-driven clinical trials. For the 44 IBCs with available biomarker data, 19 (39 %) were ER−/PR−/HER2− (triple-negative breast cancer, TNBC). For patients in which the clinical HER2 status was known, 11 (25 %) were HER2+ with complete (100 %) concordance with ERBB2 (HER2) amplification detected by the CGP assay. The 53 sequenced IBC cases harbored a total of 266 GA with an average of 5.0 GA/tumor (range 1–15). At least one alteration associated with an FDA approved therapy or clinical trial was identified in 51/53 (96 %) of cases with an average of 2.6 CRGA/case. The most frequently altered genes were TP53 (62 %), MYC (32 %), PIK3CA (28 %), ERBB2 (26 %), FGFR1 (17 %), BRCA2 (15 %), and PTEN (15 %). In the TNBC subset of IBC, 8/19 (42 %) showed MYC amplification (median copy number 8X, range 7–20) as compared to 9/32 (28 %) in non-TNBC IBC (median copy number 7X, range 6–21). Comprehensive genomic profiling uncovered a high frequency of GA in IBC with 96 % of cases harboring at least 1 CRGA. The clinical benefit of selected targeted therapies in individual IBC cases suggests that a further study of CGP in IBC is warranted.
Appendix
Available only for authorised users
Literature
1.
van Uden DJ, van Laarhoven HW, Westenberg AH, de Wilt JH, Blanken-Peeters CF (2014) Inflammatory breast cancer: an overview. Crit Rev Oncol Hematol
2.
Yamauchi H, Woodward WA, Valero V, Alvarez RH, Lucci A, Buchholz TA et al (2012) Inflammatory breast cancer: what we know and what we need to learn. Oncologist 17:891–899PubMedCentralCrossRefPubMed
3.
Robbins GF, Shah J, Rosen P, Chu F, Taylor J (1974) Inflammatory carcinoma of the breast. Surg Clin North Am 54:801–812PubMed
4.
Taylor G, Meltzer A (1938) Inflammatory carcinoma of the breast. Am J Cancer 33:33–49CrossRef
5.
Ellis DL, Teitelbaum SL (1974) Inflammatory carcinoma of the breast: a pathologic definition. Cancer 33:1045–1047CrossRefPubMed
6.
Dawood S, Merajver SD, Viens P et al (2011) International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment. Ann Oncol 22:515–523PubMedCentralCrossRefPubMed
7.
Parton M, Dowsett M, Ashley S, Hills M, Lowe F, Smith IE (2004) High incidence of HER-2 positivity in inflammatory breast cancer. Breast 13:97–103CrossRefPubMed
8.
Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN (2009) The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 14:320–368CrossRefPubMed
9.
Hance KW, Anderson WF, Devesa SS, Young HA, Levine PH (2005) Trends in inflammatory breast carcinoma incidence and survival: the surveillance, epidemiology, and end results program at the National Cancer Institute. J Natl Cancer Inst 97(13):966–975PubMedCentralCrossRefPubMed
10.
Robertson FM, Bondy M, Yang W, Yamauchi H, Wiggins S, Kamrudin S et al (2010) Inflammatory breast cancer: the disease, the biology, the treatment. CA Cancer J Clin 60:351–375CrossRefPubMed
11.
Matro JM, Li T, Cristofanilli M, Hughes ME, Ottesen RA, Weeks JC, Wong YN (2014) Inflammatory breast cancer management in the national comprehensive cancer network: the disease, recurrence pattern, and outcome. Clin Breast Cancer S1526–8209(14):00112–118
12.
Lerebours F, Bertheau P, Bieche I, Plassa LF, Champeme MH, Hacene K et al (2003) Two prognostic groups of inflammatory breast cancer have distinct genotypes. Clin Cancer Res 9(11):4184PubMed
13.
Liauw SL, Benda RK, Morris CG, Mendenhall NP (2004) Inflammatory breast carcinoma: outcomes with trimodality therapy for nonmetastatic disease. Cancer 100(5):920–928CrossRefPubMed
14.
