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ABOUT the TEST: PATIENT RESULTS TUMOR TYPE: BREAST CARCINOMA (NOS) Genomic Alterations Identified† Additional Findings† THER

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ABOUT the TEST: PATIENT RESULTS TUMOR TYPE: BREAST CARCINOMA (NOS) Genomic Alterations Identified† Additional Findings† THER Patient Name Report Date Tumor Type Breast carcinoma (NOS) Date of Birth Medical Facility Sex Female Ordering Physician Specimen Received FMI Case # Additional Recipient Specimen Site Lung Medical Record # Medical Facility ID # Date of Collection Specimen ID Pathologist Specimen Type ABOUT THE TEST: FoundationOne™ is a next-generation sequencing (NGS) based assay that identifies genomic alterations within hundreds of cancer-related genes. PATIENT RESULTS TUMOR TYPE: BREAST CARCINOMA (NOS) 20 genomic findings Genomic Alterations Identified† ERBB2 R678Q 13 therapies associated with potential clinical benefit ⧺ ⧺ PIK3CA H1047R – subclonal , N1044K, R88Q – subclonal , V344M – subclonal⧺ 0 therapies associated with lack of response TSC1 L203fs*7 ARID1A splice site 2420-2A>G 34 clinical trials ASXL1 G645fs*58 LZTR1 Q10fs*24 MLH1 S446fs*32, V267fs*1 MLL2 A1105fs*14 MSH2 A230fs*16 NOTCH3 A2233fs*9 PPP2R1A R183W – subclonal⧺ RAD50 N934fs*6 SETD2 R1492* SMARCA4 R1157W Additional Findings† Microsatellite status MSI-High Tumor Mutation Burden TMB-High; 26 Muts/Mb † For a complete list of the genes assayed and performance specifications, please refer to the Appendix ⧺ See Appendix for details THERAPEUTIC IMPLICATIONS Genomic Findings FDA-Approved Therapies FDA-Approved Therapies Potential Clinical Trials Detected (in patient’s tumor type) (in another tumor type) ERBB2 Ado-trastuzumab emtansine Afatinib Yes, see clinical trials R678Q Lapatinib section Neratinib Pertuzumab Trastuzumab For more comprehensiveSAMPLE information please log on to the Interactive Cancer Explorer™ To set up your Interactive Cancer Explorer account, contact your sales representative or call 1-888-988-3639. Electronically Signed by Sample Preparation: 7010 Kit Creek Road, Morrisville, NC 27560 / CLIA:34D2044309 Foundation Medicine, Inc. / 1-888-988-3639 Sample Analysis: 150 Second St., 1st Floor, Cambridge, MA 02141 / CLIA:22D2027531 page 1 of 56 Patient Name Report Date Tumor Type Breast carcinoma (NOS) Genomic Findings FDA-Approved Therapies FDA-Approved Therapies Potential Clinical Trials Detected (in patient’s tumor type) (in another tumor type) Microsatellite status Pembrolizumab Nivolumab Yes, see clinical trials MSI-High section PIK3CA Everolimus Temsirolimus Yes, see clinical trials H1047R - subclonal, N1044K, section R88Q - subclonal, V344M - subclonal TSC1 Everolimus Temsirolimus Yes, see clinical trials L203fs*7 section Tumor Mutation Burden None Atezolizumab Yes, see clinical trials TMB-High; 26 Muts/Mb Avelumab section Durvalumab Nivolumab Pembrolizumab ARID1A None None None splice site 2420-2A>G ASXL1 None None None G645fs*58 LZTR1 None None None Q10fs*24 MLH1 None None None S446fs*32, V267fs*1 MLL2 None None None A1105fs*14 MSH2 None None None A230fs*16 NOTCH3 None None None A2233fs*9 PPP2R1A None None None R183W - subclonal RAD50 None None None N934fs*6 SETD2 None None None R1492* SMARCA4 None None None R1157W For more comprehensiveSAMPLE information please log on to the Interactive Cancer Explorer™ To set up your Interactive Cancer Explorer account, contact your sales representative or call 1-888-988-3639. Electronically Signed by Sample Preparation: 7010 Kit Creek Road, Morrisville, NC 27560 / CLIA:34D2044309 Foundation Medicine, Inc. / 1-888-988-3639 Sample Analysis: 150 Second St., 1st Floor, Cambridge, MA 02141 / CLIA:22D2027531 page 2 of 56 Patient Name Report Date Tumor Type Breast carcinoma (NOS) GENOMIC ALTERATIONS GENE INTERPRETATION ALTERATION ERBB2 Gene and Alteration: ERBB2 (also known as HER2) encodes the receptor tyrosine kinase HER2, which R678Q is in the same family as EGFR. Amplification or overexpression of ERBB2 can lead to excessive proliferation and tumor formation1. The functional effect of ERBB2 R678Q is not clear. Although R678Q had no effect on markers of HER2 activation and was not transforming2,3, this mutation has been shown to result in upregulation of downstream MAPK signaling3. Frequency and Prognosis: ERBB2 mutations have been reported in 1-3% of breast invasive carcinoma cases4,5. HER2 is predicted to be overexpressed (as assessed by immunohistochemistry, FISH, or CNV analysis) in 12-25% of breast cancers6,7,8. The incidence of ERBB2 alterations has been found to be significantly enriched in CDH1-mutated invasive lobular breast cancers9. Phosphorylated HER2 (pHER2) was expressed in 62.5% (55/88) of HER2-positive breast cancers, and pHER2 expression was associated with development of trastuzumab resistance10. Potential Treatment Strategies: On the basis of extensive clinical evidence, ERBB2 amplification or activating mutation may predict sensitivity to therapies targeting HER2, including antibodies such as trastuzumab11,12,13,14,15,16, pertuzumab in combination with trastuzumab13,17,18, and ado-trastuzumab emtansine (T-DM1)19, as well as dual EGFR/HER2 kinase inhibitors such as lapatinib20,21,22,23, afatinib16,24,25,26,27, neratinib28,29, and dacomitinib30. In patients with breast cancer, concurrent PIK3CA or PTEN alterations that activate the PI3K pathway have been associated with resistance to therapies that target HER2, including trastuzumab and lapatinib31,32,33,34,35. However, other studies have reported conflicting results, with one study suggesting that neither PIK3CA nor PTEN alterations is associated with trastuzumab resistance36 and another study reporting a correlation between PIK3CA mutation and increased clinical response to the combination of letrozole and lapatinib37. Clinical trials of agents aimed at preventing or overcoming resistance to anti-HER2 therapies are under way, including agents targeting the PI3K-AKT pathway or HSP908,38. However, as the alteration reported here has not been fully characterized, it is not known if these therapeutic approaches would be relevant. Microsatellite Gene and Alteration: Microsatellite instability (MSI) is a condition of genetic hypermutability that status generates excessive amounts of short insertion/deletion mutations in the genome; it generally occurs MSI-High at microsatellite DNA sequences and is caused by a deficiency in DNA mismatch repair (MMR) in the tumor39. Defective MMR and consequent MSI occur as a result of genetic or epigenetic inactivation of one of the MMR pathway proteins, primarily MLH1, MSH2, MSH6, or PMS239,40,41. The tumor seen here has a high level of MSI, equivalent to the clinical definition of an MSI-high (MSI-H) tumor: one with mutations in >30% of microsatellite markers42,43,44. MSI-H status indicates high-level deficiency in MMR and typically correlates with loss of expression of at least one, and often two, MMR family proteins39,41,43,44. While approximately 80% of MSI-H tumors arise due to somatic inactivation of an MMR pathway protein, about 20% arise due to germline mutations in one of the MMR genes39, which are associated with a condition known as Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer or HNPCC)45. Lynch syndrome leads to an increased risk of colorectal, endometrial, gastric, and other cancers45,46,47 and has an estimated prevalence in the general population ranging from 1:600 to 1:200048,49,50. Therefore, in the appropriate clinical context, germline testing of MLH1, MSH2, MSH6, and PMS2 is recommended. For more comprehensiveSAMPLE information please log on to the Interactive Cancer Explorer™ To set up your Interactive Cancer Explorer account, contact your sales representative or call 1-888-988-3639. Electronically Signed by Sample Preparation: 7010 Kit Creek Road, Morrisville, NC 27560 / CLIA:34D2044309 Foundation Medicine, Inc. / 1-888-988-3639 Sample Analysis: 150 Second St., 1st Floor, Cambridge, MA 02141 / CLIA:22D2027531 page 3 of 56 Patient Name Report Date Tumor Type Breast carcinoma (NOS) GENE INTERPRETATION ALTERATION Frequency and Prognosis: The frequency of MSI in breast cancer varies widely due to difference in patient characteristics and sample sizes in different studies. In a few studies of Lynch syndrome- related breast cancer with small sample sizes (n<10), MSI was observed in 60%-85% of patients51,52,53,54,55. However, no MSI was observed in a few larger scale analysis of breast cancer samples56,57. Moreover, MSI was reported in 51% of patients with MMR-deficient breast cancer58. Furthermore, a prospective study observed increased MSI following chemotherapy treatment, and MSI was associated with incidence of secondary tumors59. Potential Treatment Strategies: On the basis of emerging clinical evidence, MSI and associated increased mutational burden60,61 may predict sensitivity to anti-PD-1 immune checkpoint inhibitors61,62, including the approved therapies nivolumab (Overman et al., 2016; ASCO Abstract 3501)63 and pembrolizumab64,65. Pembrolizumab therapy resulted in a significantly higher objective response rate in MSI-H colorectal cancer (CRC) compared with MSS CRC (40% vs. 0%)64. Similarly, a clinical study of nivolumab, alone or in combination with ipilimumab, in patients with CRC reported a significantly higher response rate in patients with tumors with high MSI than those without (Overman et al., 2016; ASCO Abstract 3501). An earlier case study reported that nivolumab therapy resulted in a complete response in a patient with MSI-H CRC63. In the Phase 1b KEYNOTE-012 trial, of 4 patients with MSI-H gastric cancer, 2 patients reported partial responses, and 2 experienced progressive disease in response to pembrolizumab66. The efficacy of immunotherapies in other MSI-H solid tumors is currently under investigation in clinical trials. PIK3CA Gene and Alteration: PIK3CA
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