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PG 3.02 Heterogeneity of triple negative subtype: gene expression profile and phenotype
S6
Speakers’ Abstracts / The Breast 24S1 (2015) S1–S25
or dual HER2 blockade with trastuzumab/lapatinib, in combination with chemotherapy. Of note, once intrinsic subtype is taken into account, the biological impact and the prognostic ability of clinical HER2 disappears [8]. For example, patients with Luminal A/HER2+ early breast cancer have similar survival outcomes as patients with Luminal A/HER2-negative tumours in the absence of adjuvant trastuzumab. Finally, within triple-negative breast cancer (TNBC), the Basallike disease predominates (70–80%), but again, all the intrinsic subtypes can also be identified. Interestingly, luminal/TNBC or HER2-enriched/TNBC show similar gene expression patterns as Luminal/HR+ or HER2-enriched/HER2+, except for ERBB2 and the rest of genes in the 17q amplicon which are not found overexpressed in HER2-enriched/TNBC [9]. Importantly, the distinction between Basal-like versus non-Basal-like within TNBC seems to be important for predicting survival following (neo)adjvuvant multi-agent chemotherapy [10], bevacizumab benefit in the neoadjuvant setting (CALGB40603) [11], and docetaxel vs. carboplatin benefit in first-line metastatic disease (TNT study) [12]. Overall, this data suggests that intrinsic molecular profiling provides clinically relevant information beyond current pathology-based classifications. Reference(s) [1] Perou CM, Sorlie T, Eisen MB, et al: Molecular portraits of human breast tumours. Nature 406: 747–752, 2000. [2] Prat A, Parker J, Karginova O, et al: Phenotypic and Molecular Characterization of the Claudin-low Intrinsic Subtype of Breast Cancer. Breast Cancer Research 12: R68, 2010. [3] Prat A, Perou CM: Deconstructing the molecular portraits of breast cancer. Molecular Oncology 5: 5–23, 2011. [4] Goldhirsch A, Winer EP, Coates AS, et al: Personalizing the treatment of women with early breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Annals of Oncology 24: 2206–2223, 2013. [5] Prat A, Cheang MCU, Mart´ın M, et al: Prognostic Significance of Progesterone Receptor-Positive Tumor Cells Within Immunohistochemically Defined Luminal A Breast Cancer. Journal of Clinical Oncology 31: 203–209, 2013. [6] Usary J, Zhao W, Darr D, et al: Predicting Drug Responsiveness in Human Cancers Using Genetically Engineered Mice. Clinical Cancer Research 19: 4889–4899, 2013. [7] Mart´ın M, Gonzalez-Rivera ´ M, Morales S, et al: Prospective study of the impact of the Prosigna™ assay on adjuvant clinical decisionmaking in an unselected population of women with estrogen receptor-positive, HER2-negative, node-negative breast cancer: A GEICAM study. San Antonio Breast Cancer Symposium 2014 abstract #P6-08-10. [8] Prat A, Carey LA, Adamo B, et al: Molecular Features and Survival Outcomes of the Intrinsic Subtypes Within HER2Positive Breast Cancer. JNCI 106, 2014. [9] Prat A, Adamo B, Cheang MCU, et al: Molecular Characterization of Basal-Like and Non-Basal-Like Triple-Negative Breast Cancer. The Oncologist 18: 123–133, 2013. [10] Prat A, Lluch A, Albanell J, et al: Predicting response and survival in chemotherapy-treated triple-negative breast cancer. Br J Cancer 111: 1532–1541, 2014. [11] Sikov W, Barry W, Hoadley K, et al: Impact of intrinsic subtype by PAM50 and other gene signatures on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NACT) +/− carboplatin (Cb) or bevacizumab (Bev): CALGB 40603/150709 (Alliance). San Antonio Breast Cancer Symposium 2014 abstract #S4-06. [12] Tutt A, Ellis P, Kilburn L, et al: TNT: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). San Antonio Breast Cancer Symposium 2014 abstract #S3-01.
Disclosure of Interest: Consultant/advisory Nanostring Technology.
