Medical Facility SAMPLE - foundationmedicine.it

Tumor Type Ovary endometrioid adenocarcinoma

Patient Name Report Date

Date of Birth 10 January 1964 Medical Facility Baylor Scott and White Cancer Center

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Electronically Signed by Jeffrey S. Ross, M.D. | Jeffrey S. Ross, M.D., Medical Director | CLIA Number: 22D2027531 | 11 August 2016

Foundation Medicine, Inc., 150 2nd Street, 1st Floor, Cambridge, MA 02141 | 1-888-988-3639 page 1 of 50

Sex Female Ordering Physician Specimen Received

FMI Case # Additional Recipient Specimen Site Ovary

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: OVARY ENDOMETRIOID ADENOCARCINOMA

22 genomic findings Genomic Alterations Identified†

PIK3CA R88Q 5 therapies associated with potential clinical benefit

0 therapies associated with lack of response

19 clinical trials

PTEN W111* ARID1A F2141fs*59 RNF43 G659fs*41

ASXL1 G645fs*58 CHEK2 Y329fs*20 CREBBP Q2248*

CTCF E363fs*30, T317fs*91 ESR1 S463P

GATA2 A75fs*5 HNF1A G292fs*25

MAP3K1 E265*, W751* MLL2 P2354fs*30 MLL3 K2797fs*26

PAX5 V26G PIK3R1 I405del QKI K134fs*14

SLIT2 Q100H

Additional Findings†

Microsatellite status MSI-High

Tumor Mutation Burden TMB-High; 33.54 Muts/Mb

THERAPEUTIC IMPLICATIONS

† For a complete list of the genes assayed and performance specifications, please refer to the Appendix SAMPLE





Patient Name

Report Date

Genomic Findings Detected

FDA-Approved Therapies (in patient’s tumor type)

FDA-Approved Therapies

(in another tumor type) Potential Clinical Trials


None Nivolumab Pembrolizumab

Yes, see clinical trials section

PIK3CA R88Q

None Everolimus Temsirolimus


PTEN W111*

None Everolimus Temsirolimus



None Atezolizumab Nivolumab Pembrolizumab


ARID1A F2141fs*59

None None Yes, see clinical trials section

RNF43 G659fs*41

None None Yes, see clinical trials section

ASXL1 G645fs*58

None None None

CHEK2 Y329fs*20

None None None

CREBBP Q2248*

None None None

CTCF E363fs*30, T317fs*91

None None None

ESR1 S463P

None None None

GATA2 A75fs*5

None None None

HNF1A G292fs*25

None None None

MAP3K1 E265*, W751*

None None None

MLL2 P2354fs*30

None None None

MLL3 K2797fs*26

None None None

PAX5 V26G

None None None

SAMPLE


Patient Name

Report Date




Genomic Findings Detected

FDA-Approved Therapies (in patient’s tumor type)

FDA-Approved Therapies

(in another tumor type) Potential Clinical Trials

PIK3R1 I405del

None None None

QKI K134fs*14

None None None

SLIT2 Q100H

None None None

Note: Genomic alterations detected may be associated with activity of certain FDA-approved drugs; however, the agents listed in this report may

have little or no evidence in the patient’s tumor type. Neither the therapeutic agents nor the trials identified are ranked in order of potential or

predicted efficacy for this patient, nor are they ranked in order of level of evidence for this patient’s tumor type.

SAMPLE


Patient Name

Report Date




GENOMIC ALTERATIONS

GENE ALTERATION


INTERPRETATION

Gene and Alteration: Microsatellite instability (MSI) is a condition of genetic hypermutability that generates excessive amounts of short insertion/deletion mutations in the genome; it generally occurs at microsatellite DNA sequences and is caused by a deficiency in DNA mismatch repair (MMR) in the tumor1. 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 PMS21,2,3. 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 markers4,5,6. 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 proteins1,3,5,6. 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 genes1, which are associated with a condition known as Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer or HNPCC)7. Lynch syndrome leads to an increased risk of colorectal, endometrial, gastric, and other cancers7,8,9 and has an estimated prevalence in the general population ranging from 1:600 to 1:200010,11,12. Therefore, in the appropriate clinical context, germline testing of MLH1, MSH2, MSH6, and PMS2 is recommended.

Frequency and Prognosis: MSI-H has been reported in 1.6-19.7% of ovarian cancer samples13,14, including 3.8% (1/26) ovarian endometrioid adenocarcinomas15, 10.0% (3/30) ovarian clear cell carcinoma (CCOC) (Strickland et al., 2016; ASCO Abstract 5514) and 84.6% (11/13) of ovarian cystadenocarcinomas16. MSI-H was also frequently observed in ovarian cystadenomas (60.0%; 6/10) and normal ovary tissue (78.6%; 11/14)16. No association of MSI-H with stage or survival was found13,17. However, increased PD-1 expression and tumor-infiltrating lymphocytes were reported in MSI-H CCOC (Strickland et al., 2016; ASCO Abstract 5514).

Potential Treatment Strategies: On the basis of emerging clinical evidence, MSI and associated increased mutational burden18,19 may predict sensitivity to anti-PD-1 immune checkpoint inhibitors19,20, including the approved therapies nivolumab (Overman et al., 2016; ASCO Abstract 3501)21 and pembrolizumab22,23. Pembrolizumab therapy resulted in a significantly higher objective response rate in MSI-H colorectal cancer (CRC) compared with MSS CRC (40% vs. 0%)22. 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 CRC21. 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 pembrolizumab24. The efficacy of immunotherapies in other MSI-H solid tumors is currently under investigation in clinical trials.

PIK3CA R88Q

Gene and Alteration: PIK3CA encodes p110-alpha, which is the catalytic subunit of phosphatidylinositol 3-kinase (PI3K). The PI3K pathway is involved in cell signaling that regulates a number of critical cellular functions, including cell growth, proliferation, differentiation, motility, and survival25,26. PIK3CA alterations that have been characterized as activating, such as observed here, are predicted to be oncogenic27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43. SAMPLE


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GENE ALTERATION

INTERPRETATION

Frequency and Prognosis: PIK3CA mutations have been reported in 10% of ovarian carcinomas analyzed in COSMIC, with a higher incidence of 34% in the included clear cell carcinomas (May 2016). The incidence of PIK3CA mutations is highly variable among different subtypes of ovarian cancer; PIK3CA mutations were detected in 12% of advanced epithelial ovarian carcinomas and specifically in 33% (32/97) of ovarian clear cell carcinomas and 3% of high-grade serous ovarian cancers in separate studies44,45,46. A study of ovarian clear cell carcinomas reported an association of coexistent alterations in ARID1A and PIK3CA with poor patient prognosis47. Overexpression of p110-alpha has been associated with a good prognosis in ovarian clear cell carcinoma, while PIK3CA amplification has been associated with shorter survival in patients with ovarian cancer48,49,50.

Potential Treatment Strategies: Clinical and preclinical data in various tumor types indicate that PIK3CA activating alterations may predict sensitivity to therapies targeting PI3K or AKT (Juric et al., 2014; ESMO Abstract 451PD, Banerji et al., 2015; ASCO Abstract 2500)51. On the basis of clinical benefit for patients with PIK3CA mutations and preclinical evidence, PIK3CA-mutated tumors may also respond to mTOR inhibitors, including everolimus and temsirolimus (Slamon et al., 2015; ASCO Abstract 512)52,53,54,55. In a Phase 1 trial of the dual PI3K/mTOR kinase inhibitor apitolisib, 79% (11/14) of patients with PIK3CA-mutated advanced solid tumors experienced disease control at the recommended Phase 2 dose (3/14 partial responses [PRs], 8/14 stable disease)56. The pan-PI3K inhibitor buparlisib has shown limited activity as monotherapy against PIK3CA-mutated tumors57,58. PI3K-alpha-selective inhibitors, such as alpelisib, may have a bigger therapeutic window than pan-PI3K inhibitors (Baselga et al., 2015; SABCS Abstract S6-01)51. Alpelisib achieved PRs for 11% of patients with PIK3CA-mutated advanced solid tumors (Juric et al., 2014; ESMO Abstract 451PD). A Phase 1 study of the pan-AKT inhibitor AZD5363 observed responses for 3/15 and 1/14 patients with PIK3CA-mutated breast cancer or other gynecological malignancies, respectively (Banerji et al., 2015; ASCO Abstract 2500). Activating mutations in PIK3CA may confer resistance to HER2-targeted therapies; combined inhibition of HER2 and the PI3K pathway may be required in tumors with ERBB2 amplification and PIK3CA mutation (Slamon et al., 2015; ASCO Abstract 512)59,60,61,62.

PTEN W111*

Gene and Alteration: PTEN encodes an inositol phosphatase that functions as a tumor suppressor by negatively regulating the PI3K-AKT-mTOR pathway; loss of PTEN can lead to uncontrolled cell growth and suppression of apoptosis63. PTEN alterations that disrupt the N-terminal PIP2 binding motif64, the phosphatase domain (amino acids 14-185)65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90, the C2 domain (amino acids 190-350)65,67,77,91,92,93,94,95,96,97 and/or C-terminal region98,99, such as observed here, are predicted to cause a loss of function. Mutations in PTEN underlie several inherited disorders collectively termed PTEN hamartoma tumor syndrome (PHTS), which includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and Proteus-like syndrome100,101. The mutation rate for PTEN in these disorders ranges from 20-85% of patients. The estimated incidence of Cowden syndrome is approximately 1:200,000, but it is widely believed that this may be an underestimate100,102. Given the association between PTEN and these inherited syndromes, in the appropriate clinical context germline testing for mutations affecting PTEN is recommended. SAMPLE


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GENE ALTERATION

INTERPRETATION

Frequency and Prognosis: Putative homozygous deletion of PTEN has been reported in 7% of cases in the Ovarian Serous Cystadenocarcinoma TCGA dataset103. Loss of heterozygosity (LOH) at the chromosomal region including PTEN has been reported in 31% (22/72) of epithelial ovarian tumors analyzed, with an incidence of 43% (13/30) in endometrioid tumors and 28% (7/25) in serous tumors and lower incidences in other histological subtypes104. Reduced PTEN expression has been reported in 55.3% (26/47) to 68.9% (104/151) of ovarian epithelial cancers105,106. In a study of endometriosis- associated ovarian cancers, loss of PTEN protein expression has been found in 37% (29/79) of cases107. Reduced PTEN expression has been suggested to be associated with poor prognosis in patients with ovarian cancer105,106,108.

