210311 Wild Guided Report.Indd

Home , Abetimus, Afelimomab, Azimilide, Benzquinamide, Bleselumab, Dexloxiglumide

********** MammakarzinomMammakarzinom DR. SENCKENBERGISCHESDR. SENCKENBERGISCHES PatientPatient name name DiagnosisDiagnosis R PATHOLOGIER PATHOLOGIE PatientPatient 1D 1D Testl234Testl234 ICD-10-CMICD-10-CM code code ;;:;;;:; spsp CaseCase 1D 1D EU001930EU001930 MeSHMeSH ID/term ID/term D001943D001943 (Breast (Breast Neoplasms) Neoplasms) W1ldlabW1ldlab DateDate of birth of birth AdditionalAdditional MeSH MeSH IDs IDs - -

SexSex FemaleFemale SampleSample type type FFPEFFPE LabtestLabtest VCF-completeVCF-complete import import (paired) (paired) GeneralGeneral dataset dataset 1D 1D105685598965 105685598965 EthnicityEthnicity EUR EUR TumorTumor cellularity cellularity 100% 100% OrganizationalOrganizational unit unit SIPV2TESTSIPV2TEST CVICVI dataset dataset 1D 1D 105685598965105685598965 CountryCountry DE DE SoftwareSoftwareversionversion 4.3.34.3.3

MutationalMutational status status of commonly of commonly mutated mutated genes genes in the in the patient patient disease disease ATMATM BRCAlBRCAl BRCA2BRCA2 CDK4CDK4 CDKN2ACDKN2A CHEK2CHEK2 EGFREGFR ERBB2ERBB2 ESRlESRl PALB2PALB2 PIK3CAPIK3CA notnot notnot notnot notnot notnot notnot notnot notnot notnot notnot 1 SNV1 SNV identifiedidentified identifiedidentified identifiedidentified identifiedidentified identifiedidentified identifiedidentified identifiedidentified identifiedidentified identifiedidentified identifiedidentified

PTENPTEN TP53TP53 notnot notnot identifiedidentified identifiedidentified

SUMMARYSUMMARY

OverviewOverview of potential of potential treatment treatment impacts impacts OverviewOverview of prognostic of prognostic and and diagnostic diagnostic findings findings ClinicalClinical trials trials found found 3 3Effective Effective 1 1lneffective lneffective o Safetyo Safety O OPrognostic Prognostic O ODiagnostic Diagnostic 6 6Trials Trials

VAF/CopyVAF/Copy PotentialPotential impact impact TreatmentTreatment DrugDrug approval approval BiomarkerBiomarker BiomarkerBiomarker score score TrialsTrials NumberNumber

AlpelisibAlpelisib ApprovedApproved PIK3CAPIK3CA ClinicallyClinically EffectiveEffective 66.67%66.67% 4 4 FulvestrantFulvestrant ApprovedApproved p.E545Ap.E545A (SNV) (SNV) r;,r;, Approved Approved -- �� PIK3CAPIK3CA EffectiveEffective EverolimusEverolimus Approved*Approved* 66.67%66.67% 2)2) Preclinical Preclinical 2 2 p.E545Ap.E545A (SNV) (SNV) -- PIK3CAPIK3CA EffectiveEffective SirolimusSirolimus OtherOther 66.67%66.67% 2)2) Preclinical Preclinical 0 0 p.E545Ap.E545A (SNV) (SNV) -- PIK3CAPIK3CA lneffectivelneffective TrastuzumabTrastuzumab Approved*Approved* 66.67%66.67% 4)4)ClinicalClinical p.E545Ap.E545A (SNV) (SNV) 1 1 �� * the* the drug drug is approved is approved for forthe the cancer cancer type type but but either either none none of theof the currently currently approved approved biomarkers biomarkers for forthis- this drug- drug were were identified, identified, or anor anapproved approved resistance resistance biomarkerbiomarker for forthe the drug drug was was identified identified in this in this patient. patient. Therefore, Therefore, the the drug drug labe[ labe[ may may not not cover cover the the analyzed analyzed patient; patient; VAF VAF = Variant = Variant allele allele frequency frequency BiomarkerBiomarker score: score: AMP AMP score score and and CVI CVI score. score. Clinically Clinically approved: approved: Approved Approved biomarker biomarker (by (bythe the FDA, FDA, EMA, EMA, or NCCN)or NCCN) to predictto predict a specific a specific effect effectin thein the patient's patient's disease.disease. Clinical: Clinical: Not Not yet yetapproved approved biomarker biomarker for forthe the patient's patient's disease. disease. Observed Observed in clinical in clinical studies studies as aas potential a potential biomarker biomarker to predictto predict a specific a specific effect effectof theof the drug.drug. Preclinical: Preclinical: This This biomarker biomarker has has not not yet yetbeen been observed/tested observed/tested in patients in patients to predict to predict a specific a specific effect effectof theof the drug. drug. lt is lt supported is supported by preclinicalby preclinical evidence evidence or or translationaltranslational data. data. YouYou can can find find more more details details on theon the biomarker biomarkerscorescore (AMP (AMP and and CVI CVI score) score) in the in the glossary. glossary.

TheodorTheodor Stern Stern Kai 7, Kai 7, SignedSigned by: by: MolecularMolecular Health Health GmbH GmbH 6059060590 Frankfurt Frankfurt ReportReportdate: date: 08 Mar 08 2021 Mar 202116:5816:58 (UTC+Ol:00) (UTC+Ol:00) Kurfürsten-AnlageKurfürsten-Anlage 21, 21, ReportReportversion: version: 3 3 6911569115 Heidelberg Heidelberg OrderOrder date: date: 08 Mar 08 2021 Mar 2021

Page Page1 of 13 1 of 13 Patient name ***** Diagnosis Mammakarzinom DR. SENCKENBERGISCHESDR. SENCKENBERGISCHES Patient name***** Diagnosis Mammakarzinom R PATHOLOGIER PATHOLOGIE PatientPatient 1D 1D Testl234Testl234 ICD-10-CMICD-10-CM code code ;;:;;;:; spsp CaseCase 1D 1D EU001930EU001930 MeSHMeSH ID/term ID/term D001943D001943 (Breast (Breast Neoplasms) Neoplasms) W1ldlabW1ldlab DateDate of birth of birth AdditionalAdditional MeSH MeSH IDs IDs - -

Sex Female Sample type FFPE Labtest VCF-complete import (paired) General dataset 1D 105685598965 BIOMARKEREthnicity EUR DETAILS Tumor cellularity 100% Organizational unit SIPV2TEST CVI dataset 1D 105685598965 Country DE Software version 4.3.3

Mutational status of commonly mutated genes in the patient disease PIK3CA p.E545A (SNV) 1 ATM BRCAl BRCA2 CDK4 CDKN2A CHEK2 EGFR ERBB2 ESRl PALB2 PIK3CA not not not not not not not not not not 1 SNV ••identified identified identified identified identified identified identified identified identified identified PIK3CA is the catalytic subunit of the lipid phosphoinositide-3-kinase (Pl3K) that activates the Pl3K/AKT signaling pathway to promote cell proliferation and survival.PTEN This variantTP53 strongly activates the downstream pathway in preclinical settings. Alpelisib plus fulvestrant is indicated for this variant for the treatment of hormonenot receptor-positive,not H ER2-negative advanced breast cancer. The HER2-positive tumor of a patient with this variant was resistance to trastuzumab. Althoughidentified not specifically identified tested for this mutation, preclinical models with activating variants are sensitive to the mTOR inhibitors everolimus and sirolimus and have reduced sensitivity to trastuzumab. A [arger study showed that HER2-positive patients with an activating PIK3CA mutation had improved progression-free survival with the addition of everolimus to trastuzumab treatment. PubMedSUMMARY 1D 21358673,28382169,27091708,31091374,23092874 Overview of potential treatment impacts Overview of prognostic and diagnostic findings Clinical trials found 3 Effective 1 lneffective o Safety O Prognostic O Diagnostic 6 Trials Potential impact Treatment Drug approval Biomarker score

Clinically Effective Alpelisib + Fulvestrant Approved, ApprovedVAF/Copy Potential impact Treatment Drug approval Biomarker Biomarker score r;, ApprovedTrials Number - Effective EverolimusAlpelisib Approved Approved*PIK3CA Clinically2, Preclinical Effective 66.67% 4 Fulvestrant Approved p.E545A (SNV) r;, Approved -� Effective - 2' Preclinical Sirolimus OtherPIK3CA Effective Everolimus Approved* 66.67% 2) Preclinical 2 p.E545A (SNV) - lneffective Trastuzumab Approved* - Clinical PIK3CA Effective Sirolimus Other 66.67% • 2) Preclinical4, 0 p.E545A (SNV) � * the drug is approved for the cancer type but either none of the currently approved biomarkers for this drug were- identified, or an approved resistance biomarker for the drug was identified in this patient. Therefore, the drug labe[ may not cover the analyzed patient.- PIK3CA ) Clinical Biomarkerlneffective score: AMP score andTrastuzumab CVI score. Clinically Approved* approved: Approved biomarker (by the66.67% FDA, EMA, or NCCN) to predict1 a specific4 effectin the patient's p.E545A (SNV) � disease. Clinical: Not yet approved biomarker for the patient's disease. Observed in clinical studies as a potential biomarker to predict a specific effectof the drug.* the Preclinical: drug is approved This biomarker for the has cancer not yettype been but observed/testedeither none of the in patients currently to approved predict a specificbiomarkers effect forof thisthe- drug.drug ltwere is supported identified, by or preclinical an approved evidence resistance or translationalbiomarker data. for the drug was identified in this patient. Therefore, the drug labe[ may not cover the analyzed patient; VAF = Variant allele frequency YouBiomarker can find more score: details AMP on score the biomarker and CVI score.score Clinically (AMP and approved: CVI score) inApproved the glossary. biomarker (by the FDA, EMA, or NCCN) to predict a specific effectin the patient's disease. Clinical: Not yet approved biomarker for the patient's disease. Observed in clinical studies as a potential biomarker to predict a specific effectof the drug. Preclinical: This biomarker has not yet been observed/tested in patients to predict a specific effectof the drug. lt is supported by preclinical evidence or translational data. You can find more details on the biomarker score (AMP and CVI score) in the glossary.

