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Published in: Annals of Surgical Oncology 10/2014

01-10-2014 | Breast Oncology

Initial Experience with Genomic Profiling of Heavily Pretreated Breast Cancers

Authors: Edgar D. Staren, MD, PhD, Donald Braun, PhD, Bradford Tan, MD, Digant Gupta, MD, MPH, Seungchan Kim, PhD, Kim Kramer, SSGB, Maurie Markman, MD

Published in: Annals of Surgical Oncology | Issue 10/2014

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Abstract

Background

Rapidly evolving advances in the understanding of theorized unique driver mutations within individual patient’s cancers, as well as dramatic reduction in the cost of genomic profiling, have stimulated major interest in the role of such testing in routine clinical practice. The aim of this study was to report our initial experience with genomic testing in heavily pretreated breast cancer patients.

Methods

Patients with primary or recurrent breast cancer managed at any of our five hospitals and whose malignancy had failed to respond to therapy or had progressed on all recognized standard-of-care options were offered the opportunity to have their cancer undergo next-generation sequencing genomic profiling.

Results

Of a total of 101 patients, 98 (97 %) had at least one specific genomic alteration identified. A total of 465 different somatic genetic abnormalities were revealed in this group of patients. Although 52 % of patients were found to have an abnormality for which an U.S. Food and Drug Administration (FDA)-approved drug was available, 69 % of patients had an FDA-approved agent for an indication other than breast cancer. The most common genomic alterations of potential clinical consequence were PIK3 (25 %), FGFR1 (16 %), AKT (11 %), PTEN (10 %), ERBB2 (8 %), JAK2 (6 %), and RAF1 (5 %).