Potential Treatment Strategies: PTEN loss or mutation leads to activation of the PI3K-AKT-mTOR pathway and may predict sensitivity to inhibitors of this pathway63,109,110. The mTOR inhibitors temsirolimus and everolimus are FDA approved to treat other indications and are being studied in clinical trials in multiple tumor types. Other mTOR inhibitors, as well as inhibitors of PI3K and AKT, are also under investigation in clinical trials, alone or in combination with other therapies. Preclinical studies suggest that PTEN-deficient cancers, in the absence of other oncogenic mutations, depend primarily on the beta isoform of PI3K (PI3K-beta)111,112,113; PI3K-beta-specific inhibitors are in clinical trials for PTEN- deficient tumors. In the context of concurrent PIK3CA mutation, PTEN loss may predict resistance to PI3K-alpha-specific inhibitors51,114. Limited preclinical data suggest that PTEN mutations may predict sensitivity to PARP inhibitors115, and a patient with a PTEN mutation but no BRCA1/2 alterations in their tumor has benefited from treatment with the PARP inhibitor olaparib (Dougherty et al., 2014; ASCO Abstract 5536)116, which is FDA approved for the treatment of ovarian cancer.


Gene and Alteration: Tumor mutation burden (TMB, also known as mutation load) is a measure of the number of somatic protein-coding base substitution and insertion/deletion mutations occurring in a tumor specimen. TMB is affected by a variety of causes, including exposure to mutagens such as ultraviolet light in melanoma117,118 and cigarette smoke in lung cancer23,119, mutations in the proofreading domains of DNA polymerases encoded by the POLE and POLD1 genes120,121,122,123,124, and microsatellite instability (MSI)120,123,124. The tumor seen here harbors a high TMB. This type of mutation load has been shown to be associated with sensitivity to immune checkpoint inhibitors, including anti- CTLA-4 therapy in melanoma125, anti-PD-L1 therapy in urothelial carcinoma126, and anti-PD-1 therapy in non-small cell lung cancer and colorectal cancer22,23, potentially due to expression of immune-reactive neoantigens in these tumors23.

Frequency and Prognosis: In a study of high grade serous ovarian cancer, homologous recombination (HR)-deficient tumors, which comprised ~50% of all samples, harbored a higher neoantigen load compared to HR-proficient tumors; higher neoantigen load was associated with longer overall survival but not disease free survival127. In endometrial carcinoma, increased mutational burden has been correlated with POLE mutation and the advanced, high-grade, endometrioid subtypes120,128,129,130. Ultramutated endometrial tumors (high TMB with POLE mutations) have also been associated with improved progression-free survival120. SAMPLE


Patient Name

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GENE ALTERATION

INTERPRETATION

Potential Treatment Strategies: On the basis of emerging clinical evidence, increased TMB may be associated with greater sensitivity to immunotherapeutic agents, including anti-CTLA-4125, anti-PD- L1126, and anti-PD-1 therapies22,23; FDA-approved agents include ipilimumab, atezolizumab, pembrolizumab, and nivolumab. In multiple solid tumor types, higher mutational burden has corresponded with response and improved prognosis. Pembrolizumab improved progression-free survival (14.5 vs. 3.4-3.7 months) in patients with non-small cell lung cancer (NSCLC) and higher mutational load (greater than 200 nonsynonymous mutations; hazard ratio = 0.19)23. In studies of patients with either NSCLC or colorectal cancer (CRC), patients whose tumors harbor elevated mutational burden reported higher overall response rates to pembrolizumab22,23. Anti-PD-1 therapies have achieved clinical benefit for certain patients with high mutational burden, including 3 patients with endometrial adenocarcinoma who reported sustained partial responses following treatment with pembrolizumab128 or nivolumab131 and two patients with biallelic mismatch repair deficiency (bMMRD)- associated ultrahypermutant glioblastoma who experienced clinically and radiologically significant responses to nivolumab132. In patients with melanoma, mutational load was associated with long-term clinical benefit from ipilimumab125,133 and anti-PD-1 treatment (Johnson et al., 2016; ASCO Abstract 105). For patients with metastatic urothelial carcinoma, those who responded to atezolizumab treatment had a significantly increased mutational load [12.4 mutations (mut) per megabase (Mb)] compared to nonresponders (6.4 mut/Mb)126.

ARID1A F2141fs*59

Gene and Alteration: ARID1A encodes the AT-rich interactive domain-containing protein 1A (ARID1A), also known as Baf250a, a member of the SWI/SNF chromatin remodeling complex. Mutation, loss, or inactivation of ARID1A has been reported in many cancers, and the gene is considered a tumor suppressor134,135,136,137. ARID1A mutations, which are mostly truncating, have been identified along the entire gene and often correlate with ARID1A protein loss135,136,137,138,139. ARID1A missense mutations are mostly uncharacterized, whereas several in-frame insertions or deletions, such as Q1334_R1335insQ and A343_A348>A, have been shown to impair ARID1A tumor suppressor activity without affecting ARID1A protein levels140.

Frequency and Prognosis: ARID1A alterations are particularly prevalent in ovarian clear cell carcinoma (46-57%), ovarian and uterine endometrioid carcinomas (24-44%), and cholangiocarcinoma (36%); they are also reported in up to 27% of gastric carcinoma, esophageal adenocarcinoma, Waldenstrom macroglobulinemia, pediatric Burkitt lymphoma, hepatocellular carcinoma, colorectal carcinoma (CRC), and urothelial carcinoma samples analyzed (COSMIC, cBioPortal, 2016)135,141,142,143,144,145. The tumor suppressor activity of ARID1A has been verified by functional assays in gastric cancer146,147, hepatocellular carcinoma148, cholangiocarcinoma149, and breast cancer cell lines150. The presence of wild-type ARID1A impaired cell proliferation and/or colony formation in soft agar, and ARID1A knockdown enhanced cell proliferation. Several studies have reported no correlation between ARID1A loss and clinicopathological parameters in ovarian clear cell or endometrioid carcinomas or other endometrial cancers151,152,153,154, whereas others suggest that ARID1A loss is a negative prognostic factor155,156. ARID1A loss is associated with microsatellite instability in ovarian and endometrial endometrioid adenocarcinomas15,129,157,158, CRC159,160,161, and gastric cancer139,147,162,163,164. ARID1A protein loss is associated with tumors of poor histological grade for many tumor types, including CRC159,160,161, cervical cancer165,166, gastric cancer139,147,162,163,164, urothelial carcinoma167,168,169, breast carcinoma150,170,171, and clear cell renal cell carcinoma172. However, prognostic data regarding patient survival are often mixed and conflicting. SAMPLE


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GENE ALTERATION

INTERPRETATION

Potential Treatment Strategies: There are no therapies approved to address the mutation or loss of ARID1A in cancer. However, on the basis of limited preclinical evidence from a study in ovarian cancer, ARID1A inactivation may predict sensitivity to inhibitors of EZH2173, which are under investigation in clinical trials. Other studies have reported that loss of ARID1A may activate the PI3K-AKT pathway and be linked with sensitivity to inhibitors of this pathway174,175,176. Loss of ARID1A expression has been associated with chemoresistance to platinum-based therapy in patients with ovarian clear cell carcinoma156,177 and to 5-fluorouracil (5-FU) in CRC cell lines178.

RNF43 G659fs*41

Gene and Alteration: RNF43 encodes a ubiquitin ligase179 that was discovered because it is overexpressed in colon cancer180. RNF43 and the homologous E3 ubiquitin ligase ZNRF3 are tumor suppressors that function as negative regulators of WNT signaling181,182,183,184,185. An additional tumor- suppressor-like role for RNF43 in colon cancer is hypothesized to occur via its interaction with the ubiquitin-protein ligase NEDL1, which is predicted to enhance the pro-apoptotic effects of p53186.

Frequency and Prognosis: Mutations in RNF43 have been reported in 18-27% of endometrial cancers187,188, 3-5% of pancreatic cancers189, 21% of ovarian mucinous carcinomas190, 9% of liver fluke- associated cholangiocarcinomas191, and up to 18% of colorectal cancers123,188. RNF43 mutations are associated with mismatch repair deficiency and microsatellite instability (MSI) in colorectal188, endometrial188, and gastric cancers192,193; one study reported RNF43 alterations in more than 50% of MSI gastric carcinomas192.

Potential Treatment Strategies: Preclinical studies have reported that RNF43 is a negative regulator of WNT signaling, and RNF43 loss or inactivation leads to WNT activation and confers sensitivity to WNT pathway inhibitors, particularly Porcupine inhibitors, in multiple tumor types181,182,183,184,185. Therefore, patients whose tumors harbor inactivating alterations in RNF43 may benefit from WNT pathway inhibitors, which are under investigation in clinical trials.