Galmarini CM, Garbovesky C, Galmarini D, Galmarini FC (2002) Clinical outcome and prognosis of patients with inflammatory breast cancer. Am J Clin Oncol 25(2):172–177CrossRefPubMed
15.
Henderson MA, McBride CM (1988) Secondary inflammatory breast cancer: treatment options. South Med J 81(12):1512–1517CrossRefPubMed
16.
Ueno NT, Buzdar AU, Singletary SE, Ames FC, McNeese MD, Holmes FA, Theriault RL, Strom EA, Wasaff BJ, Asmar L, Frye D, Hortobagyi GN (1997) Combined-modality treatment of inflammatory breast carcinoma: twenty years of experience at M. D. Anderson Cancer Center. Cancer Chemother Pharmacol 40(4):321–329CrossRefPubMed
17.
Bourgier C, Pessoa EL, Dunant A, Heymann S, Spielmann M, Uzan C et al (2012) Exclusive alternating chemotherapy and radiotherapy in nonmetastatic inflammatory breast cancer: 20 years of follow-up. Int J Radiat Oncol Biol Phys 82:690–695CrossRefPubMed
18.
Bertucci F, Finetti P, Vermeulen P, Van Dam P, Dirix L, Birnbaum D et al (2014) Genomic profiling of inflammatory breast cancer: a review. Breast 23:538–545CrossRefPubMed
19.
Silvera D, Arju R, Darvishian F, Levine PH, Zolfaghari L, Goldberg J et al (2009) Essential role for eIF4GI overexpression in the pathogenesis of inflammatory breast cancer. Nat Cell Biol 11:903–908CrossRefPubMed
20.
Vasan N, Yelensky R, Wang K, Moulder S, Dzimitrowicz H, Avritscher R et al (2014) A targeted next-generation sequencing assay detects a high frequency of therapeutically targetable alterations in primary and metastatic breast cancers: implications for clinical practice. Oncologist 19:453–458PubMedCentralCrossRefPubMed
21.
Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J et al (2013) Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 31:1023–1031CrossRefPubMed
22.
Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D et al (2011) COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 39:D945–D950PubMedCentralCrossRefPubMed
23.
Compeau PE, Pevzner PA, Tesler G (2011) How to apply de Bruijn graphs to genome assembly. Nat Biotechnol 29:987–991CrossRefPubMed
24.
25.
Colak D, Nofal A, Albakheet A, Nirmal M, Jeprel H, Eldali A et al (2013) Age-specific gene expression signatures for breast tumors and cross-species conserved potential cancer progression markers in young women. PLoS One 8:e63204PubMedCentralCrossRefPubMed
26.
Pereira CB, Leal MF, de Souza CR, Montenegro RC, Rey JA, Carvalho AA et al (2013) Prognostic and predictive significance of MYC and KRAS alterations in breast cancer from women treated with neoadjuvant chemotherapy. PLoS One 8:e60576PubMedCentralCrossRefPubMed
27.
Horiuchi D, Kusdra L, Huskey NE, Chandriani S, Lenburg ME, Gonzalez-Angulo AM et al (2012) MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition. J Exp Med 209:679–696PubMedCentralCrossRefPubMed
28.
Hook KE, Garza SJ, Lira ME, Ching KA, Lee NV, Cao J et al (2012) An integrated genomic approach to identify predictive biomarkers of response to the aurora kinase inhibitor PF-03814735. Mol Cancer Ther 11:710–719CrossRefPubMed
29.
Yang D, Liu H, Goga A, Kim S, Yuneva M, Bishop JM (2010) Therapeutic potential of a synthetic lethal interaction between the MYC proto-oncogene and inhibition of aurora-B kinase. Proc Natl Acad Sci USA 107:13836–13841PubMedCentralCrossRefPubMed
30.
Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM et al (2011) BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146:904–917PubMedCentralCrossRefPubMed
31.