board
member:
PG 3.02 Heterogeneity of triple negative subtype: gene expression profile and phenotype B.D. Lehmann *. Biochemistry, Vanderbilt University, Nashville, United States of America Triple negative breast cancer (TNBC) represents 10–20% of all breast cancers that lack estrogen receptor (ER) and progesterone receptor expression as well as amplification of the human epidermal growth factor receptor 2 (HER2). TNBCs more frequently affect younger and African-American women and are more aggressive with an increased likelihood of distant recurrence and death compared with women with other types of breast cancer. While, targeted therapies exist for ER-positive and HER2-amplified breast cancers, treatment options for TNBC are limited by a lack of molecular understanding of this disease. We recently have classified TNBC into six molecular subtypes using molecular profiling and identified representative cell lines for each TNBC subgroup. We identified two basal-like subgroups enriched in basal cytokeratins. The first, basallike 1 (BL1), is characterized by cell cycle and DNA damage response genes and cell lines that preferentially responded to cisplatin. The second, basal-like 2 (BL2), is enriched in growth factor receptors and expresses myoepthithelial markers. Two mesenchymal-like subgroups (M and MSL) were enriched in differentiation, epithelial– mesenchymal transition and growth factor pathways, in which cell lines were more sensitive to PI3K inhibitors and dasatinib. We described an immunomodulatory (IM) subgroup, defined by immune cell markers and signaling genes. Finally, we identified a luminal androgen receptor (LAR) subgroup, driven by androgen receptor (AR) signaling and PIK3CA mutations, rendering cell lines sensitive to AR antagonists and PI3K inhibitors. PIK3CA kinase mutations were highly clonal, more frequent in AR+ vs. AR− TNBC clinical samples and often associated with concurrent amplification of the PIK3CA locus. PI3K/mTOR inhibitors had an additive growth inhibitory effect when combined with genetic or pharmacological AR targeting in AR+ TNBC cells. Comparison to intrinsic molecular subtyping showed majority of BL1, BL2, IM and M to be basal-like, MSL to be enriched in normal-like subtype and LAR to be mostly consist of the luminal A subtype. Through a collaborative retrospective analysis of TNBC patients treated with sequential anthracycline + cyclophosphamide followed by taxane chemotherapy, we demonstrate TNBC subtyping of pretreatment biopsies to be an independent predictor of pathological complete response (pCR). These data show patients with tumors displaying the BL1 subtype achieve the highest pCR, while BL2 and LAR had very little response. Together with the statistically significant increased age upon diagnosis for LAR and BL2 patients, suggest that these older patients could potentially be spared the toxic side effects of anthracycline and cyclophosphamide chemotherapy. Altogether, these data provide significant insight into future clinical trial design and biomarker selection for alignment of TNBC patients to appropriate targeted therapies and chemotherapy. Disclosure of Interest: Licensing of royalties for development of TNBctype from Insight Genetics. PG 3.03 Molecular segmentation in luminal breast cancer: how to select the driver pathways S. Loi *. Division of Cancer Medicine, Division of Cancer Research, Peter MacCallum Cancer Center, Victoria Australia, Australia Next generation sequencing (NGS) has allowed us to investigate the genomic landscape of breast cancer with regards to copy number alterations and recurrent somatic mutations. To date, studies involving nearly 1000 primary breast cancer exomes/genomes have been published. These studies have confirmed the presence of
Speakers’ Abstracts / The Breast 24S1 (2015) S1–S25
or dual HER2 blockade with trastuzumab/lapatinib, in combination with chemotherapy. Of note, once intrinsic subtype is taken into account, the biological impact and the prognostic ability of clinical HER2 disappears [8]. For example, patients with Luminal A/HER2+ early breast cancer have similar survival outcomes as patients with Luminal A/HER2-negative tumours in the absence of adjuvant trastuzumab. Finally, within triple-negative breast cancer (TNBC), the Basallike disease predominates (70–80%), but again, all the intrinsic subtypes can also be identified. Interestingly, luminal/TNBC or HER2-enriched/TNBC show similar gene expression patterns as Luminal/HR+ or HER2-enriched/HER2+, except for ERBB2 and the rest of genes in the 17q amplicon which are not found overexpressed in HER2-enriched/TNBC [9]. Importantly, the distinction between Basal-like versus non-Basal-like within TNBC seems to be important for predicting survival following (neo)adjvuvant multi-agent chemotherapy [10], bevacizumab benefit in the neoadjuvant setting (CALGB40603) [11], and docetaxel vs. carboplatin benefit in first-line metastatic disease (TNT study) [12]. Overall, this data suggests that intrinsic molecular profiling provides clinically relevant information beyond current pathology-based classifications. Reference(s) [1] Perou CM, Sorlie T, Eisen MB, et al: Molecular portraits of human breast tumours. Nature 406: 747–752, 2000. [2] Prat A, Parker J, Karginova O, et al: Phenotypic and Molecular Characterization of the Claudin-low Intrinsic Subtype of Breast Cancer. Breast Cancer Research 12: R68, 2010. [3] Prat A, Perou CM: Deconstructing the molecular portraits of breast cancer. Molecular Oncology 5: 5–23, 2011. [4] Goldhirsch A, Winer EP, Coates AS, et al: Personalizing the treatment