ASXL1 G645fs*58

Gene and Alteration: ASXL1 (additional sex combs-like 1) encodes a chromatin-binding protein involved in transcriptional regulation through interaction with the polycomb complex proteins and various other transcriptional regulators194,195. Germline inactivating mutations affecting ASXL1 underlie the very rare developmental disorder Bohring-Opitz syndrome196. ASXL1 alterations that remove the PHD domain (amino acids 1491-1541), including truncating mutations and deletions, lead to aberrant epigenetic regulation195,197,198.

Frequency and Prognosis: ASXL1 mutations have been reported in various solid tumors, including 4% of colorectal cancers199, 3% of breast cancers200, 2% of hepatocellular carcinomas201, 2% (1/61) of prostate cancers202, and 1.4% (1/74) head and neck squamous cell carcinomas203. ASXL1 amplification has also been reported in 5.1% of cervical cancers204. ASXL1 mutations have mainly been studied and reported in the context of hematological malignancies, where they have been correlated with poor prognosis in myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), and myeloproliferative neoplasms (MPN)194,197,205.

Potential Treatment Strategies: There are no targeted therapies available to address genomic alterations in ASXL1. SAMPLE


Patient Name

Report Date




GENE ALTERATION

CHEK2 Y329fs*20

INTERPRETATION

Gene and Alteration: CHEK2 encodes the protein checkpoint kinase 2, a serine/threonine kinase that plays an important role in the DNA-damage response; it is a putative tumor suppressor206,207,208,209. Germline mutations in CHEK2 have been associated with uterine serous carcinoma cases and with an increased risk of breast, colorectal, and thyroid cancer, as well as non-Hodgkin lymphoma210,211,212,213,214,215,216,217. CHEK2 alterations that disrupt or remove the SQ/TQ cluster domain (SCD; amino acids 19–69), forkhead-associated domain (FHA; amino acids 115–175), and/or the kinase domain (amino acids 220–486) are predicted to be inactivating218,219,220.

Frequency and Prognosis: CHEK2 mutations have been reported in 10% of glioblastoma (GBM) samples and in carcinomas of the ovary (2.3%), endometrium (1.9%), and large intestine (1.8%), as well as in a variety of solid and hematologic cancer types at low frequency (COSMIC, 2016). In breast cancer, certain CHEK2 mutations are associated with higher grade and larger tumors as well as bilateral disease221. A study reported that a polymorphism in CHEK2 was associated with worse survival of patients with GBM, but this association lost significance after adjusting for other prognostic factors222,223. Another study in prostate cancer reported that CHEK2 expression is decreased in higher grade tumors and that CHEK2 is a tumor suppressor that decreases the growth of prostate cancer cells and regulates androgen receptor signaling224.

Potential Treatment Strategies: There are no FDA-approved or investigational therapies targeting CHEK2 loss or inactivating alterations. One study of patients with breast cancer reported that carriers of the CHEK2 H371Y mutation have a higher likelihood of response to neoadjuvant chemotherapy225, whereas another study found that CHEK2 mutation carriers have a lower frequency of objective clinical responses to neoadjuvant therapy226. A third study reported that the CHEK2 1100delC mutation is not associated with differential efficacy of chemotherapy and endocrine therapy in patients with metastatic breast cancer227.

CREBBP Q2248*

Gene and Alteration: CREBBP encodes a ubiquitously expressed transcriptional coregulatory protein that interacts with multiple transcription factors and can couple control of gene expression to chromatin remodeling via its histone acetyltransferase activity. Inherited microdeletions and truncating point mutations in CREBBP are reported to be causal in approximately 20% of cases of Rubinstein-Taybi syndrome228. The chromosomal rearrangement t(8;16)(p11;p13) is characteristic of the M4/M5 subtype of acute myeloid leukemia (AML) and results in a chimeric gene fusing MYST3/MOZ (a gene essential for development of the hematopoietic system and maintenance of hematopoietic stem cells) to CREBBP229.

Frequency and Prognosis: CREBBP mutations have been observed at high frequency in follicular lymphoma (FL, 38%, 30/80) and diffuse large B-cell lymphoma (DLBCL, 18%), and at lower frequency in acute lymphoblastic leukemia (ALL, 6%), bladder carcinoma (9%), stomach adenocarcinoma (9%), adenoid cystic carcinoma (8%, 4/51), colorectal adenocarcinoma (8%), endometrial carcinoma (6%), melanoma (5%), cervical squamous cell carcinoma (5%), and lung carcinoma (4-7%) (COSMIC, 2016). These mutations include missense substitutions clustered in the CREBBP histone acetyltransferase domain and truncating mutations throughout the gene sequence, suggesting a role for CREBBP inactivation in these diseases. CREBBP mutations have been reported to occur in the transition from prostate acinar carcinoma to squamous cell carcinoma (SCC)230, which may indicate significance for CREBBP in SCC. In two cases of relapsed pediatric B-cell ALL, CREBBP mutation conferred resistance to glucocorticoid therapy231. Reports have found CREBBP mutation in 62-68% of patients with FL232,233, which was associated with immune evasion232. AML with MYST3/CREBBP fusion was reported to occur in 60-80% of cases 9-72 months after adjuvant chemotherapy for breast cancer and was associated with a poor prognosis234,235.

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Potential Treatment Strategies: There are no targeted therapies available to address genomic alterations in CREBBP. The use of histone deacetylase (HDAC) inhibitors are being investigated in clinical trials that are recruiting patients with either lymphoma or urothelial carcinoma harboring CREBBP alterations. However, it has been reported that there is no correlation between CREBBP mutation status and response to HDAC inhibitors in DLBCL236.

CTCF E363fs*30, T317fs*91

Gene and Alteration: CTCF encodes an 11-zinc-finger protein that is implicated in a number of regulatory roles, including gene activation and repression, imprinting, insulation, methylation, and X chromosome inactivation237. CTCF plays a role in transcriptional regulation of a number of key cancer- associated genes, including the oncogene MYC238 and tumor suppressor TP53239, via maintenance of local DNA methylation status. The decreased expression levels of CTCF and/or BORIS, another 11-zinc- finger transcriptional regulator, were reported to be closely associated with global DNA methylation variability and decreased overall survival in epithelial ovarian cancer240,241.

Frequency and Prognosis: Somatic mutations in CTCF are infrequently reported in most cancers, but have been observed more commonly (~30%) in uterine corpus endometrial carcinoma (COSMIC, 2015); nearly half of the observed mutations were truncating, suggesting a tumor suppressor role for CTCF in this disease. In addition, CTCF has been found to act as a tumor suppressor in breast cancer cell line studies242,243.

Potential Treatment Strategies: No targeted therapies are available to address genomic alterations in CTCF.

ESR1 S463P

Gene and Alteration: ESR1 encodes estrogen receptor alpha (ER-alpha), one of the major estrogen receptor isoforms in humans. Along with co-activator proteins, the ER complex promotes transcription of genes involved in cell cycle progression and survival244. Alterations that occur within the ligand binding domain (LBD/AF-2) of ER-alpha, including E380Q, S463P, L536Q, Y537C/N/S, or D538G, such as observed here, have been reported to result in constitutive activity in preclinical studies; however, mutant ER-alpha shows reduced sensitivity to antiestrogens245,246,247,248,249,250,251,252,253.

Frequency and Prognosis: In the Ovarian Serous Cystadenocarcinoma TCGA dataset, putative high- level amplification of ESR1 was reported in 1.6% of samples analyzed103. Single nucleotide polymorphisms (SNPs) in the ESR1 locus are common and have been linked to increased risk of serous and mucinous ovarian cancer, and breast cancer susceptibility254,255. ER-alpha mRNA expression has been significantly correlated with progression-free survival and overall survival in patients with ovarian cancer who have had neo-adjuvant therapy256.

Potential Treatment Strategies: There are no approved therapies to address mutation of ESR1 in cancer, although ESR1 expression status may play a role in determining treatment options256. Preclinical studies suggest that ESR1-mutant tumors may be less sensitive to clinical concentrations of antiestrogens and higher doses or more potent antiestrogens may be required to inhibit ESR1 mutant cancers. Next-generation antiestrogens, such as the selective estrogen receptor degraders AZD9496, RAD1901, and GDC-0810, are under preclinical and clinical investigation. In a Phase 1 study, GDC-0810 exhibited activity in heavily pretreated ER+ breast cancer, with target engagement being observed in 90% of patients (n = 41), including 5 patients with ESR1 mutations; 42% of patients (13/31) exhibited stable disease > 6 months. In this study, 2 patients with ESR1-mutant liver metastatic tumors experienced partial responses (Dickler et al., 2015; AACR Abstract CT231)257. In preclinical studies, AZD9496 reduced tumor growth in a ESR1-mutant patient-derived xenograft model (Savi et al., 2015; AACR Abstract 3650, Weir et al., 2015 AACR Abstract DDT01-03).

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GENE ALTERATION

INTERPRETATION

GATA2 A75fs*5

Gene and Alteration: GATA2 encodes a zinc-finger transcription factor that participates in multiple facets of development, including terminal differentiation of adipocytes258, hematopoiesis259, and angiogenesis260. Inherited mutations in GATA2 represent a risk factor for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)261 and for immune deficiency characterized by insufficiency of dendritic cells, monocytes, and B and NK lymphocytes262. The alteration observed in this tumor has been shown to reduce the activity of GATA2 and is predicted to be at least partially inactivating263. Alterations within the zinc finger region have been associated with inherited neutropenia and the progression of MonoMAC syndrome to MDS/AML261,262,264,265.