Bandopadhayay P, Bergthold G, Nguyen B, Schubert S, Gholamin S, Tang Y et al (2014) BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin Cancer Res 20:912–925PubMedCentralCrossRefPubMed
32.
Lovén J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR et al (2013) Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153:320–334PubMedCentralCrossRefPubMed
33.
Balko JM, Giltnane JM, Wang K, Schwarz LJ, Young CD, Cook RS et al (2014) Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov 4:232–245PubMedCentralCrossRefPubMed
34.
Chmielecki J, Ross JS, Wang K, Frampton GM, Palmer GA, Ali SM et al (2015) Oncogenic alterations in ERBB2/HER2 represent potential therapeutic targets across tumors from diverse anatomic sites of origin. Oncologist 20:7–12CrossRefPubMed
35.
Dushkin H, Cristofanilli M (2011) Inflammatory breast cancer. J Natl Compr Cancer Netw 9:233–240
36.
Ali SM, Alpaugh RK, Downing SR, Stephens PJ, Yu JQ, Wu H et al (2014) Response of an ERBB2-mutated inflammatory breast carcinoma to human epidermal growth factor receptor 2-targeted therapy. J Clin Oncol 32:e88–e91CrossRefPubMed
37.
Lee JW, Soung YH, Seo SH, Kim SY, Park CH, Wang YP et al (2006) Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast carcinomas. Clin Cancer Res 12:57–61CrossRefPubMed
38.
Kancha RK, von Bubnoff N, Bartosch N, Peschel C, Engh RA, Duyster J (2011) Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib. PLoS One 6:e26760PubMedCentralCrossRefPubMed
39.
Cappuzzo F, Bemis L, Varella-Garcia M (2006) HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer. N Engl J Med 354:2619–2621CrossRefPubMed
40.
Mazieres J, Peters S, Lepage B, Cortot AB, Barlesi F, Beau-Faller M et al (2013) Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol 31:1997–2003CrossRefPubMed
41.
Subramaniam D, He AR, Hwang J, Deeken J, Pishvaian M, Hartley ML, Marshall JL (2015) Irreversible multitargeted ErbB family inhibitors for therapy of lung and breast cancer. Curr Cancer Drug Targets 14:775–793CrossRefPubMed
42.
43.
Ross JS, Wang K, Sheehan CE, Boguniewicz AB, Otto G, Downing SR et al (2013) Relapsed classic E-cadherin (CDH1)-mutated invasive lobular breast cancer shows a high frequency of HER2 (ERBB2) gene mutations. Clin Cancer Res 19:2668–2676CrossRefPubMed
44.
Forbes SA, Beare D, Gunasekaran P, Leung K, Bindal N, Boutselakis H et al. (2015) COSMIC: exploring the world’s knowledge of somatic mutations in human cancer. Nucleic Acids Res 43(Database issue):D805–D811PubMedCentralCrossRefPubMed
45.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2:401–404CrossRefPubMed
46.
Jankowitz RC, Abraham J, Tan AR, Limentani SA, Tierno MB, Adamson LM et al (2013) Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2-positive breast cancer: an NSABP Foundation Research Program phase I study. Cancer Chemother Pharmacol 72:1205–1212CrossRefPubMed
47.
Martin M, Bonneterre J, Geyer CE Jr, Ito Y, Ro J, Lang I et al (2013) A phase two randomised trial of neratinib monotherapy versus lapatinib plus capecitabine combination therapy in patients with HER2+ advanced breast cancer. Eur J Cancer 49:3763–3772CrossRefPubMed
48.
Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC et al (2013) Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 3:224–237PubMedCentralCrossRefPubMed
49.
Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10:116–129CrossRefPubMed
50.
Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA et al (2010) FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res 70:2085–2094PubMedCentralCrossRefPubMed
51.