of women with early breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Annals of Oncology 24: 2206–2223, 2013. [5] Prat A, Cheang MCU, Mart´ın M, et al: Prognostic Significance of Progesterone Receptor-Positive Tumor Cells Within Immunohistochemically Defined Luminal A Breast Cancer. Journal of Clinical Oncology 31: 203–209, 2013. [6] Usary J, Zhao W, Darr D, et al: Predicting Drug Responsiveness in Human Cancers Using Genetically Engineered Mice. Clinical Cancer Research 19: 4889–4899, 2013. [7] Mart´ın M, Gonzalez-Rivera ´ M, Morales S, et al: Prospective study of the impact of the Prosigna™ assay on adjuvant clinical decisionmaking in an unselected population of women with estrogen receptor-positive, HER2-negative, node-negative breast cancer: A GEICAM study. San Antonio Breast Cancer Symposium 2014 abstract #P6-08-10. [8] Prat A, Carey LA, Adamo B, et al: Molecular Features and Survival Outcomes of the Intrinsic Subtypes Within HER2Positive Breast Cancer. JNCI 106, 2014. [9] Prat A, Adamo B, Cheang MCU, et al: Molecular Characterization of Basal-Like and Non-Basal-Like Triple-Negative Breast Cancer. The Oncologist 18: 123–133, 2013. [10] Prat A, Lluch A, Albanell J, et al: Predicting response and survival in chemotherapy-treated triple-negative breast cancer. Br J Cancer 111: 1532–1541, 2014. [11] Sikov W, Barry W, Hoadley K, et al: Impact of intrinsic subtype by PAM50 and other gene signatures on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NACT) +/− carboplatin (Cb) or bevacizumab (Bev): CALGB 40603/150709 (Alliance). San Antonio Breast Cancer Symposium 2014 abstract #S4-06. [12] Tutt A, Ellis P, Kilburn L, et al: TNT: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). San Antonio Breast Cancer Symposium 2014 abstract #S3-01.
Disclosure of Interest: Consultant/advisory Nanostring Technology.
board
member:
PG 3.02 Heterogeneity of triple negative subtype: gene expression profile and phenotype B.D. Lehmann *. Biochemistry, Vanderbilt University, Nashville, United States of America Triple negative breast cancer (TNBC) represents 10–20% of all breast cancers that lack estrogen receptor (ER) and progesterone receptor expression as well as amplification of the human epidermal growth factor receptor 2 (HER2). TNBCs more frequently affect younger and African-American women and are more aggressive with an increased likelihood of distant recurrence and death compared with women with other types of breast cancer. While, targeted therapies exist for ER-positive and HER2-amplified breast cancers, treatment options for TNBC are limited by a lack of molecular understanding of this disease. We recently have classified TNBC into six molecular subtypes using molecular profiling and identified representative cell lines for each TNBC subgroup. We identified two basal-like subgroups enriched in basal cytokeratins. The first, basallike 1 (BL1), is characterized by cell cycle and DNA damage response genes and cell lines that preferentially responded to cisplatin. The second, basal-like 2 (BL2), is enriched in growth factor receptors and expresses myoepthithelial markers. Two mesenchymal-like subgroups (M and MSL) were enriched in differentiation, epithelial– mesenchymal transition and growth factor pathways, in which cell lines were more sensitive to PI3K inhibitors and dasatinib. We described an immunomodulatory (IM) subgroup, defined by immune cell markers and signaling genes. Finally, we identified a luminal androgen receptor (LAR) subgroup, driven by androgen receptor (AR) signaling and PIK3CA mutations, rendering cell lines sensitive to AR antagonists and PI3K inhibitors. PIK3CA kinase mutations were highly clonal, more frequent in AR+ vs. AR− TNBC clinical samples and often associated with concurrent amplification of the PIK3CA locus. PI3K/mTOR inhibitors had an additive growth inhibitory effect when combined with genetic or pharmacological AR targeting in AR+ TNBC cells. Comparison to intrinsic molecular subtyping showed majority of BL1, BL2, IM and M to be basal-like, MSL to be enriched in normal-like subtype and LAR to be mostly consist of the luminal A subtype. Through a collaborative retrospective analysis of TNBC patients treated with sequential anthracycline + cyclophosphamide followed by taxane chemotherapy, we demonstrate TNBC subtyping of pretreatment biopsies to be an independent predictor of pathological complete response (pCR). These data show patients with tumors displaying the BL1 subtype achieve the highest pCR, while BL2 and LAR had very little response. Together with the statistically significant increased age upon diagnosis for LAR and BL2 patients, suggest that these older patients could potentially be spared the toxic side effects of anthracycline and cyclophosphamide chemotherapy. Altogether, these data provide significant insight into future clinical trial design and biomarker selection for alignment of TNBC patients to appropriate targeted therapies and chemotherapy. Disclosure of Interest: Licensing of royalties for development of TNBctype from Insight Genetics. PG 3.03 Molecular segmentation in luminal breast cancer: how to select the driver pathways S. Loi *. Division of Cancer Medicine, Division of Cancer Research, Peter MacCallum Cancer Center, Victoria Australia, Australia Next generation sequencing (NGS) has allowed us to investigate the genomic landscape of breast cancer with regards to copy number alterations and recurrent somatic mutations. To date, studies involving nearly 1000 primary breast cancer exomes/genomes have been published. These studies have confirmed the presence of