Frequency and Prognosis: Somatic mutation of GATA2 is rarely reported in cancer, with the specific exception of cytogenetically normal AML (CN-AML), where GATA2 is mutated or expression is reduced in a majority of cases263,266. High expression of GATA2 has been reported to be a negative prognostic factor in pediatric AML and some subclasses of adult AML267,268.

Potential Treatment Strategies: There are no targeted therapies available to address genomic alterations in GATA2.

HNF1A G292fs*25

Gene and Alteration: HNF1A, also known as TCF1, is a transcription factor involved in T-cell development in the thymus and the expression of liver-specific genes. In murine models, loss of HNF1A contributes to the development of lymphomas269.

Frequency and Prognosis: Mutations in this gene have been observed in 11% of endometrial tumors270

and inactivating events have been observed in up to 50% of liver adenomas271,272,273,274. HNF1A is mutated in approximately 2% of samples analyzed across all tumor types (COSMIC, 2015).

Potential Treatment Strategies: Currently there are no therapies available to target alterations in this gene.

MAP3K1 E265*, W751*

Gene and Alteration: MAP3K1 encodes a multifunctional protein kinase and E3 ubiquitin ligase involved in several signal transduction pathways central to cancer cell biology275. Different MAP3K1 protein isoforms have been suggested to exert both pro- and anti-apoptotic influences276,277. Germline polymorphism in MAP3K1 has been hypothesized to associate with risk for at least some subtypes of breast carcinoma278, but the extent of effect is small and experimental results have been inconsistently replicated279.

Frequency and Prognosis: Somatic alterations of MAP3K1, including missense mutations, truncating alterations, and loss of heterozygosity, have been observed infrequently in a variety of human tumors, more commonly in breast280 and uterine corpus carcinomas (cBioPortal, 2016)120.

Potential Treatment Strategies: There are no targeted therapies available to address genomic alterations in MAP3K1.

MLL2 P2354fs*30

Gene and Alteration: MLL2 encodes an H3K4-specific histone methyltransferase that is involved in the transcriptional response to progesterone signaling281. Germline de novo mutations of MLL2 are responsible for the majority of cases of Kabuki syndrome, a complex and phenotypically distinctive developmental disorder282. SAMPLE


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GENE ALTERATION

INTERPRETATION

Frequency and Prognosis: Somatic alterations of MLL2 are frequently observed in lymphoma, including in the majority of follicular lymphomas, where the observed pattern of genomic alterations suggests a tumor suppressor function283. MLL2 alterations are also observed in a number of solid tumor contexts (COSMIC, 2016), being especially prevalent in squamous cell lung carcinoma284.

Potential Treatment Strategies: There are no targeted therapies available to address genomic alterations in MLL2.

MLL3 K2797fs*26

Gene and Alteration: MLL3 encodes a SET domain-containing histone methyltransferase that functions as part of a co-activator complex to methylate H3-lysine-4 (H3K4)285,286. H3K4 methylation is an epigenetic mark of transcriptionally active chromatin287. The MLL3-containing complex was reported to be recruited to promoters of p53 target genes and activate their transcription288.

Frequency and Prognosis: Mutations that are predicted to disrupt MLL3 function have been described in a number of cancer types including bladder transitional cell carcinoma, gastric adenocarcinoma, cholangiocarcinoma, and hepatocellular carcinoma (HCC)138,167,191,289. Deletions and deleterious mutations in MLL3 have been reported at a high frequency in colorectal cancers with microsatellite instability290,291. Mouse models that lack functional MLL3 have an increased incidence of urothelial tumors, and knockdown of MLL3 was reported to promote proliferation in human HCC cell lines288,289. These data suggest that MLL3 may function as a tumor suppressor.

Potential Treatment Strategies: There are no targeted therapies available to address genomic alterations in MLL3.

PAX5 V26G

Gene and Alteration: Paired box (PAX) genes such as PAX5 encode transcription factors that regulate cell differentiation and development. The protein PAX5 (also known as BSAP) is a master regulator of B-cell development292,293. PAX5 has been extensively studied in B-cell malignancies, particularly B-cell acute lymphoblastic leukemia (B-ALL), for which it has both oncogenic and tumor suppressive activities293.

Frequency and Prognosis: Compared with hematologic malignancies, PAX5 genomic alterations are rare in solid tumors and have not been extensively studied in this context (COSMIC, PubMed, 2016). However, it has been suggested that PAX5 is a tumor suppressor for various epithelial cancers, as transcriptional silencing of PAX5 by promoter methylation has been reported in multiple tumor types including non-small cell lung cancer, breast cancer, and head and neck squamous cell carcinoma294,295,296,297. In gastric cancer, PAX5 methylation is correlated with worse survival298,299. In contrast, PAX5 is believed to act as an oncogene in neuroendocrine tumors. PAX5 is frequently expressed in Merkel cell carcinoma, small cell lung carcinoma (SCLC), other pulmonary neuroendocrine carcinomas, and neuroblastoma300,301,302,303,304,305,306.

Potential Treatment Strategies: There are no therapies available to target genomic alterations in PAX5. In pulmonary neuroendocrine tumors, particularly SCLC, PAX5 is coexpressed and colocalized with active c-MET304,305, and a preclinical study of SCLC showed that PAX5 activates MET transcription304. This same study showed that combinatorial reduction of SCLC cell viability can be achieved by PAX5 knockdown and treatment with inhibitors of c-MET or topoisomerase 1304, although whether PAX5 mutations confer sensitivity to these inhibitors has not been evaluated. SAMPLE


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GENE ALTERATION

PIK3R1 I405del

INTERPRETATION

Gene and Alteration: PIK3R1 encodes the p85-alpha regulatory subunit of phosphatidylinositol 3- kinase (PI3K)307. Loss of PIK3R1 has been shown to result in increased PI3K signaling308,309,310,311, promote tumorigenesis308, and promote hyperplasia in the context of PTEN-deficiency312. Inactivating PIK3R1 mutations that disrupt the nSH2 or iSH2 domains (aa 333-623), including in-frame deletions, truncations, or certain missense mutations, are predicted to be oncogenic313,314; these alterations result in activation of PI3K-AKT signaling34,313,314,315,316,317,318,319,320. Certain truncations between amino acids 299-370 also activate the BRAF-MEK-ERK pathway321. Some PIK3R1 mutations including N453del and E666K have been characterized as neutral313,315.

Frequency and Prognosis: In the TCGA datasets, PIK3R1 mutation is most frequently observed in endometrial carcinoma (33%)120, glioblastoma (GBM; 11%)322, uterine carcinosarcoma (11%)(cBioPortal, 2016), and lower grade glioma (5%)323. PIK3R1 is also recurrently mutated in Burkitt lymphoma, and alterations were observed in 4.3% of cases324. PIK3R1 is often inactivated by in-frame insertions or deletions (indels), and the majority of this class of mutation (80%) was observed in endometrial carcinoma313,318,325, although PIK3R1 indels have been reported in other cancer types such as GBM, cervical squamous cell carcinoma, and urothelial bladder carcinoma325. In preclinical studies, PIK3R1 mutation or deletion has been shown to promote tumorigenesis in models of glioma317 and hepatocellular carcinoma308. On the basis of limited clinical data, reduced PIK3R1 expression has been associated with reduced disease-free survival in prostate cancer326 and metastasis-free survival in breast cancer327. PIK3R1 expression is not associated with overall survival in neuroendocrine tumors328.

Potential Treatment Strategies: On the basis of preclinical studies, PIK3R1 alteration may predict sensitivity to PI3K-AKT-mTOR pathway inhibitors313,314,317, specifically inhibitors of PI3K-alpha314 or AKT317. However, in Phase 2 clinical trials for patients with endometrial carcinoma, PIK3R1 mutation was not associated with clinical benefit from either the pan-PI3K inhibitor pilaralisib329 or the mTOR inhibitor temsirolimus330. One preclinical study has shown that PIK3R1 truncation mutations in the 299-370 range confer sensitivity to MEK inhibitors321.

QKI K134fs*14

Gene and Alteration: QKI encodes quaking, an RNA-binding protein that plays roles in RNA metabolism and signal transduction and is necessary for myelination and embryonic development331,332. QKI acts as a negative regulator of cell cycle progression333.

Frequency and Prognosis: Recurrent deletions of QKI have been reported in astrocytomas and glioblastomas334,335,336. Decreased expression of quaking has also been reported in colon and gastric cancer, largely due to QKI promoter hypermethylation; in one study, forced expression of quaking in colon cancer cells inhibited proliferation and tumorigenesis337,338. However, another study reported that QKI acts as an oncogene in breast cancer by repressing the expression of the tumor suppressor FOXO1339.

Potential Treatment Strategies: There are no targeted therapies approved or in clinical trials that directly address genomic alterations in QKI.

SLIT2 Q100H

Gene and Alteration: SLIT2 encodes a secreted glycoprotein which binds receptors of the ROBO family, and provides guidance for cell migration, particularly during development of the nervous system, by mediating repulsive cues. SLIT2, along with other components of the SLIT/ROBO pathway, has been reported to act as a tumor suppressor by suppressing cancer cell invasion340. SAMPLE


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GENE ALTERATION

INTERPRETATION

Frequency and Prognosis: Mutations of SLIT2, or repression of SLIT2 expression by promoter hypermethylation, have been reported in aggressive cancer types with poor prognosis, such as pancreatic ductal adenocarcinoma341 and small cell lung carcinoma342, as well as in lung, colorectal, prostate, and bladder cancers, and in acute lymphocytic leukemia343.