Page Page2 of 13 1 of 13 PatientPatient name name ***** ***** DiagnosisDiagnosis MammakarzinomMammakarzinom • DR. SENCKENBERGISCHESDR. SENCKENBERGISCHES R PATHOLOGIER PATHOLOGIE PatientPatient 1D 1D Testl234Testl234 ICD-10-CMICD-10-CM code code ;;;;;;:; spsp CaseCase 1D 1D EU001930EU001930 MeSHMeSH ID/term ID/term D001943D001943 (Breast (Breast Neoplasms) Neoplasms) W1ldlabW1ldlab DateDate of birth of birth AdditionalAdditional MeSH MeSH IDs IDs - -

Sex Female Sample type FFPE Labtest VCF-complete import (paired) General dataset 1D 105685598965 Ethnicity EUR Tumor cellularity 100% Organizational unit SIPV2TEST CVI dataset 1D 105685598965 TREATMENT DETAILS Country DE Software version 4.3.3

PotentiallyMutational effective status of commonlytreatments mutated genes in the patient disease ATM BRCAl BRCA2 CDK4 CDKN2A CHEK2 EGFR ERBB2 ESRl PALB2 PIK3CA The drugs listed as drug-drug interactions may interact with elements of the treatment. Such interactions can negatively affectthe effectivenessand/or safety not not not not not not not not not not 1 SNV of this treatment. lt is recommended that current and future medications be carefully assessed against this list. lf necessary, appropriate changes can be identified identified identified identified identified identified identified identified identified identified considered in consultation with your pharmacist. As the DrugBank database and the MH Guide database are updated asynchronously, this list may not be complete. PTEN TP53 not not Alpelisibidentified identified Drug approval in patient disease: Approved Fulvestrant Drug approval in patient disease: Approved

AlpelisibSUMMARY is a phosphatidylinositol 3-kinase (Pl3K) inhibitor with potent antitumor activity. lt works by selectively inhibiting class I Pl3K pll0a [Al79203], which is the catalytic subunit of Pl3K, a lipid kinase that plays a role in various biological processes, including proliferation, survival, differentiation,and metabolism. Alpelisib was designed to target this enzyme that appears to be mutated at a rate of nearly 30% in human cancers, leading to hyperactivation.[AlOverview of potential79209] treatment impacts Overview of prognostic and diagnostic findings Clinical trials found There are several isoform-specific Pl3K inhibitors that are under clinical development or currently approved, such as [idelalisib] used for chronic lymphocytic 3 Effective 1 lneffective o Safety O Prognostic O Diagnostic 6 Trials leukemia (CLL).[Al 79209] Approved by the FDA in May 2019, alpelisib is the first approved Pl3K inhibitor indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer in combination with [fulvestrant] for postmenopausal women and male patients. To initiate alpelisib therapy, it is required that the presence of a PlK3CA mutation in the tissue VAF/Copy and/orPotential liquid biopsy impact sample collectionTreatment should be confirmedDrug approval via FDA-approved Biomarker diagnostic tests. Alpelisib is marketedBiomarker under score the trade name Piqray and isTrials available as oral tablets. Studies evaluating the therapeutic effectivenessof alpelisib in other cancers,Number such as ovarian cancer [Al79200] and colorectal cancer [Al79203], are under ongoing investigations. Alpelisib was granted FDA approvalAlpelisib on 24 May 2019.[L6652](DB12015)Approved PIK3CA Clinically Effective 66.67% Approved 4 Fulvestrant is a drug treatment ofFulvestrant hormone receptor Approved (HR)-positive metastaticp.E545A breast (SNV)cancer in post-menopausal women with diseaser;,� progression following anti-estrogen therapy. lt is an estrogen receptor antagonist with no agonist effects,which works both by down-regulating and by degrading the estrogen receptor. While it is used as monotherapy for the treatment of breast cancers, it is also used in combination with- [alpelisib] for the treatment of HR-positive, PIK3CA Effective Everolimus Approved* 66.67% 2) Preclinical 2 human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated,p.E545A advanced (SNV) or metastatic breast cancer(D600947) Detected variants supporting this treatment effect: PIK3CA p.E545A (SNV) - PIK3CA Effective Sirolimus Other 66.67% 2) Preclinical 0 Drug-drug interactions p.E545A (SNV) / 4-Hydroxycoumarin / Alfentanil, Alprazolam, Aprepitant, Astemizole, Avanafil / Baf-312, Boceprevir, Bromocriptine Mesylate, Budesonide, Buspirone Hydrochloride, Busulfan - PIK3CA lneffective Trastuzumab Approved* 66.67% 4) Clinical / Cisapride, Clarithromycin, Clindamycin Hydrochloride, Clomipramine Hydrochloride,p.E545A (SNV) Clonidine, Clorindione, Conivaptan1 Hydrochloride,� Curcumin, Cyclobenzaprine Hydrochloride / Danoprevir,* the drug Darifenacin, is approved Darunavir, for the cancer Delavirdine type but Mesylate, either noneDesipramine of the currentlyHydrochloride, approved Digitoxin, biomarkers Dihydroergotamine for this- drug Mesylate,were identified, Diphenadione, or an approved Ditiocarb, resistance Dofetilide,biomarker Dothiepin, for the drug Dronedarone was identified in this patient. Therefore, the drug labe[ may not cover the analyzed patient; VAF = Variant allele frequency / Ebastine,Biomarker Efavirenz, score: Eliglustat AMP score Tartrate, and CVI Elvitegravir, score. Clinically Eplerenone, approved: Ergotamine Approved Tartrate, biomarker Ethosuximide, (by the FDA, Ethyl EMA, Biscoumacetate or NCCN) to predict a specific effectin the patient's / Felodipine,disease. Clinical: Fentanyl, Not Fosaprepitant yet approved Dimeglumine biomarker for / Hydrocodone the patient's disease. Bitartrate Observed / ldelalisib, in clinical lndinavir studies Sulfate, as ltraconazolea potential biomarker / Ketoconazole to predict a specific effectof the / Latuda,drug. Preclinical: Levacetylmethadol, This biomarker Levothyroxine has not Sodium, yet been Lofepramine observed/tested Hydrochloride, in patients Loperamide,to predict a specific Lopinavir, effect Lumateperoneof the drug. lt is supported by preclinical evidence or / Maraviroc,translational Melitracen, data. Meperidine Hydrochloride, Methimazole, Methysergide / Naloxone,You can findNefazodone more details Hydrochloride, on the biomarker Nisoldipine,score Nortriptyline(AMP and CVI Hydrochloride score) in the glossary. / Ospemifene / Paclitaxel, Pimozide, Posaconazole / Ranolazine, Ribociclib, Rivaroxaban / Simvastatin, Sirolimus, Stiripentol / Tadalafil, Telaprevir, Telithromycin, Temsirolimus, Terfenadine, Theophylline, Thiopental Sodium, Tianeptine, Ticagrelor, Tipranavir, Tofranil, Tolvaptan, Triazolam, Troleandomycin

Everolimus Drug approval in patient disease: Approved*

Everolimus is a derivative of Rapamycin (sirolimus), and works similarly to Rapamycin as an mTOR (mammalian target of rapamycin) inhibitor. lt is currently used as an immunosuppressant to prevent rejection of organ transplants. In a similar fashion to other mTOR inhibitors Everolimus' effectis solely on the mTORCl protein and not on the mTORC2 protein.(D601590) Detected variants supporting this treatment effect: PlK3CA p.E545A (SNV) Drug-drug interactions / 2-Methoxyethanol / 305841-29-6 / 5-Fluorouracil / 6-Deoxyerythronolide B, 6-Mercaptopurine / 9-(N-Methyl-L-lsoleucine)-Cyclosporin A

TheodorTheodor Stern Stern Kai 7, Kai 7, SignedSigned by: by: MolecularMolecular Health Health GmbH GmbH 6059060590 Frankfurt Frankfurt ReportReport date:date: 08 Mar 08 2021 Mar 202116:5816:58 (UTC+Ol:00) (UTC+Ol:00) Kurfürsten-AnlageKurfürsten-Anlage 21, 21, ReportReportversion: version: 3 3 6911569115 Heidelberg Heidelberg OrderOrder date: date: 08 Mar 08 2021 Mar 2021

Page Page3 of 13 1 of 13 PatientPatient name name ***** ***** DiagnosisDiagnosis MammakarzinomMammakarzinom • DR. SENCKENBERGISCHESDR. SENCKENBERGISCHES R PATHOLOGIER PATHOLOGIE PatientPatient 1D 1D Testl234Testl234 ICD-10-CMICD-10-CM code code ;;;;;;:; spsp CaseCase 1D 1D EU001930EU001930 MeSHMeSH ID/term ID/term D001943D001943 (Breast (Breast Neoplasms) Neoplasms) W1ldlabW1ldlab DateDate of birthof birth AdditionalAdditional MeSH MeSH IDs IDs - -