Conclusions

Almost all advanced breast cancers possess at least one well-characterized genomic alteration that might be actionable at the clinical level. Further, in most cases, a plausible argument can be advanced for the potential biological and clinical relevance of an FDA-approved antineoplastic agent not currently indicated in the treatment of breast cancer.
Literature
1.
2.
go back to reference Sabatier R, Goncalves A, Bertucci F. Personalized medicine: present and future of breast cancer management. Crit Rev Oncol Hematol. 2014;pii:S1040-8428(14)00051-1. Sabatier R, Goncalves A, Bertucci F. Personalized medicine: present and future of breast cancer management. Crit Rev Oncol Hematol. 2014;pii:S1040-8428(14)00051-1.
3.
go back to reference Mitri Z, Constantine T, O’Regan R. The HER2 receptor in breast cancer: pathophysiology, clinical use, and new advances in therapy. Chemother Res Pract. 2012;2012:743193.PubMedPubMedCentral Mitri Z, Constantine T, O’Regan R. The HER2 receptor in breast cancer: pathophysiology, clinical use, and new advances in therapy. Chemother Res Pract. 2012;2012:743193.PubMedPubMedCentral
4.
go back to reference Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295:2492–502.PubMedCrossRef Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295:2492–502.PubMedCrossRef
5.
go back to reference Eroles P, Bosch A, Perez-Fidalgo JA, Lluch A. Molecular biology in breast cancer: intrinsic subtypes and signaling pathways. Cancer Treat Rev. 2012;38:698–707.PubMedCrossRef Eroles P, Bosch A, Perez-Fidalgo JA, Lluch A. Molecular biology in breast cancer: intrinsic subtypes and signaling pathways. Cancer Treat Rev. 2012;38:698–707.PubMedCrossRef
6.
go back to reference Giordano A, Tagliabue E, Pupa SM. Promise and failure of targeted therapy in breast cancer. Front Biosci (Schol Ed). 2012;4:356–74.PubMedCrossRef Giordano A, Tagliabue E, Pupa SM. Promise and failure of targeted therapy in breast cancer. Front Biosci (Schol Ed). 2012;4:356–74.PubMedCrossRef
7.
go back to reference Curtis C, Shah SP, Chin SF, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486(7403):346–52.PubMedPubMedCentral Curtis C, Shah SP, Chin SF, et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486(7403):346–52.PubMedPubMedCentral
8.
go back to reference Ma CX, Ellis MJ. The Cancer Genome Atlas: clinical applications for breast cancer. Oncology (Williston Park). 2013;27:1263–9. Ma CX, Ellis MJ. The Cancer Genome Atlas: clinical applications for breast cancer. Oncology (Williston Park). 2013;27:1263–9.
9.
go back to reference Cizkova M, Dujaric ME, Lehmann-Che J, et al. Outcome impact of PIK3CA mutations in HER2-positive breast cancer patients treated with trastuzumab. Br J Cancer. 2013;108:1807–9.PubMedCrossRefPubMedCentral Cizkova M, Dujaric ME, Lehmann-Che J, et al. Outcome impact of PIK3CA mutations in HER2-positive breast cancer patients treated with trastuzumab. Br J Cancer. 2013;108:1807–9.PubMedCrossRefPubMedCentral
10.
go back to reference Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395–402.PubMedCrossRef Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395–402.PubMedCrossRef
11.
go back to reference Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6:117–27.PubMedCrossRef Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6:117–27.PubMedCrossRef
12.
go back to reference Serra V, Markman B, Scaltriti M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008;68:8022–30.PubMedCrossRef Serra V, Markman B, Scaltriti M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008;68:8022–30.PubMedCrossRef
13.
go back to reference Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817–26.PubMedCrossRef Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817–26.PubMedCrossRef
14.
16.
go back to reference Balko JM, Giltnane JM, Wang K, et al. Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov. 2014;4:232–45.PubMedCrossRefPubMedCentral Balko JM, Giltnane JM, Wang K, et al. Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov. 2014;4:232–45.PubMedCrossRefPubMedCentral
17.
go back to reference Jeselsohn R, Yelensky R, Buchwalter G, et al. Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res. 2014;20:1757–67.PubMedCrossRef Jeselsohn R, Yelensky R, Buchwalter G, et al. Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res. 2014;20:1757–67.PubMedCrossRef
18.
go back to reference Saal LH, Holm K, Maurer M, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005;65:2554–9.PubMedCrossRef Saal LH, Holm K, Maurer M, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005;65:2554–9.PubMedCrossRef
19.
go back to reference Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008;68:6084–91.PubMedCrossRefPubMedCentral Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008;68:6084–91.PubMedCrossRefPubMedCentral
20.
go back to reference Quintas-Cardama A, Verstovsek S. Molecular pathways: Jak/STAT pathway: mutations, inhibitors, and resistance. Clin Cancer Res. 2013;19:1933–40.PubMedCrossRef Quintas-Cardama A, Verstovsek S. Molecular pathways: Jak/STAT pathway: mutations, inhibitors, and resistance. Clin Cancer Res. 2013;19:1933–40.PubMedCrossRef
21.
go back to reference Zhao W, Du Y, Ho WT, Fu X, Zhao ZJ. JAK2V617F and p53 mutations coexist in erythroleukemia and megakaryoblastic leukemic cell lines. Exp Hematol Oncol. 2012;1:15.PubMedCrossRefPubMedCentral Zhao W, Du Y, Ho WT, Fu X, Zhao ZJ. JAK2V617F and p53 mutations coexist in erythroleukemia and megakaryoblastic leukemic cell lines. Exp Hematol Oncol. 2012;1:15.PubMedCrossRefPubMedCentral
22.
go back to reference Gonzalez-Angulo AM, Ferrer-Lozano J, Stemke-Hale K, et al. PI3K pathway mutations and PTEN levels in primary and metastatic breast cancer. Mol Cancer Ther. 2011;10:1093–101.PubMedCrossRefPubMedCentral Gonzalez-Angulo AM, Ferrer-Lozano J, Stemke-Hale K, et al. PI3K pathway mutations and PTEN levels in primary and metastatic breast cancer. Mol Cancer Ther. 2011;10:1093–101.PubMedCrossRefPubMedCentral
23.
24.
go back to reference Liedtke C, Broglio K, Moulder S, et al. Prognostic impact of discordance between triple-receptor measurements in primary and recurrent breast cancer. Ann Oncol. 2009;20:1953–8.PubMedCrossRefPubMedCentral Liedtke C, Broglio K, Moulder S, et al. Prognostic impact of discordance between triple-receptor measurements in primary and recurrent breast cancer. Ann Oncol. 2009;20:1953–8.PubMedCrossRefPubMedCentral
25.
go back to reference Von Hoff DD, Stephenson JJ Jr, Rosen P, et al. Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010;28:4877–83.CrossRef Von Hoff DD, Stephenson JJ Jr, Rosen P, et al. Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010;28:4877–83.CrossRef
Metadata
Title
Initial Experience with Genomic Profiling of Heavily Pretreated Breast Cancers
Authors
Edgar D. Staren, MD, PhD
Donald Braun, PhD
Bradford Tan, MD
Digant Gupta, MD, MPH
Seungchan Kim, PhD
Kim Kramer, SSGB
Maurie Markman, MD
Publication date
01-10-2014
Publisher
Springer US
Published in
Annals of Surgical Oncology / Issue 10/2014
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-014-3925-x

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