Choi Y, Lee HJ, Jang MH, Gwak JM, Lee KS, Kim EJ et al (2013) Epithelial-mesenchymal transition increases during the progression of in situ to invasive basal-like breast cancer. Hum Pathol 44:2581–2589CrossRefPubMed
52.
Ho HK, Yeo AH, Kang TS, Chua BT (2014) Current strategies for inhibiting FGFR activities in clinical applications: opportunities, challenges and toxicological considerations. Drug Discov Today 19:51–62CrossRefPubMed
53.
Brady N, Chuntova P, Bade LK, Schwertfeger KL (2013) The FGF/FGFR axis as a therapeutic target in breast cancer. Expert Rev Endocrinol Metab 8:391–402PubMedCentralCrossRefPubMed
54.
Dieci MV, Arnedos M, Andre F, Soria JC (2013) Fibroblast growth factor receptor inhibitors as a cancer treatment: from a biologic rationale to medical perspectives. Cancer Discov 3:264–279CrossRefPubMed
55.
Brooks AN, Kilgour E, Smith PD (2012) Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer. Clin Cancer Res 18:1855–1862CrossRefPubMed
56.
Ali SM, Alpaugh RK, Buell JK, Stephens PJ, Yu JQ, Wu H et al (2014) Antitumor response of an ERBB2 amplified inflammatory breast carcinoma with EGFR mutation to the EGFR-TKI erlotinib. Clin Breast Cancer 14:e14–e16CrossRefPubMed
57.
58.
Vasan N, Yelensky R, Wang K, Moulder S, Dzimitrowicz H, Avritscher R et al (2014) A targeted next-generation sequencing assay detects a high frequency of therapeutically targetable alterations in primary and metastatic breast cancers: implications for clinical practice. Oncologist 19:453–458PubMedCentralCrossRefPubMed
59.
Ali SM, Ou SH, He J, Peled N, Chmielecki J, Pinder MC et al. (2014) Identifying ALK rearrangements that are not detected by FISH with targeted next-generation sequencing of lung carcinoma. J Clin Oncol 32:5s (suppl; abstr 8049)CrossRef
60.
Krishnamurthy S, Woodward W, Yang W, Reuben JM, Tepperberg J, Ogura D, Niwa S, Huo L, Gong Y, El-Zein R, Gonzalez-Angulo AM, Chavez-Macgregor M, Alvarez R, Lucci A, Valero V, Ueno NT (2013) Status of the anaplastic lymphoma kinase (ALK) gene in inflammatory breast carcinoma. Springerplus 2:409PubMedCentralCrossRefPubMed
Metadata
Title
Comprehensive genomic profiling of inflammatory breast cancer cases reveals a high frequency of clinically relevant genomic alterations
Authors
Jeffrey S. Ross
Siraj M. Ali
Kai Wang
Depinder Khaira
Norma A. Palma
Juliann Chmielecki
Gary A. Palmer
Deborah Morosini
Julia A. Elvin
Sandra V. Fernandez
Vincent A. Miller
Philip J. Stephens
Massimo Cristofanilli
Publication date
01-11-2015
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2015
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-015-3592-z

Other articles of this Issue 1/2015

Breast Cancer Research and Treatment 1/2015 Go to the issue

Clinical trial

Molecular subtyping improves diagnostic stratification of patients with primary breast cancer into prognostically defined risk groups

Preclinical Study

Development of triple-negative breast cancer radiosensitive gene signature and validation based on transcriptome analysis

Epidemiology

Does the age of breast cancer diagnosis in first-degree relatives impact on the risk of breast cancer in BRCA1 and BRCA2 mutation carriers?

Clinical trial

Complete blood counts, liver function tests, and chest x-rays as routine screening in early-stage breast cancer: value added or just cost?

Preclinical study

Improving breast cancer services for African-American women living in St. Louis

Editorial

DCIS does not need treatment… really?
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits