Companion Diagnostic (CDx) Associated Findings PIK3CA

PIK3CA E542K

PPAATIENTTIENT PHYPHYSICIANSICIAN SPECIMENSPECIMEN

DISEASE Breast carcinoma (NOS) NAME DATE OF BIRTH SEX MEDICAL RECORD #

ORDERING PHYSICIAN

MEDICAL FACILITY

ADDITIONAL RECIPIENT

MEDICAL FACILITY ID PATHOLOGIST

SPECIMEN SITE SPECIMEN ID SPECIMEN TYPE DATE OF COLLECTION SPECIMEN RECEIVED

Companion Diagnostic (CDx) Associated FindingsGENOMIC FINDINGS DETECTED FDFDAA-APPR-APPROOVED THERVED THERAPEUTIC OPAPEUTIC OPTIONSTIONS

Piqray® (Alpelisib)

For Microsatellite Instability (MSI) results, confirmatory testing using a validated orthogonal method should be performed.

OOTHER ALTHER ALTERATERATIONS & BIOMARKERS IDENTIFIEDTIONS & BIOMARKERS IDENTIFIED

Results reported in this section are not prescriptive or conclusive for labeled use of any specific therapeutic product. Seeprofessional services section for additional information.

MicrMicroossatatellitellite se sttatusatus MS-Stable §

TTumor Mutumor Mutational Burational Burdenden 5 Muts/Mb §

CDK4CDK4 amplification §

ESR1ESR1 Y537S

FFGFR2GFR2 amplification §

PPTENTEN T319fs*1TP53TP53 splice site 559+1G>A

§ Refer to appendix for limitation statements related to detection of any copy number alterations, gene rearrangements, BRCA1/2 alterations, LOH, MSI, or TMB results inthis section.

Please refer to appendix for Explanation of Clinical Significance Classification and for variants of unknown significance (VUS).

FoundationOne®CDx (F1CDx) is a next generation sequencing basedin vitro diagnostic device for detection of substitutions, insertionand deletion alterations (indels), and copy number alterations(CNAs) in 324 genes and select gene rearrangements, as well asgenomic signatures including microsatellite instability (MSI) andtumor mutational burden (TMB) using DNA isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue specimens. The test isintended as a companion diagnostic to identify patients who maybenefit from treatment with the targeted therapies listed in Table 1in accordance with the approved therapeutic product labeling.Additionally, F1CDx is intended to provide tumor mutation profilingto be used by qualified health care professionals in accordance withprofessional guidelines in oncology for patients with solid malignantneoplasms. Genomic findings other than those listed in Table 1 arenot prescriptive or conclusive for labeled use of any specifictherapeutic product.

The test is also used for detection of genomic loss of heterozygosity(LOH) from FFPE ovarian tumor tissue. Positive homologousrecombination deficiency (HRD) status (F1CDx HRD defined astBRCA-positive and/or LOH high) in ovarian cancer patients isassociated with improved progression-free survival (PFS) fromRubraca (rucaparib) maintenance therapy in accordance with theRUBRACA product label.

The F1CDx assay will be performed at Foundation Medicine, Inc.sites located in Cambridge, MA and Morrisville, NC.

TABLE 1: COMPANION DIAGNOSTIC INDICATIONS

INDICINDICAATIONTION BIOMARKERBIOMARKER THERAPTHERAPYY

Non-small cNon-small cellelllung canclung cancerer(NS(NSCLCLC)C)

EGFR exon 19 deletions and EGFR exon 21 L858R alterations Gilotrif® (Afatinib), Iressa® (Gefitinib), Tagrisso® (Osimertinib), or Tarceva® (Erlotinib)

EGFR exon 20 T790M alterations Tagrisso® (Osimertinib)

ALK rearrangements Alecensa® (Alectinib), Xalkori® (Crizotinib), or Zykadia® (Ceritinib)

BRAF V600E Tafinlar® (Dabrafenib) in combination with Mekinist® (Trametinib)

MelanomaMelanoma

BRAF V600E Tafinlar® (Dabrafenib) or Zelboraf® (Vemurafenib)

BRAF V600E and V600K Mekinist® (Trametinib) or Cotellic® (Cobimetinib) in combination with Zelboraf®(Vemurafenib)

BrBreast canceast cancerer

ERBB2 (HER2) amplification Herceptin® (Trastuzumab), Kadcyla® (Ado-trastuzumab emtansine), or Perjeta®(Pertuzumab)

PIK3CA C420R, E542K, E545A, E545D [1635G>T only], E545G,E545K, Q546E, Q546R, H1047L, H1047R, and H1047Y alterations Piqray® (Alpelisib)

CColorolorectalectalcanccancerer

KRAS wild-type (absence of mutations in codons 12 and 13) Erbitux® (Cetuximab)

KRAS wild-type (absence of mutations in exons 2, 3, and 4) andNRAS wild type (absence of mutations in exons 2, 3, and 4) Vectibix® (Panitumumab)

OvOvarianariancanccancerer BRCA1/2 alterations Lynparza® (Olaparib) or Rubraca® (Rucaparib)

PATIENT TUMOR TYPEBreast carcinoma (NOS)

REPORT DATE

ORDERED TEST #

ABOUT THE TESABOUT THE TESTT FoundationOne®CDx is the first FDA-approved broad companion diagnostic for solid tumors.

Electronically signed by Matthew Hiemenz, M.D. | Julia Elvin, M.D., Ph.D., Laboratory Director CLIA: 22D2027531Shakti Ramkissoon, M.D., Ph.D., M.M. Sc, Laboratory Director CLIA: 34D2044309 Foundation Medicine, Inc. | 1.888.988.3639

Sample PSample Prrepareparaation:tion: 150 Second St., 1st Floor, Cambridge, MA 02141 ·· CLIA: 22D2027531Sample AnalySample Analysis:sis: 150 Second St., 1st Floor, Cambridge, MA 02141 ·· CLIA: 22D2027531

PPoosstt-Sequencing Analy-Sequencing Analysis:sis: 150 Second St., 1st Floor. Cambridge, MA 02141 ·· CLIA: 22D2027531

FDA APPROVED CLAIMS - PAGE 1 of 1

SAMPLE

jrioles

IU_Claims_Stamp

Interpretive content on this page and subsequentpages is provided as a professional service, and isnot reviewed or approved by the FDA.

PPAATIENTTIENT

DISEASE Breast carcinoma (NOS)

NAME

DATE OF BIRTH

SEX

MEDICAL RECORD #

PHYPHYSICIANSICIAN

ORDERING PHYSICIAN

MEDICAL FACILITY

ADDITIONAL RECIPIENT

MEDICAL FACILITY ID

PATHOLOGIST

SPESPECIMENCIMEN

SPECIMEN SITE

SPECIMEN ID

SPECIMEN TYPE

DATE OF COLLECTION

SPECIMEN RECEIVED

Biomarker FindingsMicrMicrosatosatellitellite statuse status -- MS-StableTTumor Mutational Burumor Mutational Burdenden -- 5 Muts/Mb

Genomic FindingsFor a complete list of the genes assayed, please refer to the Appendix.

CDK4CDK4 amplificationamplificationESR1ESR1 Y53Y537S7SPIK3CPIK3CAA E542KE542KPPTENTEN T319fT319fs*1s*1FFGFR2GFR2 amplificationamplificationTP53TP53 splicsplice site site 55e 559+1G>A9+1G>A

33 Disease rDisease releelevvant gant genes with no renes with no reporeportable alttable altererations:ations: BRBRCCA1, BRA1, BRCCA2,A2,ERBB2ERBB2

88 TTherherapies with Capies with Clinical Benefitlinical Benefit

33 TTherherapies with Lack of Rapies with Lack of Responseesponse

3535 CClinical Tlinical Trialsrials

ABOUT THE TESABOUT THE TESTT FoundationOne®CDx is the first and only FDA-Approvedcomprehensive companion diagnostic for all solid tumors.

BIOMARKER FINDINGSBIOMARKER FINDINGS

Microsatellite status - MS-Stable No therNo therapies or clinical trials.apies or clinical trials. see Biomarker Findings section

Tumor Mutational Burden - 5 Muts/Mb No therNo therapies or clinical trials.apies or clinical trials. see Biomarker Findings section

AACTIONABILITYCTIONABILITY

PATIENT TUMOR TYPE

Breast carcinoma (NOS) COUNTRY CODE

REPORT DATE ORDERED TEST #

The content provided as a professional service by Foundation Medicine, Inc., has not been reviewed or approved by the FDA.




PROFESSIONAL SERVICES - PAGE 1 of 26

SAMPLE

GENOMIC FINDINGSGENOMIC FINDINGS

CDK4 - amplification

10 T10 Trialsrials see psee p.. 1717

Palbociclib 1

Ribociclib 1

none

ESR1 - Y537S


Fulvestrant 1

Anastrozole1

Exemestane1

Letrozole1

none

PIK3CA - E542K


Alpelisib 1

Everolimus 2A

Temsirolimus

PTEN - T319fs*1


Everolimus 2A Temsirolimus

FGFR2 - amplification


none Erdafitinib

Pazopanib

1. Patient may be resistant toindicated therapy

GENOMIC FINDINGS WITH NO REPORTABLE THERAPEUTIC OR CLINICAL TRIAL OPTIONS

For more information regarding biological and clinical significance, including prognostic, diagnostic, germline, and potential chemosensitivityimplications, see the Genomic Findings section.

NONOTETE Genomic alterations detected may be associated with activity of certain FDA-approved drugs; however, the agents listed in this report may have varied clinical 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.

THERAPIES WITH CLINICAL BENEFITTHERAPIES WITH CLINICAL BENEFIT(IN P(IN PAATIENT'S TUTIENT'S TUMOR TYPE)MOR TYPE)

THERAPIES WITH CLINICAL BENEFITTHERAPIES WITH CLINICAL BENEFIT(IN O(IN OTHER TUTHER TUMOR TYPE)MOR TYPE)

NCCN category

p. 8TP53 -TP53 - splice site 559+1G>A

PATIENT TUMOR TYPE

Breast carcinoma (NOS) COUNTRY CODE

REPORT DATE ORDERED TEST #






SAMPLE

BIOMARKERBIOMARKER

Microsatellite statusRESULRESULTTMS-Stable

POPOTENTIAL TREATENTIAL TREATMENT STMENT STRATRATEGIESTEGIESOn the basis of clinical evidence, MSS tumors aresignificantly less likely than MSI-H tumors torespond to anti-PD-1 immune checkpointinhibitors1-3, including approved therapiesnivolumab and pembrolizumab4. In a retrospectiveanalysis of 361 patients with solid tumors treated

with pembrolizumab, 3% were MSI-H andexperienced a significantly higher ORR comparedwith non-MSI-H cases (70% vs. 12%, p=0.001)5.

FREQUENCFREQUENCY & PROGNOY & PROGNOSISSISNo MSI was observed in two large scale analysesof breast cancer samples6-7. However, in Lynchsyndrome-related breast cancer, MSI has beenreported in 51-85% of cases8-13. A prospectivestudy observed increased MSI followingchemotherapy treatment, and MSI is associatedwith incidence of secondary tumors14.

FINDING SUMMARFINDING SUMMARYYMicrosatellite instability (MSI) is a condition of

genetic hypermutability that generates excessiveamounts of short insertion/deletion mutations inthe genome; it generally occurs at microsatelliteDNA sequences and is caused by a deficiency inDNA mismatch repair (MMR) in the tumor15.Defective MMR and consequent MSI occur as aresult of genetic or epigenetic inactivation of oneof the MMR pathway proteins, primarily MLH1,MSH2, MSH6, or PMS215-17. This sample ismicrosatellite-stable (MSS), equivalent to theclinical definition of an MSS tumor: one withmutations in none of the tested microsatellitemarkers18-20. MSS status indicates MMRproficiency and typically correlates with intactexpression of all MMR family proteins15,17,19-20.

BIOMARKERBIOMARKER

Tumor MutationalBurdenRESULRESULTT5 Muts/Mb

POPOTENTIAL TREATENTIAL TREATMENT STMENT STRATRATEGIESTEGIESOn the basis of clinical evidence in solid tumors,increased TMB may be associated with greatersensitivity to immunotherapeutic agents,including anti-PD-L121-23 and anti-PD-1therapies21-24. Higher TMB has corresponded withincreased ORR and OS from treatment withimmune checkpoint inhibitors in pan-tumorstudies21-24. Analyses across several solid tumortypes have identified that patients with higherTMBs (≥16-20 Muts/Mb) achieved greater clinicalbenefit using PD-1/PD-L1 monotherapy,compared with patients treated withchemotherapy25 or those with lower TMBs22.Additionally, higher TMB is significantlyassociated with improved OS with immunecheckpoint inhibitor treatment for patients withadvanced cancer across 9 solid tumor types21.

However, the KEYNOTE 158 trial foundsignificant improvement in ORR in a large cohortof patients with a TMB of ≥10 Muts/Mbcompared with those with TMBs <10 acrossmultiple solid tumor types, with similar findingsobserved in the KEYNOTE 028 and 012 trials24.Together, these studies suggest that patients withTMB ≥10 Muts/Mb may derive clinical benefitfrom PD-1/PD-L1 inhibitors.

FREQUENCFREQUENCY & PROGNOY & PROGNOSISSISBreast carcinoma harbors a median TMB of 3.8muts/Mb, and 3.1% of cases have high TMB (>20muts/Mb)26. The Breast Invasive Carcinoma TCGAanalysis reported an average (non-silent) mutationload of 0.84 muts/Mb for luminal A tumors, 1.38muts/Mb for luminal B tumors, 2.05 muts/Mb forHER2-enriched tumors, and 1.68 muts/Mb forbasal-like tumors27. In breast cancer, TMB issignificantly higher in recurrent versus primarytumors and CDH1-mutated versus CDH1-wildtypetumors28. Higher frequencies of TMB high(>20Mut/mb) have also been reported inmetastatic invasive lobular carcinomas (8.9%)compared to metastatic invasive ductal carcinomas(1.6%)28. In estrogen receptor-positive breastcancer, increased mutation load measured intissue (> mean of 1.25 muts/Mb) associated with

shorter OS (HR of 2.02) in an analysis of theTCGA data29. In another study, the number ofmutated genes associated with higher tumorgrade30. Although the number of mutated genesdid not correlate with OS by multivariate analysis,cases with 22 or more mutated genes hadsignificantly worse OS than cases with fewer than22 mutated genes (HR of 4.6)30.

FINDING SUMMARFINDING SUMMARYYTumor mutational burden (TMB, also known asmutation load) is a measure of the number ofsomatic protein-coding base substitution andinsertion/deletion mutations occurring in a tumorspecimen. TMB is affected by a variety of causes,including exposure to mutagens such asultraviolet light in melanoma31-32 and cigarettesmoke in lung cancer33-34, mutations in theproofreading domains of DNA polymerasesencoded by the POLE and POLD1 genes35-39, andmicrosatellite instability (MSI)35,38-39. This sampleharbors a TMB level associated with lower rates ofclinical benefit from treatment with PD-1- or PD-L1-targeting immune checkpoint inhibitorscompared with patients with tumors harboringhigher TMB levels, based on several studies inmultiple solid tumor types22-23.

ORDERED TEST #

PATIENT TUMOR TYPE

Breast carcinoma (NOS)REPORT DATE

BIOMARKER FINDINGBIOMARKER FINDINGSS






SAMPLE

GENEGENE

CDK4ALALTERATERATIONTIONamplification

POPOTENTIAL TREATENTIAL TREATMENT STMENT STRATRATEGIESTEGIESCDK4 amplification or activation may predictsensitivity to CDK4/6 inhibitors such asabemaciclib, palbociclib, and ribociclib40-43.Clinical benefit has been reported for patientswith CDK4-amplified solid tumors in response to

treatment with palbociclib40,44 and ribociclib45.On the basis of a Phase 1b study, PTEN loss ofexpression may be associated with resistance tocombination therapy with CDK4/6 inhibitorssuch as ribociclib and aromatase inhibitors suchas letrozole46.

FREQUENCFREQUENCY & PROGNOY & PROGNOSISSISPutative high-level amplification of CDK4 occursin 2% of breast invasive carcinoma cases27. CDK4protein expression has been detected in 70% ofbreast carcinomas in one study and did notcorrelate with patient survival47.

FINDING SUMMARFINDING SUMMARYYCDK4 encodes the cyclin-dependent kinase 4,which regulates the cell cycle, senescence, andapoptosis48. CDK4 and its functional homologCDK6 are activated by D-type cyclins and promotecell cycle progression by inactivating the tumorsuppressor Rb49-50. Amplification of thechromosomal region that includes CDK4 has beenreported in multiple cancer types, including lungcancer, glioblastoma, and liposarcoma, and hasbeen associated with overexpression of CDK4protein40,51-57.

GENEGENE

ESR1ALALTERATERATIONTIONY537S

TRANSTRANSCRIPT NUCRIPT NUMBERMBERNM_000125

CCODING SEODING SEQUENCE EFFEQUENCE EFFECTCT1610A>C

POPOTENTIAL TREATENTIAL TREATMENT STMENT STRATRATEGIESTEGIESTherapies that directly target ER-alpha, such asselective ER modulators (SERMs) and the selectiveER degrader (SERD) fulvestrant, as well asaromatase inhibitors (AIs) that inhibit estrogenproduction, are approved to treat ER-positive(ER+) and/or hormone receptor-positive (HR+)breast cancer (NCCN Guidelines v1.2019). AItreatment has also been reported to provideclinical benefit in a subset of HR+ gynecologicmalignancies58-62. Clinical data suggest that ESR1mutations may confer sensitivity to the first-generation SERD fulvestrant in breast cancer63-64.A retrospective analysis of ESR1 mutations ingynecologic malignancies reported clinical benefitfor patients with ESR1 mutations and fulvestranttreatment as a monotherapy or in combination,including 1 patient with peritoneal serouscarcinoma and an ESR1 Y537N mutation whoexperienced prolonged clinical benefit (48+months) from fulvestrant monotherapy65. Thetherapeutic utility of SERMs, includingtoremifene66, raloxifene67, and tamoxifen68, forESR1 mutation-positive breast cancer is unclear.Although ESR1 mutations have been reported in

patients who progressed on tamoxifen66,69-70, aretrospective analysis of primary breast tumorsreported that patients with non-emergent ESR1mutations experienced improved (Y537N) orsimilar (Y537S or D538G) median progression-freesurvival (PFS) relative to those lacking ESR1mutation68. Preclinical studies suggest that certainESR1 mutations (Y537S and D538G) may be lesssensitive to clinical concentrations ofantiestrogens, and higher doses or more potentantiestrogens may be required to inhibit tumorswith these mutations68,71-73. Clinical data suggestthat ESR1 mutations may confer sensitivity to thefirst-generation SERD fulvestrant63-64. In a studyof patients with breast cancer treated withfulvestrant as monotherapy or in combinationwith palbociclib, ESR1 Y537S was the mostcommonly acquired mutation, suggesting thatY537S may decrease fulvestrant sensitivity74.Next-generation SERDs, including AZD9496,elacestrant, GDC-0927, and LSZ102, are in clinicaldevelopment. A Phase 1 study of elacestrant forthe treatment of patients with ER+, HER2– breastcancer reported 1 PR, 1 CR, and a mediantreatment duration of 18 weeks; 9/16 had at leastone ESR1 mutation, and 6/16 were previouslytreated with fulvestrant75. In another Phase 1study, elacestrant achieved a median PFS of 4.5months and 5 PRs for heavily pretreated patientswith ER+, HER2– breast cancer, 4 of whomharbored ESR1 mutations76. A Phase 1 study ofGDC-0927 for the treatment of ER+, HER2–metastatic breast cancer reported an unconfirmedORR of 13% (3/24), 2 of which harbored an ESR1mutation; a patient with ESR1 D538G had SD onstudy for over 490 days77. Preliminary data from aPhase 1 study of LSZ102 for the treatment of HR+

breast cancer observed SD for 31% (14/45) ofcases78.