Potential Treatment Strategies: There are no approved therapies to directly target genomic alterations in SLIT2.

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THERAPIES

There are no approved therapies in this patient's tumor type that are specific to the reported genomic alterations.

ADDITIONAL THERAPIES – FDA-APPROVED IN OTHER TUMOR TYPES

THERAPY SUMMARY OF DATA IN OTHER TUMOR TYPE

Nivolumab Approved Indications: Nivolumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby reducing inhibition of the antitumor immune response. It is FDA approved to treat unresectable or metastatic melanoma as both a single agent and in combination with the immunotherapy ipilimumab. Nivolumab is also approved to treat non- small cell lung cancer (NSCLC) following disease progression on prior treatments, advanced renal cell carcinoma following antiangiogenic therapy, and classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post- transplantation brentuximab vedotin.

Gene Association: On the basis of emerging clinical data showing strong efficacy of nivolumab for patients with microsatellite instability (MSI)-high colorectal cancer (CRC) (Overman et al., 2016; ASCO Abstract 3501)21 and additional clinical data predicting association between MSI and markers of response to anti-PD-1 therapy18,19,20, MSI-high tumors may be sensitive to nivolumab. On the basis of emerging clinical data in patients with non-small cell lung cancer (Spigel et al., 2016; ASCO Abstract 9017)23, colorectal cancer22, or melanoma (Johnson et al., 2016; ASCO Abstract 105) and case reports in endometrial cancer128,131 and glioblastoma132, high tumor mutation burden (TMB) may predict sensitivity to anti-PD-1 therapies such as nivolumab.

Supporting Data: A Phase 2 study of nivolumab for patients with platinum-resistant ovarian cancer reported an overall response rate of 15% (3/20), a disease control rate of 45% (9/20), median progression-free survival of 3.5 months, and median overall survival of 20 months (at study termination); 10% (2/20) of patients experienced durable complete responses344. A Phase 1 trial of nivolumab included 17 cases with ovarian cancer and observed disease control for 24% (1/17 partial response, 3/17 stable disease) of these patients345. A case study reported partial responses to nivolumab in 2 patients with endometrial carcinoma harboring high tumor mutation burden; response was ongoing at 7-9 months131.

Pembrolizumab Approved Indications: Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and

blocks its interaction with the ligands PD-L1 and PD-L2 to enhance antitumor immune responses. It is FDA approved to treat unresectable or metastatic melanoma, PD-L1-positive metastatic non-small cell lung cancer (NSCLC) refractory to prior therapy, and recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) that has progressed on or after platinum chemotherapy.

Gene Association: On the basis of emerging clinical evidence in patients with microsatellite instability (MSI)-high and hypermutant18,19 cancers, MSI may predict sensitivity to pembrolizumab22,23. On the basis of emerging clinical data in patients with non-small cell lung cancer (Spigel et al., 2016; ASCO Abstract 9017)23, colorectal cancer22, or melanoma (Johnson et al., 2016; ASCO Abstract 105) and case reports in endometrial cancer128,131 and glioblastoma132, high tumor mutation burden (TMB) may predict sensitivity to anti-PD-1 therapies such as pembrolizumab. SAMPLE


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Supporting Data: Preliminary results from a study of pembrolizumab in 26 patients with advanced ovarian cancer reported 1 complete response, 2 partial responses and 6 stable disease (Varga et al., 2015; ASCO Abstract 5510). Pembrolizumab achieved clinical benefit for 25% [3/24 partial responses (PRs) and 3/24 stable disease (SD)] of patients with previously treated advanced endometrial carcinoma and PD-L1 expression in at least 1% of cells; the 6-month progression-free survival and overall survival (OS) rates were 19% and 69%, respectively (Ott et al., 2016; ASCO Abstract 5581). Preliminary results from a Phase 2 study of pembrolizumab for patients with MMR-deficient recurrent endometrial cancer reported 1 complete response (CR), 4 PRs, and 3 SDs; the patient who achieved a CR remained disease-free for 17 months (Fader et al., 2016; SGO Abstract 3). A patient with PD-L1-positive POLE-mutant endometrial adenocarcinoma and high tumor mutational burden experienced a PR to pembrolizumab for more than 14 months128. In a Phase 1/2 study of pembrolizumab and epacadostat in multiple solid tumor types, a PR was reported for 1 of 2 patients with endometrial adenocarcinoma (Gangadhar et al., 2015; SITC Abstract 511). A Phase 2 basket study of pembrolizumab for patients with mismatch repair-deficient non-colorectal advanced solid tumors (n=29) reported objective responses for 48% (14/29), SD for 24% (7/29), and 1-year OS for 79% of patients (Diaz et al., 2016; ASCO Abstract 3003).

Everolimus Approved Indications: Everolimus is an orally available mTOR inhibitor that is FDA approved to treat

renal cell carcinoma (RCC) following antiangiogenic therapy; pancreatic neuroendocrine tumors and well-differentiated non-functional neuroendocrine tumors of the lung or gastrointestinal tract; and, in association with tuberous sclerosis complex (TSC), renal angiomyolipoma and subependymal giant cell astrocytoma. Everolimus is also approved to treat hormone receptor-positive, HER2-negative advanced breast cancer in combination with exemestane following prior therapy with letrozole or anastrozole, as well as in combination with the multikinase inhibitor lenvatinib to treat advanced RCC following prior antiangiogenic therapy.

Gene Association: Activation of PIK3CA may predict sensitivity to inhibitors of the PI3K-AKT-mTOR pathway such as everolimus52. In one report documenting the response in 23 patients harboring PIK3CA mutations in a variety of breast or gynecological malignancies to various regimens that included the mTOR inhibitors sirolimus or temsirolimus, 2/23 patients experienced stable disease and 7/23 experienced a partial response346. PTEN inactivation may predict benefit from mTOR inhibitors, such as everolimus, based on clinical data in various tumor types. For patients with prostate cancer, PTEN loss correlated with response to single-agent everolimus347. Retrospective clinical data suggest that patients with advanced breast cancer and PTEN inactivation, particularly in the context of HER2- positive disease, may benefit from everolimus combined with targeted therapy and/or chemotherapy348,349,350.

Supporting Data: A Phase 1 clinical trial of everolimus, with bevacizumab and panitumumab, in patients with advanced solid tumors reported long-term disease control in three ovarian cancer patients351. A case study of a patient with platinum-resistant recurrent ovarian clear cell carcinoma reported achievement of stable disease in response to everolimus monotherapy352. A study of the mTOR inhibitor ridaforolimus as a single-agent reported no clinical response in 5 patients with uterine carcinosarcoma353. A Phase 1b trial of a combination of everolimus and the MEK inhibitor trametinib in patients with solid tumors reported frequent adverse events and the study was unable to identify a recommended Phase 2 dose and schedule for the combination354.

Temsirolimus Approved Indications: Temsirolimus is an intravenous mTOR inhibitor that is FDA approved for the

treatment of advanced renal cell carcinoma. SAMPLE


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Gene Association: Activation of PIK3CA may predict sensitivity to inhibitors of the PI3K-AKT-mTOR pathway such as temsirolimus52. Out of four patients with mesenchymal/metaplastic breast cancer (MpBCs) and PIK3CA alterations treated with temsirolimus-involving regimens in one study, one achieved a complete response (PIK3CA H1047R) and two achieved stable disease, with one lasting >6 months53. In another report documenting the response in 23 patients harboring PIK3CA mutations in a variety of breast or gynecological malignancies to various regimens that included the mTOR inhibitors temsirolimus or sirolimus, 2/23 patients experienced stable disease and 7/23 experienced a partial response346. PTEN inactivation may predict benefit from mTOR inhibitors, such as temsirolimus, based on clinical data in various tumor types. Out of 10 patients with metaplastic breast cancer and PTEN alterations, 2 cases responded to temsirolimus or everolimus plus doxorubicin and bevacizumab (Basho et al., 2015; SABCS Abstract P3-14-02)53. Temsirolimus achieved stable disease for 6 of 7 patients with PTEN-deficient cervical carcinoma355. Clinical studies in renal cell carcinoma356,357, glioblastoma358,359, or endometrial cancer360,361,362,363 did not observe a correlation of PTEN deficiency with response to temsirolimus, although several patients with those tumor types and PTEN loss have benefited from mTOR inhibitors.

Supporting Data: In a Phase 1 trial of 74 patients with breast and gynecological malignancies examining the combination of temsirolimus, liposomal doxorubicin, and bevacizumab, researchers reported that 38% of patients experienced either a complete response (1/74), partial response (19%), or stable disease (18%)364. Another Phase 1 study of temsirolimus in combination with bevacizumab reported that 62% (8/13) patients with ovarian or primary peritoneal serous carcinoma achieved stable disease for >6 months365. A Phase 2 clinical trial of temsirolimus showed only modest activity in patients with recurrent epithelial ovarian or primary peritoneal cancers, but 13/54 patients experienced progression-free survival for 6 months or more366.

Atezolizumab Approved Indications: Atezolizumab is a monoclonal antibody that binds to PD-L1 and blocks its

interaction with PD-1 in order to enhance antitumor immune responses. It is FDA approved to treat patients with advanced urothelial carcinoma who progress during or following platinum-based chemotherapy.

Gene Association: On the basis of emerging clinical data in patients with urothelial carcinoma126, non-small cell lung cancer (Spigel et al., 2016; ASCO Abstract 9017), or melanoma (Johnson et al., 2016; ASCO Abstract 105), high tumor mutation burden (TMB) may predict sensitivity to anti-PD-L1 therapies such as atezolizumab.