/ Abatacept,Sex Abetimus,Female Acalabrutinib, Sample typeAcetazolamide, FFPE Acteoside, LabtestAdalimumab, AdenovirusVCF-complete Type 7Vaccine import Live, (paired) Afelimomab, GeneralAldesleukin, dataset Aldosterone, 1D 105685598965 Alefacept, Alemtuzumab, Alprazolam, Altretamine, Aminoglutethimide, Amobarbital, Amphotericin B, Amprenavir, Anakinra, Anthrax Vaccine, Antilymphocyte Ethnicity EUR Tumor cellularity 100% Organizational unit SIPV2TEST CVI dataset 1D 105685598965 lmmunoglobulin (Horse), Antithymocyte lmmunoglobulin (Rabbit), Apremilast, Aprobarbital, Arsenic Trioxide, Avasimibe, Ave9633, Azacitidine, Azathioprine / BacillusCountry Calmette-Guerin DE Substrain Connaught Live Antigen, Bacillus Calmette-Guerin Substrain Danish 1331 Live Antigen, BacillusSoftware Calmette-Guerinversion 4.3.3 SubstrainMutational Tice statusLive Antigen, of commonly Baf-312, mutated Barbexaclone, genes in Barbital, the patient Baricitinib, disease Basiliximab, Beclomethasone Dipropionate, Begelomab, Belatacept, Belimumab, Belinostat, Bendamustine, Betamethasone, Betamethasone Sodium Phosphate, Bevacizumab, Bexarotene, Bifonazole, Black Cohosh, Bleomycin, Bleselumab,ATM Blinatumomab,BRCAl Bortezomib,BRCA2 Bosentan,CDK4 Brequinar,CDKN2A Briakinumab, CHEK2 Brigatinib, EGFR Brodalumab, ERBB2 Bryostatin ESRl 1, Budesonide, PALB2 Busulfan, PIK3CAButalbital / Cabergoline,not Calcitriol,not Canakinumab,not Candicidin,not Capecitabine,not Capsaicin,not Carbomycin,not Carboplatin,not Carfilzomib,not Carmustine,not Castanospermine,1 SNV Cepeginterferonidentified Alfa-2b,identified Cephradine, identified Ceritinib, identified Cerivastatin identified Sodium, Certolizumabidentified Pegol,identified Chlorambucil, identified Chloramphenicol, identified Ciclesonide,identified Cimetidine, Cisapride, Cisplatin, Cladribine, Clevidipine, Clobazam, Clobetasol, Clocortolone Acetate, Clofarabine, Clofibrate, Clonidine, Cloprednol, Coltuximab Ravtansine, Corticotropin,PTEN Cortisone,TP53 Cortisone Acetate, Cortivazol, Curcumin Sulfate, Cyclophosphamide, Cyproterone Acetate, Cytarabine / Dabrafenib,not Dacarbazine,not Daclizumab, Dalfopristin, Danoprevir, Dapoxetine, Decitabine, Deferasirox, Deflazacort, Delavirdine Mesylate, Deoxyspergualin, Dexamethasoneidentified lsonicotinate,identified Dexrazoxane, Diazepam, Dicloxacillin Sodium, Diethylstilbestrol, Digitoxin, Dihydroergocornine, Dihydroergocristine, Dihydroergocryptine, Dimethyl Fumarate, Dimethyl Sulfoxide, Dinutuximab, Dipyrone, Dirithromycin, Disopyramide Phosphate, Ditiocarb, Docetaxel, Doramectin, Dothiepin, Doxepin Hydrochloride, Doxifluridine, Doxycycline / Echinacea, Eculizumab, Edetate Calcium Disodium, Efalizumab, Efonidipine, Elbasvir, Eliglustat Tartrate, Elvitegravir, Emapalumab, Epinephrine, Epirubicin, Epofolate,SUMMARY Epothilone B, Epothilone D, Eprinomectin [Usan:Usp:lnn], Ergoloid Mesylates, Eribulin, Esketamine Hydrochloride, Eslicarbazepine, Eslicarbazepine Acetate, Estradiol Benzoate, Estradiol Cypionate, Estradiol Dienanthate, EstradiolValerate, Etanercept, Ethotoin, Ethyl Alcohol, Etoricoxib, EtravirineOverview of potential treatment impacts Overview of prognostic and diagnostic findings Clinical trials found / Felbamate, Fernring, Fentanyl, Flecainide Acetate, Floxacillin, Floxuridine, Fluclorolone, Flucytosine, Fludarabine, Fludrocortisone, Flunisolide, Fluocinolone Acetonide,3 Effective Fluocortin, Fluocortolone,1 lneffective Fluperolone, o Safety Fluprednidene, FluprednideneO Acetate,Prognostic Fluprednisolone, O Diagnostic Flurithromycin, Fluticasone, Fluticasone6 Trials Furoate, Fluticasone Propionate, Fluvastatin Sodium, Formestane, Formocortal, Fosaprepitant Dimeglumine, Fostamatinib / Gallium Nitrate (Anhydrous), Gemcitabine, Gemtuzumab Ozogamicin, Glatiramer Acetate, Glycerol Phenylbutyrate, Golimumab, Gpi-1485, Griseofulvin, Guselkumab, Gusperimus VAF/Copy Potential impact Treatment Drug approval Biomarker Biomarker score Trials / Halometasone, Human Adenovirus E Serotype 4 Strain Cl-68578 Antigen, Hydralazine Hydrochloride,Number Hydrocodone Bitartrate, Hydrocortisone, Hydrocortisone Aceponate, Hydrocortisone Acetate, Hydrocortisone Succinate, Hydroxyurea, Hypericin / lbritumomab Tiuxetan, ldarubicin, lfosfamide, lndisulam, lnfliximab, Interferon Alfa, Interferon Alfa-2a, Recombinant, Interferon Alfa-2b, Interferon Alfa-Nl, Alpelisib Approved PIK3CA Clinically InterferonEffective Alfa-N3, Interferon Alfacon-1, Interferon Beta-lb, Interferon Gamma-lb, lrbesartan, lrinotecan,66.67% lxabepilone, lxekizumab 4 Fulvestrant Approved p.E545A (SNV) r;, Approved / Ketamine Hydrochloride, Ketazolam, Kitasamycin, Kos-1584 � / Lanreotide, Lenalidomide, Lenvatinib, Lesinurad, Lestaurtinib, Linezolid, Lipegfilgrastim, Lisuride, Lomustine,- Lorvotuzumab Mertansine, Lumefantrine, PIK3CA LysergideEffective Everolimus Approved* 66.67% 2) Preclinical 2 / Magnacort, Manidipine, Matromycin, Mechlorethamine Hydrochloride, Medicalp.E545A Cannabis, (SNV) Melengestrol, Melengestrol Acetate, Melphalan, Mepartricin, Mephenytoin, Mepolizumab, Meprednisone, Mequitazine, Metergoline, Methimazole, Methohexital Sodium, Methotrexate,- Methylergonovine, Methylphenobarbital, Methylprednisolone Sodium Succinate, Methysergide,PIK3CA Metyrapone, Midecamycin, Miocamycin, Mirtazapine, Mirvetuximab Soravtansine, Effective Sirolimus Other 66.67% 2) Preclinical 0 Mitemcinal, Mitomycin C, Mizoribine, Mometasone, Mometasone Furoate, Monomethylp.E545A (SNV) Fumarate, Muromonab, Mycophenolate Mofetil, Mycophenolic Acid / Nafcillin Sodium, Naloxone, Nelarabine, Niacin, Nicergoline, Nitric Oxide, Nk-012, Norfloxacin, Norgestimate, Noscapine / Obinutuzumab, Ocrelizumab, Octreotide Acetate, Olaparib, Omega Interferon, Opipramol, Oritavancin, Orlistat,- Orphenadrine, Osimertinib, Oxaliplatin, PIK3CA lneffective Trastuzumab Approved* 66.67% 4) Clinical Oxcarbazepine, Oxethazaine, Oxybutynin, Oxymetholone, Ozanimod p.E545A (SNV) 1 / Panobinostat, Paramethasone, Pasireotide, Peficitinib, Pegaspargase, Peginterferon Alfa-2a, Peginterferon Beta-la, Pegvisomant,� Pemetrexed, Penicillamine,* the drug isPentostatin, approved forPeppermint the cancer Oil, type Perampanel, but either Pergolide none of Mesylate,the currently Phenelzine approved Sulfate, biomarkers Phenylalanine, for this- drugPhenylbutazone, were identified, Pilocarpine, or an approved Pimecrolimus, resistance Piperaquine,biomarker Pirarubicin, for the drug Pirfenidone, was identified Pomalidomide, in this patient. Pralatrexate, Therefore, the Prednisolone, drug labe[ may Prednisolone not cover Hemisuccinate,the analyzed patient; Prednisolone VAF = Variant Sodium allele Phosphate, frequency Prednisone Acetate,Biomarker Prednylidene, score: AMPProbenecid, score and Procainamide CVI score. Clinically Hydrochloride, approved: Procarbazine, Approved Propoxyphene biomarker (by Hydrochloride,the FDA, EMA, or Propylthiouracil NCCN) to predict a specific effectin the patient's / Quinupristindisease. Clinical: Not yet approved biomarker for the patient's disease. Observed in clinical studies as a potential biomarker to predict a specific effectof the / Rabeprazole,drug. Preclinical: Raloxifene, This biomarkerRaltitrexed, has Ravulizumab, not yet been Remacemide, observed/tested Resveratrol, in patients Revefenacin, to predict Ribociclib,a specific effect Ridaforolimus,of the drug. Rifabutin, lt is supported Rifapentine, by preclinical Rilonacept, evidence or Risankizumab,translational Rituximab, data. Rofecoxib, Rokitamycin, Roxithromycin, Rozanolixizumab, RubellaVirus Vaccine, Rufinamide, Rutin, Ruxolitinib / Saracatinib,You can find Sarilumab, more details Secobarbital on the biomarker Sodium,score Secukinumab, (AMP and Selamectin,CVI score) in Seratrodast, the glossary. Siltuximab, Sirukumab, Sitaxentan, Solithromycin, Somatostatin, Sotalol Hydrochloride, Stepronin, Stiripentol, Streptozocin, Sulfasalazine, Sulfinpyrazone / Tedizolid Phosphate, Telithromycin, Temozolomide, Teniposide, Tepoxalin, Terbinafine, Terfenadine, Terguride, Teriflunomide, Tetracycline, Thalidomide, Theophylline, Thiamylal Sodium, Thioguanine, Thiopental Sodium, Thiotepa, Tildipirosin, Tilmicosin, Tixocortol, Tocilizumab, Tofisopam, Tofranil, Topiramate, Topiroxostat, Tositumomab, Trabectedin, Trametinib, Tranylcypromine Sulfate, Trastuzumab Emtansine, Tretinoin, Triclabendazole, Trifluridine, Trilostane, Trimipramine Maleate, Triptolide, Trofosfamide, Troglitazone, Tylosin, Tylvalosin, TyphoidVaccine Live / Unii-J0086219x6 / Valproic Acid, Vapreotide, Varicella ZasterVaccine (Live/Attenuated), Vedolizumab, Vibrio Cholerae Cvd 103-Hgr Strain Live Antigen, Vilanterol, Vindesine, Vinorelbine, Vitamin E, Voclosporin, Vorinostat, Voxelotor / Wartmannin, Win 55212-2 /Yellow FeverVaccine / Zafirlukast, Zidovudine

Sirolimus Drug approval in patient disease: Other

A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. lt is bioactive only when bound to immunophilins. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties.(DB00877) Detected variants supporting this treatment effect:

Page Page4 of 13 1 of 13 Patient name ********** Diagnosis MammakarzinomMammakarzinom • DR. SENCKENBERGISCHESDR. SENCKENBERGISCHES Patient name Diagnosis R PATHOLOGIER PATHOLOGIE PatientPatient 1D 1D Testl234Testl234 ICD-10-CMICD-10-CM code code ;;;;;;:; spsp CaseCase 1D 1D EU001930EU001930 MeSHMeSH ID/term ID/term D001943D001943 (Breast (Breast Neoplasms) Neoplasms) W1ldlabW1ldlab DateDate of birth of birth AdditionalAdditional MeSH MeSH IDs IDs - -

PIK3CASex p.E545A Female(SNV) Sample type FFPE Labtest VCF-complete import (paired) General dataset 1D 105685598965 Drug-drugEthnicity interactions EUR Tumor cellularity 100% Organizational unit SIPV2TEST CVI dataset 1D 105685598965 / 167354-41-8Country / 2-MethoxyethanolDE / 5-Fluorouracil / 6-Mercaptopurine / 9-(N-Methyl-L-lsoleucine)-Cyclosporin A Software version 4.3.3 / Abatacept, Abemaciclib, Abetimus, Acalabrutinib, Acetaminophen, Acetazolamide, Acetylsalicylic Acid, Acteoside, Adalimumab, Adenovirus Type 7 Vaccine Live,Mutational Afelimomab, status Albendazole, of commonly Aldesleukin, mutated genesAldosterone, in the patient Alectinib, disease Alefacept, Alemtuzumab, Alpelisib, Altretamine, Ambrisentan, Aminoglutethimide, Amitriptyline Hydrochloride, Amobarbital, Amodiaquine Hydrochloride, Amoxapine, Amphotericin B, Amprenavir, Amsacrine, Anakinra, Annamycin, Anthrax Vaccine,ATM Antilymphocyte BRCAl lmmunoglobulinBRCA2 (Horse),CDK4 AntithymocyteCDKN2A lmmunoglobulin CHEK2 (Rabbit),EGFR Apixaban,ERBB2 Apremilast, ESRl Aprepitant, PALB2 Aprobarbital, PIK3CA Argatroban, not not not not not not not not not not 1 SNV Aripiprazole, Aripiprazole Lauroxil, Arsenic Trioxide, Artemether, Astemizole, Asunaprevir, Atazanavir Sulfate, Atovaquone, Avasimibe, Axitinib, Azacitidine, identified identified identified identified identified identified identified identified identified identified Azathioprine, Azelastine Hydrochloride, Azimilide Hydrochloride, Azithromycin / Bacillus Calmette-Guerin Substrain Connaught Live Antigen, Bacillus Calmette-Guerin Substrain Danish 1331 Live Antigen, Bacillus Calmette-Guerin PTEN TP53 Substrain Tice Live Antigen, Baf-312, Bafilomycin Al, Bafilomycin Bl, Barbexaclone, Barbital, Baricitinib, Basiliximab, Beclomethasone Dipropionate, not not Begelomab, Belatacept, Belimumab, Belinostat, Bendamustine, Benzquinamide, Benzyl Alcohol, Betamethasone, Betamethasone Sodium Phosphate, identified identified Bevacizumab, Bexarotene, Bicalutamide, Bifonazole, Biricodar, Bisoprolol Fumarate, Black Cohosh, Bleomycin, Bleselumab, Blinatumomab, Boceprevir, Bortezomib, Bosentan, Brequinar, Briakinumab, Brigatinib, Brodalumab, Bromocriptine Mesylate, Budesonide, Buprenorphine, Busulfan, Butalbital / Cabazitaxel, Cabergoline, Calcitriol, Canagliflozin, Canakinumab, Candesartan, Candesartan Cilexetil, Cannabidiol, Capecitabine, Capsaicin, Carboplatin, Carfilzomib,SUMMARY Carmustine, Caspofungin Acetate, Castanospermine, Cefoperazone, Cepeginterferon Alfa-2b, Cephradine, Cerebyx, Ceritinib, Cerivastatin Sodium, Certolizumab Pegol, Cetirizine, Chlorambucil, Chloramphenicol, Chloroform, Chloroquine, Chlorpheniramine Maleate, Chlorpromazine, Cholesterol, Cholic Acid, Ciclesonide, Cilostazol, Cimetidine, Ciprofloxacin, Cisapride, Cisplatin, Citalopram Hydrobromide, Cladribine, Clobazam, Clobetasol, Clocortolone Acetate,Overview Clofarabine, of potential Clofazimin, treatment Clofibrate, impacts Clomipramine Hydrochloride, Clonidine,Overview Cloprednol, of prognostic Cobicistat, and diagnostic Cocaine Hydrochloride,findings Colforsin,Clinical Concanamycin trials found A, Conivaptan3 Effective Hydrochloride, 1 lneffective Copanlisib, Corticotropin,o Safety Cortisone, Cortisone Acetate,O Prognostic Cortivazol, Curcumin,O Diagnostic Curcumin Sulfate, Cyclophosphamide,6 Trials Cyclosporine, Cyproterone Acetate, Cytarabine / Dabigatran Etexilate, Dabrafenib, Dacarbazine, Daclatasvir Dihydrochloride, Daclizumab, Dacomitinib, Dactinomycin, Dalfopristin, Dalmane, Danazol, Danoprevir, Dapoxetine, Dapsone, Darbepoietin, Darunavir, Dasatinib, Daunorubicin, Decitabine, Deferasirox, Deflazacort, Delavirdine Mesylate, VAF/Copy Deoxyspergualin,Potential impact Desipramine Hydrochloride,Treatment Desloratadine,Drug approval Desmethylsertraline, Biomarker Desvenlafaxine, Deutetrabenazine,Biomarker Dexamethasone, score DexamethasoneTrials lsonicotinate, Dexloxiglumide, Dexrazoxane, Dextromethorphan, Dhea Sulfate, Diazepam, Diclofenac,Number Dicloxacillin Sodium, Diethylstilbestrol, Digitoxin, Dihydroergocornine, Dihydroergocristine, Dihydroergocryptine, Dihydroergotamine Mesylate, Dimethyl Fumarate, Dimethyl Sulfoxide, Dinutuximab, Dipyridamole, Dipyrone, DisopyramideAlpelisib Phosphate, Disulfiram,Approved Ditiocarb, Docetaxel,PIK3CA Dofequidar, Domperidone, Doravirine, Dovitinib, DoxazosinClinically Mesylate, Effective 66.67% Approved 4 Doxifluridine, Doxorubicin, Doxycycline,Fulvestrant Duloxetine Hydrochloride,Approved Dutasteridep.E545A (SNV) r;,� / Echinacea, Eculizumab, Edetate Calcium Disodium, Efalizumab, Efavirenz, Elacridar, Elbasvir, Elexacaftor,Eliglustat Tartrate, Elvitegravir, Emapalumab, Enasidenib, Entrectinib, Enzalutamide, Epinephrine, Epirubicin, Eplerenone, Ergoloid Mesylates, Ergonovine, Ergotamine- Tartrate, Eribulin, Erlotinib, PIK3CA Effective Everolimus Approved* 66.67% 2) Preclinical 2 Esketamine Hydrochloride, Eslicarbazepine, Eslicarbazepine Acetate, Esomeprazolep.E545A Magnesium,(SNV) Estradiol, Estradiol Benzoate, Estradiol Cypionate, Estradiol Dienanthate, Estradiol Valerate, Estramustine, Estriol, Etanercept, Ether, Ethotoin, Ethyl Alcohol, Etoposide, Etoricoxib, Etravirine / Fedratinib, Felbamate, Fernring, Fenofibrate,Fentanyl, Finasteride, Flibanserin, Floxacillin, Floxuridine, Fluclorolone,- Fluconazole, Flucytosine, Fludarabine, PIK3CA Fludrocortisone,Effective Flunisolide, FluocinoloneSirolimus Acetonide, Other Fluocortin, Fluocortolone, Fluoxetine, Flupentixol,66.67% Fluperolone, Fluphenazine,2) Fluprednidene, Preclinical 0 Fluprednidene Acetate, Fluprednisolone, Flutamide, Fluticasone, Fluticasonep.E545A Furoate, (SNV) Fluticasone Propionate, Fluvastatin Sodium, Fluvoxamine Maleate, Formestane, Formocortal, Fosamprenavir Calcium, Fosaprepitant Dimeglumine, Fosnetupitant, Fostamatinib,- Fusidic Acid / Gallium Nitrate (Anhydrous), Gefitinib, Gemcitabine, Gemtuzumab Ozogamicin,PIK3CA Genistein, Gestodene, Glasdegib, Glatiramer Acetate, Glecaprevir, Glyburide, lneffective Trastuzumab Approved* 66.67% 4) Clinical Glycerin, Glycerol Phenylbutyrate, Golimumab, Gpi-1485, Gramicidin, Grepafloxacinp.E545A Hydrochloride, (SNV) Griseofulvin, Guselkumab,1 Gusperimus� / Halofantrine Hydrochloride, Halometasone, Haloperidol, Hm-30181, Human Adenovirus E Serotype 4 Strain Cl-68578 Antigen, Hycanthone, Hydralazine Hydrochloride,* the drug is Hydrocortisone, approved for the Hydrocortisone cancer type butAceponate, either none Hydrocortisone of the currently Acetate, approved Hydrocortisone biomarkers Cypionate, for this- Hydrocortisonedrug were identified, Sodium or Phosphate,an approved resistance Hydbiomarkerrocortisone for Succinate, the drug was Hyd identified roxych loroq in uthisi ne, patient. Hydroxyprogesterone Therefore, the drugCaproate, labe[ Hydmayroxyu not cover rea, Hyd theroxyzi analyzed ne, Hyperici patient;n VAF = Variant allele frequency / lbritumomabBiomarker Tiuxetan,score: AMP lbrutinib, score and lbuprofen, CVI score. lcotinib, Clinically ldarubicin, approved: ldelalisib, Approved lfosfamide, biomarker lloperidone, (by the FDA, lmatinib, EMA, lndalpine,or NCCN) tolndinavir predict Sulfate,a specific lndisulam, effectin the patient's lndomethacin,disease. Clinical: lnfliximab, Not yet Interferon approved Alfa, biomarker Interferon for Alfa-2a, the patient's Recombinant, disease. Interferon Observed Alfa-2b, in clinical Interferon studies Alfa-Nl,as a potential Interferon biomarker Alfa-N3, to Interferon predict a Alfacon-1,specific effect of the Interferondrug. Preclinical: Beta-lb, Interferon This biomarker Gamma-lb, has not lrbesartan, yet been lrinotecan, observed/tested lsavuconazonium in patients toSulfate, predict lsoniazid, a specific lstradefylline, effectof the drug.lvacaftor, lt is supportedlvermectine, by lvosidenib, preclinical evidence or lxekizumabtranslational data. / JuxtapidYou can / find Ketamine more details Hydrochloride, on the biomarker Ketazolamscore (AMP and CVI score) in the glossary. / Laniquidar, Lanreotide, Lansoprazole, Lapatinib, Ledipasvir, Lemborexant, Lenalidomide, Lenvatinib, Lesinurad, Lestaurtinib, Letermovir, Levacetylmethadol, Levamlodipine, Levofloxacin, Levothyroxine Sodium, Lidocaine, Linezolid, Liothyronine Sodium, Liotrix, Lipegfilgrastim, Lisuride, Lomustine, Lonafarnib, Lopinavir, Lorlatinib, Losartan Potassium, Lovastatin, Loxapine, Lumefantrine, Lusutrombopag, Lysergide / Magnacort,Mechlorethamine Hydrochloride, Medical Cannabis, Medroxyprogesterone Acetate, Mefloquine Hydrochloride, Megestrol Acetate, Melengestrol, Melengestrol Acetate, Melphalan, Mepacrine, Meperidine Hydrochloride, Mepolizumab, Meprednisone, Mequitazine, Metergoline, Methadone Hydrochloride, Methimazole, Methohexital Sodium, Methotrexate, Methylergonovine, Methylphenobarbital, Methylprednisolone Sodium Succinate, Methysergide, Metronidazole, Metyrapone, Miconazole, Midostaurin, Mifepristone, Milnacipran, Mirabegron, Miralax, Mirtazapine, Mitomycin C, Mitotane, Mitoxantrone Hydrochloride, Mizoribine, Mometasone, Mometasone Furoate, Monensin, Monomethyl Fumarate, Muromonab, Mycophenolate Mofetil, Mycophenolic Acid / Nabiximols, Nafcillin Sodium, Naloxone, Naproxen, Nateglinide, Nefazodone Hydrochloride, Nelarabine, Nelfinavir Mesylate, Neratinib, Netupitant, Nevirapine, Niacin, Nicergoline, Nigericin, Nilotinib, Nitric Oxide, Nk-012, Norethindrone, Norfloxacin, Norgestimate, Norgestrel, Nortriptyline Hydrochloride, Noscapine / Obinutuzumab, Ocrelizumab, Octreotide Acetate, Olaparib, Omega Interferon, Ondansetron, Ont-093, Oritavancin, Orlistat, Orphenadrine, Osimertinib, Oxaliplatin, Oxcarbazepine, Oxethazaine, Oxybutynin, Oxycodone Hydrochloride, Oxymetholone, Ozanimod

Page Page5 of 13 1 of 13 PatientPatient name name ***** ***** DiagnosisDiagnosis MammakarzinomMammakarzinom • DR. SENCKENBERGISCHESDR. SENCKENBERGISCHES R PATHOLOGIER PATHOLOGIE PatientPatient 1D 1D Testl234Testl234 ICD-10-CMICD-10-CM code code ;;;;;;:; spsp CaseCase 1D 1D EU001930EU001930 MeSHMeSH ID/term ID/term D001943D001943 (Breast (Breast Neoplasms) Neoplasms) W1ldlabW1ldlab DateDate of birth of birth AdditionalAdditional MeSH MeSH IDs IDs - -

/ Paclitaxel,Sex Palbociclib,Female Panobinostat,Sample type Paramethasone, FFPE Paritaprevir,Labtest Paroxetine, Pasireotide,VCF-complete Peficitinib, import Pegaspargase, (paired) PeginterferonGeneral datasetAlfa-2a, Peginterferon1D 105685598965 Beta-la, Pegvisomant, Pemetrexed, Penicillamine, Pentamidine, Pentazocine Hydrochloride, Pentobarbital, Pentostatin, Peppermint Oil, Perampanel, Ethnicity EUR Tumor cellularity 100% Organizational unit SIPV2TEST CVI dataset 1D 105685598965 Pergolide Mesylate, Phenelzine Sulfate, Phenobarbital, Phenylalanine, Phenylbutazone, Phenytoin, Pibrentasvir, Pilocarpine, Pimecrolimus, Pimozide, Piperaquine,Country Piperine,DE Pirarubicin, Pirfenidone, Platelet Activating Factor, Plavix, Pomalidomide, Ponatinib, Posaconazole, Pralatrexate,Software version Praziquantel, 4.3.3 Prazosin Hydrochloride,Mutational status Prednisolone, of commonly Prednisolone mutated Hemisuccinate,genes in the patient Prednisolone disease Sodium Phosphate, Prednisone, Prednisone Acetate, Prednylidene, Primaquine, Primidone, Probenecid, Procarbazine, Progesterone, Promethazine, Propafenone Hydrochloride, Propofol, Propoxyphene Hydrochloride, Propranolol, Propylthiouracil,ATM Protonix,BRCAl ProtriptylineBRCA2 HydrochlorideCDK4 CDKN2A CHEK2 EGFR ERBB2 ESRl PALB2 PIK3CA / Quercetin,not Quetiapinenot Fumarate,not Quinidine, not Quinine Sulfate,not Quinupristinnot not not not not 1 SNV / Rabeprazole,identified Raloxifene,identified Raltitrexed, identified Ranitidine, identified Ravulizumab, identified Reboxetine, identified Regorafenib, identified Remacemide, identified Reserpine, identified Resveratrol, identified Revefenacin, Reversin 121, Ribociclib, Rifabutin, Rifampin, Rifamycin Sodium, Rifapentine, Rilonacept, Rilpivirine, Risankizumab, Risperidone, Ritonavir, Rituximab, Rivaroxaban, Rocephin,PTEN Rofecoxib,TP53 Rolapitant, Romidepsin, Rosuvastatin Calcium, Roxithromycin, Rozanolixizumab, RubellaVirus Vaccine, Rucaparib, Rufinamide, Rutin, Ruxolitinibnot not / Safinamideidentified Mesylate, identified Salinomycin, Salmeterol, Sapropterin Dihydrochloride, Saquinavir, Saracatinib, Sarecycline, Sarilumab, Saxagliptin, Scopolamine, Secobarbital Sodium, Secukinumab, Selegiline, Seproxetine, Seratrodast, Sildenafil, Siltuximab, Simeprevir, Simvastatin, Sirukumab, Sitaxentan, Sofosbuvir, Somatostatin, Sorafenib, Spironolactone, St.John'S Wort, Staurosporine, Stepronin, Stiripentol, Streptozocin, Sulfasalazine, Sulfinpyrazone, Sunitinib, Suvorexant / Tacrolimus,SUMMARY Tadalafil, Tamoxifen, Taractan, Tariquidar, Taurocholic Acid, Tedizolid Phosphate, Tegafur, Telmisartan, Temozolomide, Teniposide, Tenofovir Disoproxil Fumarate, Tepoxalin, Terazosin Hydrochloride, Terbinafine, Terfenadine, Terguride, Teriflunomide, Tesmilifene, Testosterone, Testosterone Enanthate,Overview Testosterone of potential Undecanoate,treatment impacts Tetracycline, Tezacaftor,Thalidomide, ThiamylalOverview of Sodium, prognostic Thioguanine, and diagnostic Thiopental findings Sodium, Thiotepa, ClinicalTicagrelor, trials found Tipifarnib, Tipranavir, Tixocortol, Tocilizumab, Tofisopam, Tofranil, Tolvaptan, Topiramate, Topiroxostat, Toremifene, Tositumomab, Trabectedin, Trametinib, Tranylcypromine3 Effective Sulfate, 1 Trastuzumab lneffective Emtansine, o Safety Trazodone Hydrochloride, Tretinoin,O Prognostic Triclabendazole, O Diagnostic Trifluoperazine, Triflupromazine, Trifluridine,6 Trials Trilostane, Trimethoprim, Trimipramine Maleate, Triptolide, Trofosfamide, Troglitazone, TyphoidVaccine Live / Udenafil / Valbenazine, Valinomycin, Valproic Acid, Valspodar,Vandetanib, Vapreotide, Vardenafil Hydrochloride,VAF/Copy Varicella ZasterVaccine (Live/Attenuated), Potential impact Treatment Drug approval Biomarker Biomarker score Trials Vedolizumab, Velpatasvir, Venetoclax, Venlafaxine Hydrochloride, Vibrio Cholerae Cvd 103-Hgr NumberStrain Live Antigen, Vicriviroc, Vilanterol, Vinblastine, Vincristine, Vindesine, Vinorelbine, Vitamin E, Voacamine, Voclosporin, Voriconazole, Vorinostat, Vortioxetine, Voxelotor, Voxilaprevir / Wartmannin /Yellow FeverVaccine, Yohimbine / Zafirlukast, Zaleplon, Zidovudine, Zimeldine, Ziprasidone Hydrochloride, Zoloft,Zomepirac, Zontivity Alpelisib Approved PIK3CA Clinically Effective 66.67% Approved 4 Fulvestrant Approved p.E545A (SNV) r;,� Potentially ineffectivetreatments - PIK3CA Effective Everolimus Approved* 66.67% 2) Preclinical 2 Trastuzumab Drug approval in patientp.E545A disease: (SNV) Approved* - Produced PIK3CA Effectivein CHO cell cultures, trastuzumabSirolimus is a recombinantOther lgGl kappa, humanized monoclonal66.67% antibody [A40276] that selectively2) binds Preclinical with high affinity0 in a cell-based assay (Kd = 5 nM) to the extracellular domain of the human epidermalp.E545A (SNV) growth factor receptor protein (HER2) [FDA label]. lt is used as a treatment of human epidermal growth factor receptor (HER)-2+ metastatic breast cancer, where there is a proven amplification of the HER-2 oncogene or over-expression of the HER-2 protein in tumours. lt is suggested that the overexpression or gene amplification- of HER2 has been found in about 20-30% of PIK3CA lneffective Trastuzumab Approved* 66.67% 4) Clinical breast cancers and elevated activation of HER2 triggers multiple downstreamp.E545A pathways (SNV) leading to abnormal proliferation1 of cancer� cells [Al21]. Trastuzumab binds to HER2 and suppresses cancer cells growth, proliferation, and survival directly and indirectly [Al21]. In December* the drug 2017, is approved FDA approved for the Ogivri cancer (trastuzumab-dkst) type but either none as a biosimilarof the currently to Herceptin approved (trastuzumab) biomarkers for for the this -treatment drug were of patientsidentified, with or breast an approved or metastatic resistance stomachbiomarker cancer for (gastric the drug or was gastroesophageal identified in this junction patient. adenocarcinoma) Therefore, the drug whose labe[ tu may mors not overexpress cover the analyzedthe HER2 patient; gene (H VAFER2+). = Variant lt displays allele biosimilar frequency properties as HerceptinBiomarker according score: AMP to clinical score anddata. CVI While score. Ogivri Clinically is the first approved: biosimilar Approved approved biomarker in the U.S. (by for the the FDA, treatment EMA, or of NCCN) breast to cancer predict or astomach specific cancer,effectin it theis the patient's seconddisease. biosimilar Clinical: approved Not yet in approved the U.S. forbiomarker the treatment for the of patient's cancer. disease.Herzuma Observed (trastuzumab-pkrb) in clinical studies is a biosimilar as a potential drug approved biomarker in Decemberto predict a2018 specific for the effect of the treatmentdrug. Preclinical: of HER2-overexpressing This biomarker breast has notcancer. yet beenKANJINTI observed/tested (trastuzumab-anns) in patients is another to predict biosimilar a specific approved effectof bythe the drug. FDA lt inisJune supported 2019.[L6715](DB00072) by preclinical evidence or translational data. Detected variants supporting this treatment effect: You can find more details on the biomarker score (AMP and CVI score) in the glossary. PIK3CA p.E545A (SNV)