FREQUENCFREQUENCY & PROGNOY & PROGNOSISSISThe most frequent ESR1 mutations includeD538G, Y537S, Y537N, and E380Q, withconcurrent ESR1 mutations detected in up to 40%of ER+ breast cancer samples harboring an ESR1alteration64,71,79-80. In the TCGA breast invasivecarcinoma datasets, ESR1 amplification wasobserved in 2 to 3% of cases and ESR1 mutationwas observed in fewer than 1% of cases27,81. Rarelyidentified in patients with localized disease, ESR1mutations are more frequently detected inmetastatic breast cancers (11–54%)70,79,82-83,predominantly during progression on hormonaltherapy63,69,79,82,84-87. ESR1 mutation is associatedwith shorter median PFS and OS in patients withadvanced breast cancer63,87. The prevalence,significance, and correlation with proteinexpression of ESR1 amplification in breast cancerremains controversial88-96.

FINDING SUMMARFINDING SUMMARYYESR1 encodes estrogen receptor alpha (ER-alpha),one of the major estrogen receptor isoforms inhumans. Along with co-activator proteins, the ERcomplex promotes transcription of genes involvedin cell cycle progression and survival97.Alterations that occur within the ligand bindingdomain of ER-alpha, as seen here, result in ligand-independent activation82,84-85,98-104. Emergingclinical63-64,66,69,82,87,105 and preclinical64,71,84-85

evidence suggests that these alterations conferresistance to aromatase inhibitors includinganastrozole, letrozole, and exemestane.

ORDERED TEST #

PATIENT TUMOR TYPE


GENOMIC FINDINGGENOMIC FINDINGSS






SAMPLE

GENEGENE

PIK3CAALALTERATERATIONTIONE542K

TRANSTRANSCRIPT NUCRIPT NUMBERMBERNM_006218

CCODING SEODING SEQUENCE EFFEQUENCE EFFECTCT1624G>A

POPOTENTIAL TREATENTIAL TREATMENT STMENT STRATRATEGIESTEGIESClinical and preclinical data in various tumortypes indicate that PIK3CA activating alterationsmay predict sensitivity to therapies targeting PI3Kor AKT106-107. On the basis of clinical benefit forpatients with PIK3CA mutations and preclinicalevidence, PIK3CA-mutated tumors may alsorespond to mTOR inhibitors, including everolimusand temsirolimus108-113. In a Phase 1 trial of thedual PI3K/mTOR kinase inhibitor apitolisib, 79%(11/14) of patients with PIK3CA-mutatedadvanced solid tumors experienced disease controlat the recommended Phase 2 dose (3/14 PRs, 8/14SDs)114. The addition of everolimus to exemestanefor the treatment of hormone-receptor-positive(HR+)/HER2-negative advanced breast cancer hasshown clinical benefit regardless of PIK3CAstatus115. In the BELLE-2 trial for patients withendocrine-resistant HR+ breast cancer, thecombination of the pan-PI3K inhibitor buparlisibwith fulvestrant resulted in increased PFS (7.0 vs.3.2 months) and ORR (18% vs. 4%) compared toplacebo with fulvestrant in patients with PIK3CAmutation; no significant improvement in PFS orORR was observed in patients without PIK3CAmutation116. The pan-PI3K inhibitor buparlisib hasshown limited activity as monotherapy againstPIK3CA-mutated tumors117-120. PI3K-alpha-