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Supporting Data: Atezolizumab has been studied primarily for the treatment of non-small cell lung cancer (NSCLC) (Smith et al., 2016; ASCO Abstract 9028, Mazieres et al., 2016; ASCO Abstract 9032, Besse et al., 2015; ECC Abstract 16LBA, Spigel et al., 2015; ASCO Abstract 8028)367,368 and urothelial carcinoma (Balar et al., 2016; ASCO Abstract LBA4500, Dreicer et al., 2016; ASCO Abstract 4515)126,369. A study of atezolizumab as monotherapy for patients with advanced solid tumors reported a median progression-free survival (PFS) of 18 weeks and an overall response rate (ORR) of 21%, including confirmed responses in 26% (11/43) of melanomas, 13% (7/56) of renal cell carcinomas (RCC) and 13% (1/6) of colorectal cancers (CRCs)368. A Phase 1a study of atezolizumab reported an ORR of 15% (9/62), median PFS of 5.6 months, and median overall survival (OS) of 28.9 months for patients with clear cell RCC370. A Phase 1b study evaluated atezolizumab combined with nab-paclitaxel for patients with previously treated metastatic triple-negative breast cancer (mTNBC) and reported confirmed objective responses for 42% (10/24) of patients; no dose-limiting toxicities were observed (Adams et al., 2016; ASCO Abstract 1009). A Phase 1b study evaluated atezolizumab in combination with the MEK inhibitor cobimetinib for advanced solid tumors and enrolled 23 patients with CRC, who were mostly (22/23) KRAS-mutant; 17% (4/23) of these patients achieved objective partial responses, with three of the responders being mismatch repair (MMR)-proficient and one of them having unknown MMR status. In addition, stable disease was observed for 22% (5/23) of patients, and no dose-limiting toxicities were encountered (Bendell et al., 2016; ASCO Abstract 3502).

Genomic alterations detected may be associated with activity of certain approved drugs; however, the agents listed in this report may have little or no evidence in the patient’s tumor type.

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CLINICAL TRIALS TO CONSIDER

IMPORTANT: While every effort is made to ensure the accuracy of the information contained below, the information available in the public domain is continually updated and should be investigated by the physician or research staff. This is not meant to be a complete list of available trials. In order to conduct a more thorough search, please go to www.clinicaltrials.gov and use the search terms provided below. For more information about a specific clinical trial, type the NCT ID of the trial indicated below into the search bar.

GENE RATIONALE FOR POTENTIAL CLINICAL TRIALS

High microsatellite instability (MSI) and mutational burden may predict response to anti-PD-1

Microsatellite

status MSI-High

immunotherapies.

Examples of clinical trials that may be appropriate for this patient are listed below. These trials were identified through a search of the trial website clinicaltrials.gov using keyword terms such as "PD-1", "pembrolizumab", "nivolumab", "ovarian endometrioid carcinoma", "solid tumor", and/or "advanced cancer".

TITLE PHASE TARGETS LOCATIONS NCT ID A Phase Ib/II Study of Pembrolizumab and Monoclonal Antibody Therapy in Patients With Advanced Cancer (PembroMab

Phase 1/Phase 2

PD-1, EGFR, ERBB2

Arizona NCT02318901

A Phase Ib/II Study of Pembrolizumab Plus Chemotherapy in Patients With Advanced Cancer (PembroPlus)

Phase 1/Phase 2

PD-1 Arizona NCT02331251

A First-in-Human Study of Repeat Dosing With REGN2810, a Monoclonal, Fully Human Antibody to Programmed Death - 1 (PD 1), as Single Therapy and in Combination With Other Anti-Cancer Therapies in Patients With Advanced Malignancies

Phase 1 PD-1 Arizona, California, Colorado, Connecticut, District of Columbia, Florida, Georgia, Illinois, Massachusetts, Missouri, New Jersey, New York, North Carolina, Ohio, Oklahoma, Oregon, Pennsylvania, Tennessee, Texas, Barcelona (Spain), Madrid (Spain)

NCT02383212

A Phase 1, Open-label Study to Evaluate the Safety and Tolerability of MEDI0680 (AMP-514) in Combination With MEDI4736 in Subjects With Advanced Malignancies

Phase 1/Phase 2

PD-1, PD-L1 California, Florida, New Jersey, New York, Oregon, South Carolina, Washington

NCT02118337

Phase 1/2 Clinical Study of Niraparib in Combination With Pembrolizumab in Patients With Advanced or Metastatic Triple-Negative Breast Cancer and in Patients With Recurrent Ovarian Cancer

Phase 1/Phase 2

PARP, PD-1 Arizona, Massachusetts, Michigan, Ohio, Oklahoma, Tennessee

NCT02657889 SAMPLE

http://www.clinicaltrials.gov/








PIK3CA R88Q

PIK3CA activating mutations or amplification may lead to activation of the PI3K-AKT-mTOR pathway, and may therefore indicate sensitivity to inhibitors of PI3K, AKT, and/or mTOR.

Examples of clinical trials that may be appropriate for this patient are listed below. These trials were identified through a search of the trial website clinicaltrials.gov using keyword terms such as "PI3K", "mTOR", "AKT", "everolimus", "temsirolimus", "ovarian endometrioid carcinoma", "solid tumor", and/or "advanced cancer".

TITLE PHASE TARGETS LOCATIONS NCT ID A Phase Ib Study of the Oral PARP Inhibitor Olaparib With the Oral mTORC1/2 Inhibitor AZD2014 or the Oral AKT Inhibitor AZD5363 for Recurrent Endometrial, Triple Negative Breast, and Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Phase 1/Phase 2

PARP, mTORC1, mTORC2, AKT

Texas NCT02208375

A Phase 1, Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MLN0128 (an Oral mTORC 1/2 Inhibitor) as a Single Agent and in Combination With Paclitaxel in Adult Patients With Advanced Nonhematologic Malignancies

Phase 1 mTORC1, mTORC2

Florida, Oklahoma, Tennessee NCT02412722

A Phase 1b Open-Label Three-Arm Multi-Center Study To Assess The Safety And Tolerability Of PF-05212384 ((PI3K/mTOR Inhibitor) In Combination With Other Anti-Tumor Agents

Phase 1 PI3K, mTOR, EGFR, ERBB2, ERBB4

California, Massachusetts, Michigan, Pennsylvania, South Carolina, Barcelona (Spain), British Columbia (Canada), London (United Kingdom), Madrid (Spain), Milan (Italy), Ontario (Canada), Roma (Italy)

NCT01920061

An Open-label Phase 1b Study of ARQ 092 in Combination With Carboplatin Plus Paclitaxel in Subjects With Selected Solid Tumors

Phase 1 AKT Michigan, Texas NCT02476955

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PTEN W111*

Loss or inactivation of PTEN may predict sensitivity to PI3K-AKT-mTOR pathway inhibitors or PARP inhibitors.

Examples of clinical trials that may be appropriate for this patient are listed below. These trials were identified through a search of the trial website clinicaltrials.gov using keyword terms such as "PTEN", "PI3K", "AKT", "mTOR", "everolimus", "temsirolimus", "PARP", "olaparib", "rucaparib", "BMN 673", "ABT-888", "veliparib", "E7449", "niraparib", "ovarian endometrioid carcinoma", "solid tumor", and/or "advanced cancer".

TITLE PHASE TARGETS LOCATIONS NCT ID A Phase I Multi-centre Trial of the Combination of Olaparib (PARP Inhibitor) and AZD5363 (AKT Inhibitor) in Patients With Advanced Solid Tumours

Phase 1 PARP, AKT Newcastle upon Tyne (United Kingdom), Surrey (United Kingdom)

NCT02338622

A Phase Ib Study of the Oral PARP Inhibitor Olaparib With the Oral mTORC1/2 Inhibitor AZD2014 or the Oral AKT Inhibitor AZD5363 for Recurrent Endometrial, Triple Negative Breast, and Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Phase 1/Phase 2

PARP, mTOR, AKT

Texas NCT02208375

A Phase I Trial of the Combination of the PARP Inhibitor ABT-888 With Intraperitoneal Floxuridine (FUDR) in Epithelial Ovarian, Primary Peritoneal and Fallopian Tube Cancers

Phase 1 PARP Maryland, Minnesota, Missouri NCT01749397

A Phase 1, Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MLN0128 (an Oral mTORC 1/2 Inhibitor) as a Single Agent and in Combination With Paclitaxel in Adult Patients With Advanced Nonhematologic Malignancies

Phase 1 mTORC1, mTORC2

Florida, Oklahoma, Tennessee NCT02412722

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Tumor Mutation

Burden TMB-High; 33.54

Muts/Mb

High tumor mutational burden may predict response to anti-PD-1 and anti-PD-L1 immune checkpoint inhibitors.

Examples of clinical trials that may be appropriate for this patient are listed below. These trials were identified through a search of the trial website clinicaltrials.gov using keyword terms such as "PD-L1", "B7-H1", "PD-1", "pembrolizumab", "nivolumab", "atezolizumab", "MPDL3280A", "durvalumab", "MEDI4736", "avelumab", "MSB0010718C", "BMS-936559", "CT-011", "ovarian endometrioid carcinoma", "solid tumor", and/or "advanced cancer".