Treatments with potential for adverse reaction No treatments with potential for adverse reaction reported

TheodorTheodor Stern Stern Kai 7, Kai 7, SignedSigned by: by: MolecularMolecular Health Health GmbH GmbH 6059060590 Frankfurt Frankfurt ReportReport date:date: 08 Mar 08 2021 Mar 202116:5816:58 (UTC+Ol:00) (UTC+Ol:00) Kurfürsten-AnlageKurfürsten-Anlage 21, 21, ReportReportversion: version: 3 3 6911569115 Heidelberg Heidelberg OrderOrder date: date: 08 Mar 08 2021 Mar 2021

Page Page6 of 13 1 of 13 PatientPatient name name ***** ***** DiagnosisDiagnosis MammakarzinomMammakarzinom • DR. SENCKENBERGISCHESDR. SENCKENBERGISCHES R PATHOLOGIER PATHOLOGIE PatientPatient 1D 1D Testl234Testl234 ICD-10-CMICD-10-CM code code ;;;;;;:; spsp CaseCase 1D 1D EU001930EU001930 MeSHMeSH ID/term ID/term D001943D001943 (Breast (Breast Neoplasms) Neoplasms) W1ldlabW1ldlab DateDate of birthof birth AdditionalAdditional MeSH MeSH IDs IDs - -

Sex Female Sample type FFPE Labtest VCF-complete import (paired) General dataset 1D 105685598965 CLINICALEthnicity TRIALS EUR Tumor cellularity 100% Organizational unit SIPV2TEST CVI dataset 1D 105685598965 Country DE Software version 4.3.3

TheMutational following tristatus als are of potentiallycommonly bestmutated suited genes for your in the patient's patient indication,disease considering all reported treatment recommendations. See https://clinicaltrials.gov (clinicalATM tri als fromBRCAl NCT) or https://apps.who.int/trialsearchBRCA2 CDK4 CDKN2A (clinical trialsCHEK2 from other registries)EGFR for ERBB2more information. ESRl PALB2 PIK3CA not not not not not not not not not not 1 SNV Titleidentified identified identified identifiedTrial identifiedIntervention identified Diseaseidentified identifiedLocation identified identifiedAge and sex phase PTEN TP53 andlD not not Impactidentified of eHealth-support identified on Quality of Life Phase 4; Fulvestrant Breast Neoplasms Mainz Age: 18, Gender: in Metastatic Breast Cancer Patients Treated NCT03220 Female With Palbociclib and Endocrine Therapy 178 (PRECYCLE) EligibilitySUMMARY criteria: lnclusion:ERBB2 protein expression: no expression, PGR protein expression, ESRl protein expression Overview of potential treatment impacts Overview of prognostic and diagnostic findings Clinical trials found Study Assessing the Efficacyand Safety of Phase 3; Alpelisib Breast Neoplasms Erlangen, Leipzig, Age: 18, Gender: Both Alpelisib3 Effective + Nab-paclitaxel 1 inlneffective Subjects With o SafetyNCT04251 O Prognostic O DiagnosticMuenchen, Bavaria, ... 6 Trials Advanced TNBC Who Carry Either a PIK3CA 533 Mutation or Have PTEN Loss Without PIK3CA Mutation (EPIK-B3) VAF/Copy Potential impact Treatment Drug approval Biomarker Biomarker score Trials Eligibility criteria: Number lnclusion:ERBB2 protein expression: no expression, ESRl protein expression: no expression, PGR protein expression: no expression Stratification:PTEN SCNA: loss, AlpelisibPIK3CA mutation Approved PIK3CA Clinically Effective 66.67% Approved 4 A Study Evaluating the Efficacyand Fulvestrant Safety of PhaseApproved 2/ Fulvestrant p.E545ABreast (SNV) Neoplasms Berlin, Bonn, Dresden,r;,� Age: 18, Gender: Both GDC-0077 + Palbociclib+ Fulvestrant vs Phase 3; - Placebo+ Palbociclib + Fulvestrant in NCT04191 PIK3CA Effective Everolimus Approved* 66.67% 2) Preclinical 2 Patients With PIK3CA-Mutant, Hormone 499 p.E545A (SNV) Receptor-Positive, Her2-Negative, Locally Advanced or Metastatic Breast Cancer - PIK3CA Effective Sirolimus Other 66.67% 2) Preclinical 0 Eligibility criteria: p.E545A (SNV) lnclusion:PIK3CA mutation, ERBB2 protein expression: no expression, ESRl protein expression, PGR protein -expression PIK3CA lneffective Trastuzumab Approved* 66.67% 4) Clinical Study Assessing the Efficacyand Safety of Phase 2; Alpelisib; p.E545ABreast (SNV) Neoplasms Augsburg, Berlin,1 Age: 18, Gender: Both Alpelisib Plus Fulvestrant or Letrozole, Based NCT03056 Fulvestrant Dresden, ... � on* Priorthe drug Endocrine is approved Therapy, for inthe Patients cancer With type but755 either none of the currently approved biomarkers for this- drug were identified, or an approved resistance PIK3CAbiomarker Mutation for the With drug Advanced was identified Breast in this patient. Therefore, the drug labe[ may not cover the analyzed patient; VAF = Variant allele frequency CancerBiomarker Who Have score: Progressed AMP score on and or AfterCVI score. Clinically approved: Approved biomarker (by the FDA, EMA, or NCCN) to predict a specific effectin the patient's Priordisease. Treatments Clinical: (BYLieve) Not yet approved biomarker for the patient's disease. Observed in clinical studies as a potential biomarker to predict a specific effectof the Eligibilitydrug. Preclinical: criteria: This biomarker has not yet been observed/tested in patients to predict a specific effectof the drug. lt is supported by preclinical evidence or lnclusion:PGRtranslational proteindata. expression, ESRl protein expression, ERBB2 protein expression: no expression, PIK3CA mutation You can find more details on the biomarker score (AMP and CVI score) in the glossary. The XENERA™ 1 Study Tests Xentuzumab in Phase 2; Everolimus Breast Neoplasms Erlangen, Heidelberg, Age: 18, Gender: Combination With Everolimus and NCT03659 Karlsruhe, ... Female Exemestane in Women With Hormone 136 Receptor Positive and HER2-negative Breast Cancer That Has Spread Eligibility criteria: lnclusion:PGR protein expression, ESRl protein expression, ERBB2 protein expression: no expression Dose EScalation lnduction of EvERolimus Phase 2; Everolimus Breast Neoplasms Bielefeld, Dresden, Age: 18, Gender: (Desiree) NCT02387 Sachsen, Erlangen, ... Female 099 Eligibility criteria: lnclusion:PGR protein expression, ERBB2 protein expression, ESRl protein expression

Page Page7 of 13 1 of 13 Patient name ********** Diagnosis Mammakarzinom DR. SENCKENBERGISCHESDR. SENCKENBERGISCHES Patient name Diagnosis Mammakarzinom R PATHOLOGIER PATHOLOGIE PatientPatient 1D 1D Testl234Testl234 ICD-10-CMICD-10-CM code code ;;;;;;:; spsp CaseCase 1D 1D EU001930EU001930 MeSHMeSH ID/term ID/term D001943D001943 (Breast (Breast Neoplasms) Neoplasms) W1ldlabW1ldlab DateDate of birth of birth AdditionalAdditional MeSH MeSH IDs IDs - -