selective inhibitors such as alpelisib or PI3K-beta-sparing inhibitors such as taselisib may havebigger therapeutic windows than pan-PI3Kinhibitors107. In PIK3CA-mutated advanced solidtumors, alpelisib and taselisib have achieved lowORRs (0% [0/55] to 6% [7/111]) but a high DCR(55% [36/55] to 58% [64/111])121. In the Phase 3SOLAR-1 study, the addition of alpelisib tofulvestrant improved PFS (11.0 vs. 5.7 months,HR=0.65) and ORR (26.6 vs. 12.8%) in PIK3CA-mutated HR+/HER2– breast cancer comparedwith placebo with fulvestrant106. Combination ofalpelisib with letrozole in advanced HR+/HER2–breast cancer achieved an ORR of 25% (4/16) and aDCR of 62% (10/16) in patients with PIK3CA-mutated tumors and an ORR of 10% (1/10) and aDCR of 70% (7/10) in patients with PIK3CA-wild-type tumors122. In the Phase 3 SANDPIPER study,the addition of taselisib to fulvestrant improvedPFS (7.4 vs. 5.4 months, HR=0.70) and ORR (27.3vs. 11.9%) in PIK3CA-mutated HR+/HER2– breastcancer compared with placebo with fulvestrant123;additionally, patients with multiple PIK3CAmutations achieved a higher ORR followingtreatment with taselisib (30.2%, n=43) ascompared with those treated with placebo (8.7%,n=23) or with patients with single PIK3CA-mutated tumors treated with either taselisib(18.1%, n=193) or placebo (10.0%, n=80)124. AKTinhibitors ipatasertib and capivasertib have alsobeen tested in breast cancer. Two Phase 2 studieshave reported improved PFS from the addition ofeither ipatasertib (9.0 vs. 4.9 months, HR = 0.44)or capivasertib (9.3 vs. 3.7 months, HR = 0.30) topaclitaxel in metastatic triple-negative breastcancer harboring PIK3CA/AKT1/PTENalterations, compared with paclitaxel andplacebo125. Responses to capivasertib were alsoreported in 20% (3/15) of patients with PIK3CA-mutated breast cancer in an earlier study126.

However, a Phase 1 trial reported no PFS benefitfor patients with PIK3CA-mutated, ER+/HER2-metastatic breast cancer from the addition ofcapivasertib to paclitaxel compared with paclitaxelplus placebo (10.9 vs. 10.8 months)127. Activatingmutations in PIK3CA may confer resistance toHER2-targeted therapies; combined inhibition ofHER2 and the PI3K pathway may be required inHER2-positive tumors with PIK3CAmutation128-132. In the context of concurrentPIK3CA mutation, PTEN loss or mutation maypredict resistance to PI3K-alpha-specificinhibitors107,133-134.

FREQUENCFREQUENCY & PROGNOY & PROGNOSISSISMutations in PIK3CA have been reported in25-40% of breast cancer cases27,135-138. Althoughdouble PIK3CA mutations are frequently observedin hormone-receptor-positive, HER2-negativebreast cancers, as compared with other receptorsubtypes (15.4% vs. 5.4%, p=0.004), this did notimpact invasive disease-free survival or OS forpatients when compared with single PIK3CAmutations by univariate and multivariate analysisin 1 retrospective study124. Mutations in codingexon 20 (H1047R) of PIK3CA have been associatedwith a better prognosis in breast carcinoma thanmutations occurring in coding exon 9 (E542K)139.

FINDING SUMMARFINDING SUMMARYYPIK3CA encodes p110-alpha, which is the catalyticsubunit of phosphatidylinositol 3-kinase (PI3K).The PI3K pathway is involved in cell signaling thatregulates a number of critical cellular functions,including cell growth, proliferation,differentiation, motility, and survival140-141.PIK3CA alterations that have been characterizedas activating, such as observed here, are predictedto be oncogenic142-160.

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GENOMIC FINDINGGENOMIC FINDINGSS






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Companion Diagnostic (CDx) Associated Findings PIK3CA