TITLE PHASE TARGETS LOCATIONS NCT ID A Phase Ib/II Study of Nivolumab Plus Chemotherapy in Patients With Advanced Cancer (NivoPlus)

Phase 1/Phase 2

mTOR, PD-1 Arizona NCT02423954

A Phase 1, Open-label Study to Evaluate the Safety and Tolerability of MEDI0680 (AMP-514) in Combination With MEDI4736 in Subjects With Advanced Malignancies

Phase 1/Phase 2

PD-1, PD-L1 California, Florida, New Jersey, New York, Oregon, South Carolina, Washington

NCT02118337

A Phase 1 Dose Escalation and Cohort Expansion Study of the Safety, Tolerability, and Efficacy of Anti-LAG-3 Monoclonal Antibody (BMS-986016) Administered Alone and in Combination With Anti-PD-1 Monoclonal Antibody (Nivolumab, BMS-936558) in Advanced Solid Tumors

Phase 1 LAG-3, PD-1 Illinois, Maryland, Massachusetts, New York, Oregon, Barcelona (Spain), Helsinki (Finland), Pamplona (Spain)

NCT01968109

A Phase Ib Study of the Safety and Pharmacology of Atezolizumab (Anti-PD-L1 Antibody) Administered With Bevacizumab and/or With Chemotherapy in Patients With Advanced Solid Tumors

Phase 1 PD-1, VEGFA Colorado, Connecticut, District of Columbia, Illinois, Massachusetts, New York, North Carolina, Tennessee

NCT01633970

Matched Paired Pharmacodynamics and Feasibility Study of Pembrolizumab in Combination With Chemotherapy in Frontline Ovarian Cancer

Phase 2 PD-1 Texas NCT02520154

A Phase II, Open-label, Single-arm, Multicenter Study to Evaluate Efficacy and Safety of Pembrolizumab Monotherapy in Subjects With Advanced Recurrent Ovarian Cancer (KEYNOTE- 100)

Phase 2 PD-1 California, Connecticut, Florida, Georgia, Illinois, Louisiana, Maine, Massachusetts, Minnesota, New York, Pennsylvania, South Carolina, Texas, Virginia, Wisconsin, (Australia), (Belgium), (Canada), (Finland), (France), (Germany), (Israel), (Italy), (Jamaica), (Japan), (Lithuania), (Netherlands), (Norway), (Poland), (Russian Federation),

NCT02674061 SAMPLE






(South Africa), (Spain), (Sweden), (United Kingdom)

SAMPLE








ARID1A F2141fs*59

On the basis of preclinical evidence, ARID1A loss or inactivation may predict sensitivity to EZH2 inhibitors.

Examples of clinical trials that may be appropriate for this patient are listed below. These trials were identified through a search of the trial website clinicaltrials.gov using keyword terms such as "EZH2", "EPZ-6438", "E7438", "ovarian endometrioid carcinoma", "solid tumor", and/or "advanced cancer".

TITLE PHASE TARGETS LOCATIONS NCT ID An Open-Label, Multicenter, Phase 1/2 Study of E7438 (EZH2 Histone Methyl Transferase [HMT] Inhibitor) as a Single Agent in Subjects With Advanced Solid Tumors or With B-cell Lymphomas

Phase 1/Phase 2

EZH2 Bologna (Italy), Bordeaux (France), Caen (France), Clayton (Australia), Creteil (France), Geelong (Australia), Glasgow (United Kingdom), Lille (France), London (United Kingdom), Lyon (France), Manchester (United Kingdom), Marseille (France), Melbourne (Australia), Montpellier (France), Montreal (Canada), Nantes (France), Napoli (Italy), Pierre Benite (France), Rennes (France), Rouen (France), Southampton (United Kingdom), Villejuif Cedex (France)

NCT01897571

A Phase I Open-label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK2816126 in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma, Transformed Follicular Lymphoma, Other Non-Hodgkin's Lymphomas, Solid Tumors and Multiple Myeloma

Phase 1 EZH2 Illinois, New York, Southampton (United Kingdom), Surrey (United Kingdom), Villejuif cedex (France)

NCT02082977

SAMPLE








RNF43 G659fs*41

Based on preclinical evidence, tumors with loss or inactivation of RNF43 may be sensitive to inhibitors of the Wnt signaling pathway.

Examples of clinical trials that may be appropriate for this patient are listed below. These trials were identified through a search of the trial website clinicaltrials.gov using keyword terms such as "beta catenin", "WNT", "DKK1", "DKK3, "SFRP1", "calcimycin", "PRI-724", "ovarian carcinoma", and/or "solid tumor".

TITLE PHASE TARGETS LOCATIONS NCT ID A Phase 1A/B Study to Evaluate the Safety and Tolerability of ETC-1922159 in Advanced Solid Tumours

Phase 1 PORCN Texas NCT02521844

SAMPLE






APPENDIX

VARIANTS OF UNKNOWN SIGNIFICANCE

Note: One or more variants of unknown significance (VUS) were detected in this patient's tumor. These variants may not have been

adequately characterized in the scientific literature at the time this report was issued, and/or the genomic context of these

alterations makes their significance unclear. We choose to include them here in the event that they become clinically meaningful in

the future.

ARID1A L853I

ARID1B G384fs*46,N1659S

CIC P1107H,P49S

CREBBP R2104C

EPHA5 V592I

FGFR4 K466E

FLT3 FLT4 FOXP1 HNF1A IRS2 JAK2 P60T splice site 2851- F661S Q216R A1245T,G387W,P1 M186V

KDM5C P554S

2_2851delAGG

LZTR1

MAP3K1 F1322Y

MCL1 A139S

091fs*15

MET

MPL R102P

MYCN T58M

Q476K

NOTCH1

NSD1 I1122F,R2633Q

PIK3CG C724G

I1084M

PIK3R1

PLCG2 T961M

PTCH1 G50del

M2056I

RAF1

RPTOR A1258V

SMO A272V

R544del

SPOP

TET2 S1760del

Q601fs*7 W131C

SAMPLE






APPENDIX

GENES ASSAYED IN FOUNDATIONONE

FoundationOne is designed to include all genes known to be somatically altered in human solid tumors that are validated targets for

therapy, either approved or in clinical trials, and/or that are unambiguous drivers of oncogenesis based on current knowledge. The

current assay interrogates 315 genes as well as introns of 28 genes involved in rearrangements. The assay will be updated periodically

to reflect new knowledge about cancer biology.

DNA Gene List: Entire Coding Sequence for the Detection of Base Substitutions, Insertion/Deletions, and Copy Number Alterations

ABL1

ARAF

ABL2

ARFRP1

ACVR1B

ARID1A

AKT1

ARID1B

AKT2

ARID2

AKT3

ASXL1

ALK

ATM

AMER1 (FAM123B)

ATR

APC

ATRX

AR

AURKA

AURKB AXIN1 AXL BAP1 BARD1 BCL2 BCL2L1 BCL2L2 BCL6 BCOR

BCORL1 BLM BRAF BRCA1 BRCA2 BRD4 BRIP1 BTG1 BTK C11orf30 (EMSY)

CARD11 CBFB CBL CCND1 CCND2 CCND3 CCNE1 CD274 CD79A CD79B

CDC73 CDH1 CDK12 CDK4 CDK6 CDK8 CDKN1A CDKN1B CDKN2A CDKN2B

CDKN2C CEBPA CHD2 CHD4 CHEK1 CHEK2 CIC CREBBP CRKL CRLF2

CSF1R CTCF CTNNA1 CTNNB1 CUL3 CYLD DAXX DDR2 DICER1 DNMT3A

DOT1L EGFR EP300 EPHA3 EPHA5 EPHA7 EPHB1 ERBB2 ERBB3 ERBB4

ERG ERRFI1 ESR1 EZH2 FAM46C FANCA FANCC FANCD2 FANCE FANCF

FANCG FANCL FAS FAT1 FBXW7 FGF10 FGF14 FGF19 FGF23 FGF3

FGF4 FGF6 FGFR1 FGFR2 FGFR3 FGFR4 FH FLCN FLT1 FLT3

FLT4 FOXL2 FOXP1 FRS2 FUBP1 GABRA6 GATA1 GATA2 GATA3 GATA4

GATA6 GID4 (C17orf39) GLI1 GNA11 GNA13 GNAQ GNAS GPR124 GRIN2A GRM3

GSK3B H3F3A HGF HNF1A HRAS HSD3B1 HSP90AA1 IDH1 IDH2 IGF1R

IGF2 IKBKE IKZF1 IL7R INHBA INPP4B IRF2 IRF4 IRS2 JAK1

JAK2 JAK3 JUN KAT6A (MYST3) KDM5A KDM5C KDM6A KDR KEAP1 KEL

KIT KLHL6 KMT2A (MLL) KMT2C (MLL3) KMT2D (MLL2) KRAS LMO1 LRP1B LYN LZTR1

MAGI2 MAP2K1 MAP2K2 MAP2K4 MAP3K1 MCL1 MDM2 MDM4 MED12 MEF2B

MEN1 MET MITF MLH1 MPL MRE11A MSH2 MSH6 MTOR MUTYH

MYC MYCL (MYCL1) MYCN MYD88 NF1 NF2 NFE2L2 NFKBIA NKX2-1 NOTCH1

NOTCH2 NOTCH3 NPM1 NRAS NSD1 NTRK1 NTRK2 NTRK3 NUP93 PAK3

PALB2 PARK2 PAX5 PBRM1 PDCD1LG2 PDGFRA PDGFRB PDK1 PIK3C2B PIK3CA

PIK3CB PIK3CG PIK3R1 PIK3R2 PLCG2 PMS2 POLD1 POLE PPP2R1A PRDM1

PREX2 PRKAR1A PRKCI PRKDC PRSS8 PTCH1 PTEN PTPN11 QKI RAC1

RAD50 RAD51 RAF1 RANBP2 RARA RB1 RBM10 RET RICTOR RNF43

ROS1 RPTOR RUNX1 RUNX1T1 SDHA SDHB SDHC SDHD SETD2 SF3B1

SLIT2 SMAD2 SMAD3 SMAD4 SMARCA4 SMARCB1 SMO SNCAIP SOCS1 SOX10

SOX2 SOX9 SPEN SPOP SPTA1 SRC STAG2 STAT3 STAT4 STK11

SUFU SYK TAF1 TBX3 TERCTERT (promoter only ) TET2 TGFBR2 TNFAIP3 TNFRSF14

TOP1 TOP2A TP53 TSC1 TSC2 TSHR U2AF1 VEGFA VHL WISP3

WT1 XPO1 ZBTB2 ZNF217 ZNF703

DNA Gene List: For the Detection of Select Rearrangements ALK BCL2 BCR BRAF BRCA1 BRCA2 BRD4 EGFR ETV1 ETV4