TheMutational following referencesstatus of commonly were cited mutated in this report: genes in the patient disease ATM BRCAl BRCA2 CDK4 CDKN2A CHEK2 EGFR ERBB2 ESRl PALB2 PIK3CA Andrenot F et al. Alpelisibnot for PIK3CA-Mutated,not Hormonenot Receptor-Positivenot notAdvanced Breastnot Cancer. Thenot New Englandjournalnot ofnot medicine. 20191 SNV 05; 380(20) (PubMedidentified 1D: 31091374 identified) identified identified identified identified identified identified identified identified Xu YC et al. Integration of Receptor Tyrosine Kinases Determines Sensitivity to Pl3Ka-selective Inhibitors in Breast Cancer. Theranostics. 20177(4) (PubMed I D: 28382169PTEN) TP53 not not Andreidentified Fet al. Molecular identified Alterations and Everolimus Efficacy in Human Epidermal Growth Factor Receptor 2-Overexpressing Metastatic Breast Cancers: Combined Exploratory Biomarker Analysis From BOLERO-1 and BOLER0-3. Journal of clinical oncology : officialjournal of the American Society of Clinical Oncology. 2016 06; 34(18) (PubMed 1D: 27091708)

ChandarlapatySUMMARY Se t al. Frequent mutational activation of the Pl3K-AKT pathway in trastuzumab-resistant breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2012 Dec; 18(24) (PubMed 1D: 23092874) Overview of potential treatment impacts Overview of prognostic and diagnostic findings Clinical trials found Weigelt B et al. PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs. Oncogene. 2011 Jul; 30(29)3 (PubMedEffective 1D: 213586731 lneffective) o Safety O Prognostic O Diagnostic 6 Trials

VAF/Copy Potential impact Treatment Drug approval Biomarker Biomarker score Trials Number

Alpelisib Approved PIK3CA Clinically Effective 66.67% 4 Fulvestrant Approved p.E545A (SNV) r;, Approved - � PIK3CA Effective Everolimus Approved* 66.67% 2) Preclinical 2 p.E545A (SNV) - PIK3CA Effective Sirolimus Other 66.67% 2) Preclinical 0 p.E545A (SNV) - PIK3CA lneffective Trastuzumab Approved* 66.67% 4) Clinical p.E545A (SNV) 1 � * the drug is approved for the cancer type but either none of the currently approved biomarkers for this- drug were identified, or an approved resistance biomarker for the drug was identified in this patient. Therefore, the drug labe[ may not cover the analyzed patient; VAF = Variant allele frequency Biomarker score: AMP score and CVI score. Clinically approved: Approved biomarker (by the FDA, EMA, or NCCN) to predict a specific effectin the patient's disease. Clinical: Not yet approved biomarker for the patient's disease. Observed in clinical studies as a potential biomarker to predict a specific effectof the drug. Preclinical: This biomarker has not yet been observed/tested in patients to predict a specific effectof the drug. lt is supported by preclinical evidence or translational data. You can find more details on the biomarker score (AMP and CVI score) in the glossary.

TheodorTheodor Stern Stern Kai 7, Kai 7, SignedSigned by: by: MolecularMolecular Health Health GmbH GmbH 6059060590 Frankfurt Frankfurt ReportReport date:date: 08 Mar 08 2021 Mar 202116:5816:58 (UTC+Ol:00) (UTC+Ol:00) Kurfürsten-AnlageKurfürsten-Anlage 21, 21, ReportReportversion: version: 3 3 6911569115 Heidelberg Heidelberg OrderOrder date: date: 08 Mar 08 2021 Mar 2021

Page Page8 of 13 1 of 13 PatientPatient name name ***** ***** DiagnosisDiagnosis MammakarzinomMammakarzinom • DR. SENCKENBERGISCHESDR. SENCKENBERGISCHES R PATHOLOGIER PATHOLOGIE PatientPatient 1D 1D Testl234Testl234 ICD-10-CMICD-10-CM code code ;;;;;;:; spsp CaseCase 1D 1D EU001930EU001930 MeSHMeSH ID/term ID/term D001943D001943 (Breast (Breast Neoplasms) Neoplasms) W1ldlabW1ldlab DateDate of birth of birth AdditionalAdditional MeSH MeSH IDs IDs - -

Sex Female Sample type FFPE Labtest VCF-complete import (paired) General dataset 1D 105685598965 DESCRIPTIONEthnicity EUR KEY Tumor cellularity 100% Organizational unit SIPV2TEST CVI dataset 1D 105685598965 Country DE Software version 4.3.3

Mutational status of commonly mutated genes in the patient disease • Potentially effectivetreatments. These treatment recommendations are based solely on tumor biology and do not override your oncologist's clinical treatmentATM planBRCAl. BRCA2 CDK4 CDKN2A CHEK2 EGFR ERBB2 ESRl PALB2 PIK3CA not not not not not not not not not not 1 SNV • Potentially ineffectivetreatments. These treatments, in combination with the biomarkers identified in the patient tumor, have been reported to predict lackidentified of effectiveness. identifiedTreatment identified of a patient identified with any ofidentified these reported identified drugs mayidentified lead to disease identified progression identified. identified • Treatments with potential to cause an adverse reaction. These treatments, in combination with the biomarkers identified in the patient tumor, have been reportedPTEN to predictTP53 safety issues. Treatment of a patient with any of these reported drugs may lead to serious drug-related toxicities. not not • Biomarkers identified in the patient tumor that have been reported to have a prognostic relevance . identified identified • Biomarkers identified in the patient tumor that have been reported to have a diagnostic relevance. A The report contains conflicting evidence ab out the potential effectof the treatment. SUMMARY

Overview of potential treatment impacts Overview of prognostic and diagnostic findings Clinical trials found 3 Effective 1 lneffective o Safety O Prognostic O Diagnostic 6 Trials

VAF/Copy Potential impact Treatment Drug approval Biomarker Biomarker score Trials Number

Page Page9 of 13 1 of 13 PatientPatient name name ***** ***** DiagnosisDiagnosis MammakarzinomMammakarzinom • DR. SENCKENBERGISCHESDR. SENCKENBERGISCHES R PATHOLOGIER PATHOLOGIE PatientPatient 1D 1D Testl234Testl234 ICD-10-CMICD-10-CM code code ;;;;;;:; spsp CaseCase 1D 1D EU001930EU001930 MeSHMeSH ID/term ID/term D001943D001943 (Breast (Breast Neoplasms) Neoplasms) W1ldlabW1ldlab DateDate of birth of birth AdditionalAdditional MeSH MeSH IDs IDs - -

Sex Female Sample type FFPE Labtest VCF-complete import (paired) General dataset 1D 105685598965 Ethnicity EUR Tumor cellularity 100% Organizational unit SIPV2TEST CVI dataset 1D 105685598965 MOLECULAR HEALTH GLOSSARY Country DE Software version 4.3.3

AMPscore:Mutational status of commonly mutated genes in the patient disease DisplaysATM the classificationBRCAl of a biomarkerBRCA2 accordingCDK4 to the CDKN2Arecommendations CHEK2 of the AssociationEGFR forERBB2 Molecular PathologyESRl (AMP).PALB2 Source: MarilynPIK3CA M. Li, Michael Datto,not Eric J. Duncavage,not Shashikantnot Kulkarni,not Neal 1. Lindeman,not Somak notRoy, Apostolianot M. Tsimberidou,not Cindy L. notVnencak-Jones, not Daynna J. 1Wolff, SNV Anas Younes, and Marinaidentified N. Nikiforovaidentified "Standards identifiedand Guidelinesidentified for theidentified Interpretation identified and Reporting identified of Sequence identified Variants inidentified Cancer," Journalidentified of Molecular Diagnostics, vol.19, no. l, pp. 4-23 ,2017, doi: 10.1016/j.jmoldx.2016.10.002. PTEN TP53 not • Tier IA:not Variants of strong clinical significance. FDA-approved therapy or biomarkers included in professional guidelines. identifiedTier IB:identified Variants of strong clinical significance. Well-powered studies with consensus from experts in the field. • Tier IIC: Variants of potential clinical significance. FDA-approved therapies for differentcancer types or investigational therapies. Multiple small published studies with some consensus. • Tier IID: Variants of potential clinical significance. Preclinical trials or a few case reports without consensus. SUMMARYTier III: Variants of unknown clinical significance. • Tier IV: Benign or likely benign variants. Overview of potential treatment impacts Overview of prognostic and diagnostic findings Clinical trials found Note 3that Effective in the evidence-based 1 lneffective variant categorizationo Safety context, therapy refers toO the Prognostic combination ofO variant, Diagnostic drug, and disease. 6 Trials Biomarker: In general, a biomarker is any characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathological processes, or pharmacological response to a therapeutic intervention. In the context of MH Guide,VAF/Copy reported biomarkers predict a patient's response to Potential impact Treatment Drug approval Biomarker Biomarker score Trials therapy and are based on the characterization of the patient/tumor genomic DNA. Depending Numberon the analysis type, such genomic characteristics can include single nucleotide variants (SNVs), insertions and deletions (indels), fusion genes, and copy number alterations (CNAs).