ETV5 ETV6 FGFR1 FGFR2 FGFR3 KIT MSH2 MYB MYC NOTCH2

NTRK1 NTRK2 PDGFRA RAF1 RARA RET ROS1 TMPRSS2

Additional Assays: For the Detection of Select Cancer Biomarkers

Microsatellite status

Tumor Mutation Burden

SAMPLE






APPENDIX

FOUNDATIONONE PERFORMANCE SPECIFICATIONS

ACCURACY

Sensitivity: Base SubstitutionsAt Mutant Allele Frequency ≥10% >99.9% (CI* 99.6%-100%)

At Mutant Allele Frequency 5-10% 99.3% (CI* 98.3%-99.8%)

Sensitivity: Insertions/Deletions (1-40 bp)At Mutant Allele Frequency ≥20% 97.9% (CI* 92.5%-99.7%)

At Mutant Allele Frequency 10-20% 97.3% (CI* 90.5%-99.7%)

Sensitivity: Copy Number Alterations—Amplifications

(ploidy <4, Amplification with Copy Number ≥8)

At ≥30% tumor nuclei >99.0% (CI* 93.6%-100%)

At 20% tumor nuclei 92.6% (CI* 66.1%-99.8%)

Sensitivity: Copy Number Alterations—Deletions

(ploidy <4, Homozygous Deletions)

At ≥30% tumor nuclei 97.2% (CI* 85.5%-99.9%)

At 20% tumor nuclei 88.9% (CI* 51.8%-99.7%)

Sensitivity: Rearrangements (selected rearrangements in specimens with ≥20% tumor nuclei)**

>90.0% 1

>99.0% for ALK fusion2

(CI* 89.1%-100%)

Sensitivity: Microsatellite status At ≥20% tumor nuclei 97.0% (CI* 89.6%-99.6%)

Specificity: all variant types Positive Predictive Value (PPV) >99.0%

Specificity: Microsatellite status Positive Predictive Value (PPV) >95.0%

Accuracy: Tumor Mutation Burden At ≥20% tumor nuclei >90.0%

REPRODUCIBILITY (average concordance between replicates)

96.4% inter-batch precision

98.9% intra-batch precision

95.8% microsatellite status precision

96.4% tumor mutation burden precision

* 95% Confidence Interval

** Performance for gene fusions within targeted introns only. Sensitivity for gene fusions occurring outside targeted introns or in highly repetitive intronic sequence contexts is reduced. 1 Based on analysis of coverage and rearrangement structure in the COSMIC database for the solid tumor fusion genes where alteration prevalence could be established, complemented

by detection of exemplar rearrangements in cell line titration experiments. 2 Based on ALK rearrangement concordance analysis vs. a standard clinical FISH assay described in: Yelensky, R. et al. Analytical validation of solid tumor fusion gene detection in a

comprehensive NGS-based clinical cancer genomic test, In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA.

Philadelphia (PA): AACR; 2014. Abstract nr 4699

Assay specifications were determined for typical median exon coverage of approximately 500X. For additional information regarding the validation of FoundationOne, please refer to

the article, Frampton, GM. et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing, Nat Biotechnol (2013 Oct. 20).

Microsatellite status (a measure of microsatellite instability, or “MSI”) is determined by assessing indel characteristics at 114 homopolymer repeat loci in or near the targeted gene

regions of the FoundationOne test. Microsatellite status is assayed for all FoundationOne samples. MSI-High results are reported in all tumor types. In select tumor types, other

Microsatellite status results may be reported (MS-Stable, MSI-Ambiguous, MSI-Unknown) when relevant. Microsatellite status result may be reported as "Unknown" if the sample is

not of sufficient quality to confidently determine Microsatellite status.

Tumor Mutation Burden (TMB) is determined by measuring the number of somatic mutations occurring in sequenced genes on the FoundationOne and FoundationOne Heme tests and

extrapolating to the genome as a whole. TMB is assayed for all FoundationOne and FoundationOne Heme samples. TMB-High results are reported in all tumor types. In select tumor

types, other TMB results may be reported (TMB-Intermediate, TMB-Low, TMB-Unknown) when relevant. TMB results are determined as follows: TMB-High corresponds to greater than

or equal to 20 mutations per megabase (Muts/Mb); TMB-Intermediate corresponds to 6-19 Muts/Mb; TMB-Low corresponds to less than or equal to 5 Muts/Mb. Tumor Mutation

Burden may be reported as "Unknown" if the sample is not of sufficient quality to confidently determine Tumor Mutation Burden.

For additional information specific to the performance of this specimen, please contact Foundation Medicine, Inc. at 1-888-988-3639. SAMPLE






APPENDIX

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ABOUT FOUNDATIONONE™

FoundationOne™: FoundationOne was developed and its performance characteristics determined by Foundation Medicine, Inc. (Foundation Medicine). FoundationOne has not been cleared or approved by the United States Food and Drug Administration (FDA). The FDA has determined that such clearance or approval is not necessary. FoundationOne may be used for clinical purposes and should not be regarded as purely investigational or for research only. Foundation Medicine’s clinical reference laboratory is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) as qualified to perform high-complexity clinical testing.

Diagnostic Significance: FoundationOne identifies alterations to select cancer-associated genes or portions of genes (biomarkers). In some cases, the Test Report also highlights selected negative test results regarding biomarkers of clinical significance.

Qualified Alteration Calls (Equivocal and Subclonal): An alteration denoted as “amplification – equivocal” implies that the FoundationOne assay data provide some, but not unambiguous, evidence that the copy number of a gene exceeds the threshold for identifying copy number amplification. The threshold used in FoundationOne for identifying a copy number amplification is five (5) for ERBB2 and six (6) for all other genes. Conversely, an alteration denoted as “loss – equivocal” implies that the FoundationOne assay data provide some, but not unambiguous, evidence for homozygous deletion of the gene in question. An alteration denoted as “subclonal” is one that the FoundationOne analytical methodology has identified as being present in <10% of the assayed tumor DNA.

The Report incorporates analyses of peer-reviewed studies and other publicly available information identified by Foundation Medicine; these analyses and information may include associations between a molecular alteration (or lack of alteration) and one or more drugs with potential clinical benefit (or potential lack of clinical benefit), including drug candidates that are being studied in clinical research.

NOTE: A finding of biomarker alteration does not necessarily indicate pharmacologic effectiveness (or lack thereof) of any drug or treatment regimen; a finding of no biomarker alteration does not necessarily indicate lack of pharmacologic effectiveness (or effectiveness) of any drug or treatment regimen.

Alterations and Drugs Not Presented in Ranked Order: In this Report, neither any biomarker alteration, nor any drug associated with potential clinical benefit (or potential lack of clinical benefit), are ranked in order of potential or predicted efficacy.

Level of Evidence Not Provided: Drugs with potential clinical benefit (or potential lack of clinical benefit) are not evaluated for source or level of published evidence.

No Guarantee of Clinical Benefit: This Report makes no promises or guarantees that a particular drug will be effective in the treatment of disease in any patient. This Report also makes no promises or guarantees that a drug with potential lack of clinical benefit will in fact provide no clinical benefit.

No Guarantee of Reimbursement: Foundation Medicine makes no promises or guarantees that a healthcare provider, insurer or other third party payor, whether private or governmental, will reimburse a patient for the cost of FoundationOne.

Treatment Decisions are Responsibility of Physician: Drugs referenced in this Report may not be suitable for a particular patient. The selection of any, all or none of the drugs associated with potential clinical benefit (or potential lack of clinical benefit) resides entirely within the discretion of the treating physician. Indeed, the information in this Report must be considered in conjunction with all other relevant information regarding a particular patient, before the patient’s treating physician recommends a course of treatment.

Decisions on patient care and treatment must be based on the independent medical judgment of the treating physician, taking into consideration all applicable information concerning the patient’s condition, such as patient and family history, physical examinations, information from other diagnostic tests, and patient preferences, in accordance with the standard of care in a given community. A treating physician’s decisions should not be based on a single test, such as this Test, or the information contained in this Report.

Certain sample or variant characteristics may result in reduced sensitivity. These include: subclonal alterations in heterogeneous samples, low sample quality or with homozygous losses of <3 exons; and deletions and insertions >40bp, or in repetitive/high homology sequences. FoundationOne is performed using DNA derived from tumor, and as such germline events may not be reported. The following targets typically have low coverage resulting in a reduction in sensitivity: SDHD exon 6 and TP53 exon 1.

FoundationOne complies with all European Union (EU) requirements of the IVD Directive 98/79EC. As such, the FoundationOne Assay has been registered for CE mark by our EU Authorized Representative, Qarad b.v.b.a, Cipalstraat 3, 2440 Geel, Belgium. SAMPLE

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