Biomarker score: Alpelisib Approved PIK3CA Clinically Effective 66.67% Approved 4 Displays the AMP score and the CVIFulvestrant score of the biomarker.Approved p.E545A (SNV) r;,� CVI score: - PIK3CA The clinicalEffective variant interpretation Everolimus(CVI) scores 7-1 indicateApproved* the reliability of a biomarker to predict66.67% a specific patient outcome. This can2) includePreclinical predictive 2 treatment effects;in this case, the scores 7-1 apply for biomarkers associatedp.E545A with a single(SNV) drug or drug combination. The CVI scores are defined as follows: 7, Clinically approved: The biomarker has been approved by a regulatory agency such as the FDA to predict a -specific effect (i.e., response, resistance, or PIK3CA Effective Sirolimus Other 66.67% 2) Preclinical 0 toxicity) in the patient's disease or cancer type. p.E545A (SNV) 6, Clinical: Patient's disease: The biomarker has not yet been approved by a regulatory agency for the patient's disease. However, the biomarker has been observed in at least one large cohort study to predict a specific effectof the drug (i.e., to be effective,resistance) - in the patient's disease. Other diseases: The PIK3CA biomarkerlneffective has been approved by Trastuzumaba regulatory agency Approved* to predict a specific effectof the drug (response,66.67% resistance) with other diseases4) or Clinicalconditions. This CVI p.E545A (SNV) 1 will be available for matching with the less-specific disease Neoplasms in CVls. Biomarkers predicting toxicity: For all disease matches,� this score indicates that* therethe drug is evidence is approved from afor randomized the cancer controlled type but eithertrial or none its meta-analysis of the currently for biomarkers approved biomarkerspredicting a for drug this- to drugbe toxic. were identified, or an approved resistance 5, Clinical:biomarker The for biomarker the drug haswas not identified yet been in approvedthis patient. by Therefore, a regulatory the agency drug labe[ for the may patient's not cover disease. the analyzed However, patient; this biomarker VAF = Variant has beenallele observed frequency to predict a specificBiomarker effectof score: the drug AMP (i.e., score response, and CVI resistance) score. Clinically on patients approved: with other Approved diseases biomarker or conditions. (by the For FDA, biomarkers EMA, or NCCN) predicting to predict a drug a to specificbe effective effector in resistant,the patient's theredisease. is evidence Clinical: from Not some yet patientsapproved in biomarkerseveral cohort for the studies patient's and additionaldisease. Observed preclinical in clinicalevidence. studies For biomarkers as a potential predicting biomarker a drug to predict to be toxic, a specific there effectis of the evidencedrug. Preclinical: from >l prospective This biomarker studies hasor meta-analyses not yet been observed/tested from prospective in and/or patients retrospective to predict a studies.specific effectof the drug. lt is supported by preclinical evidence or 4, Clinical:translational The biomarker data. has not yet been approved by a regulatory agency for the patient's disease. However, this biomarker has been observed to predict a specificYou can effect findof more the drug details (i.e., on response, the biomarker resistance)score on (AMP patients and CVI with score) other in diseases the glossary. or conditions. For biomarkers predicting a drug to be effectiveor resistant, there is evidence from a few clinical case reports and additional preclinical evidence. For biomarkers predicting a drug to be toxic, there is evidence from a prospective study, >l retrospective studies, or >l cohort studies. 3, Preclinical: The biomarker has not yet been observed/tested in patients to predict a specific effect.The biomarker has been observed in preclinical experiments. There is experimental evidence from cell lines or mouse models, for example. 2, Preclinical: The biomarker has not yet been observed/tested in patients or preclinical models to predict a specific effect.However, this effectcan be inferred when drug-sensitivity data are available for another variant. This applies only if the two variants have the identical functional impact on the same downstream pathway. 1, Preclinical: The biomarker has not yet been observed/tested in patients or preclinical models to predict a specific effect.However, this effectcan be inferred when drug-sensitivity data are available for another variant. This applies only if both variants have the identical functional impact on the protein. Drug approval: The development stage of the treatment for the patient's indication in the patient's country.

Approved - This drug is launched for the primary or a secondary patient disease. • Off-label- This drug is launched for a disease other than the primary or secondary patient diseases. lnvestigational- This drug is currently under clinical development in the patient disease. • Other- None of the other stages are applicable. The drug is, for example, suspended, discontinued, or withdrawn. Other is also used for the drug approval stage of drug classes.

Page Page10 of 113 of 13 Patient name ********** Diagnosis Mammakarzinom DR. SENCKENBERGISCHESDR. SENCKENBERGISCHES Patient name Diagnosis Mammakarzinom R PATHOLOGIER PATHOLOGIE PatientPatient 1D 1D Testl234Testl234 ICD-10-CMICD-10-CM code code ;;;;;;:; spsp CaseCase 1D 1D EU001930EU001930 MeSHMeSH ID/term ID/term D001943D001943 (Breast (Breast Neoplasms) Neoplasms) W1ldlabW1ldlab DateDate of birth of birth AdditionalAdditional MeSH MeSH IDs IDs - -

Drug-drugSex interactions:Female Sample type FFPE Labtest VCF-complete import (paired) General dataset 1D 105685598965 A drug-drug interaction is a situation in which a substance (usually another drug) affectsthe activity of one or both drugs when both are administered Ethnicity EUR Tumor cellularity 100% Organizational unit SIPV2TEST CVI dataset 1D 105685598965 together. In the M H Guide report, drug-drug interactions are reported where a drug is predicted to affectthe activity of the agent(s) in the treatment option. Country DE Software version 4.3.3 Meditations with potential for adverse reaction or ineffectiveness.: MedicationsMutational with status potential of commonly for adverse mutated reaction genes or ineffectivenessin the patient disease refers to Molecular Health's ability to identifytreatments that are predicted to be associated with negative physiological responses to a drug therapy (i.e., drug resistance and toxicity). ATM BRCAl BRCA2 CDK4 CDKN2A CHEK2 EGFR ERBB2 ESRl PALB2 PIK3CA Opennot trials: not not not not not not not not not 1 SNV Clinicalidentified tri als that areidentified currently recruitingidentified patientsidentified with specificidentified disease indication(s)identified toidentified assess the clinicalidentified efficacy identifiedand safety ofidentified the listed treatment. Potential impact: The specificPTEN drug effectTP53 predicted by the identified mutation (i.e. response, resistance, or toxicity). not not PubMedidentified ID: identified A PubMed identifier is a unique number assigned to each PubMed record - also termed PMID. A PMID can be used to retrieve a specific publication from the PubMed database by entering the PMID in the search box on the PubMed site at http://www.ncbi.nlm.nih.gov/pubmed. Treatment:SUMMARY The generic name of the therapeutic agent listed on the report.

Overview of potential treatment impacts Overview of prognostic and diagnostic findings Clinical trials found 3 Effective 1 lneffective o Safety O Prognostic O Diagnostic 6 Trials

VAF/Copy Potential impact Treatment Drug approval Biomarker Biomarker score Trials Number

TheodorTheodor Stern Stern Kai 7, Kai 7, SignedSigned by: by: MolecularMolecular Health Health GmbH GmbH 6059060590 Frankfurt Frankfurt ReportReport date:date: 08 Mar 08 2021 Mar 202116:5816:58 (UTC+Ol:00) (UTC+Ol:00) Kurfürsten-AnlageKurfürsten-Anlage 21, 21, ReportReportversion: version: 3 3 6911569115 Heidelberg Heidelberg OrderOrder date: date: 08 Mar 08 2021 Mar 2021

Page Page11 of 113 of 13 PatientPatient name name ***** ***** DiagnosisDiagnosis MammakarzinomMammakarzinom • DR. SENCKENBERGISCHESDR. SENCKENBERGISCHES R PATHOLOGIER PATHOLOGIE PatientPatient 1D 1D Testl234Testl234 ICD-10-CMICD-10-CM code code ;;;;;;:; spsp CaseCase 1D 1D EU001930EU001930 MeSHMeSH ID/term ID/term D001943D001943 (Breast (Breast Neoplasms) Neoplasms) W1ldlabW1ldlab DateDate of birthof birth AdditionalAdditional MeSH MeSH IDs IDs - -

Sex Female Sample type FFPE Labtest VCF-complete import (paired) General dataset 1D 105685598965 Ethnicity EUR Tumor cellularity 100% Organizational unit SIPV2TEST CVI dataset 1D 105685598965 MOLECULAR HEALTH DISCLAIMER Country DE Software version 4.3.3

MolecularMutational Health status GmbH of commonly (MH) develops mutated and operatesgenes in thesoftware patientsystems disease for the integrated analysis of clinical and genomic patient data to support physicians in choosingATM the optimalBRCAl treatment BRCA2 for individual CDK4 patients withCDKN2A respect toCHEK2 effectiveness EGFRand safety. ERBB2 ESRl PALB2 PIK3CA Molecularnot Health Guidenot (MH Guide)not is a bioinformaticsnot softwarenot tool to aidnot clinical decisionnot makingnot by processingnot genetic variantnot data from1 aSNV patient's tumor throughidentified a variant detectionidentified pipeline.identified This enablesidentified generation identified of a customizable identified clinical identified report with identified a summary ofidentified potentially effectiveidentifiedmedications, potentially ineffectivemedications, and medications that may pose a higher risk of adverse reactions. The MHPTEN Guide VariantTP53 Detection Pipeline covers: not not identified1. Primary identified identification of genetic alterations from next-generation sequencing (NGS) data by the MH Guide Variant Detection Pipeline, either from the patient's tumor (targeted panel analysis) or from both the patient's tumor and the control sample (whole exome analysis) (optional). 2. Aggregation, integration, collation, and maintenance of up-to-date biomedical reference information relevant for clinical decision support in SUMMARYclinical oncology. 3. Mapping of the patient's genetic alterations to the biomedical reference information. 4. Integration of the patient's genetic alterations based on the mapping to biomedical reference information. Overview5. Computational of potential treatment integration impacts of the above information into a summaryOverview of potentially of prognostic effective, andineffective, diagnosticand findings toxic medications, for Clinicalthe individual trials found patient. Also, prognostic and diagnostic biomarkers may be detected and shown for the given disease context. 3 6.EffectiveGeneration of1 a customizablelneffective clinicalo Safety report by a trained user (MH-certifiedO Prognostic physician), providingO Diagnostic links to the sources of evidence of the6 Trials information displayed for full traceability.

The information consolidated in the clinical report provided to the patient's treating physicianVAF/Copy is the result of a comprehensive filter setting based on values Potential impact Treatment Drug approval Biomarker Biomarker score Trials defined by the MH-certified physician. The MH-certified physician is neither a contractor nor anNumber employee of MH. The information provided in the report must be evaluated by the treating physician in conjunction with all other relevant clinical information of the patient before the appropriate course of medication is selected by the treating physician. The selection of any, all, or none of the medications identified in the report is at the sole discretion of the treating physician Alpelisib Approved PIK3CA Clinically and notEffective of MH or the MH medical staff. 66.67% Approved 4 Fulvestrant Approved p.E545A (SNV) r;,� The information provided in this disclaimer may not be applicable when the product is used in other configurations- than the MH standard configuration. PIK3CA MH GuideEffective is designed for processingEverolimus the molecular dataApproved* from patients diagnosed with cancer. 66.67%Diseases beyond this are out of the scope2) Preclinical of the application. 2 In particular, the following data cannot be determined using MH Guide: blood groups;p.E545A infections (SNV) and infectious diseases; irregular anti-erythrocytic antibodies; the hereditary disease phenylketonuria; the HLA tissue groups DR, A, and B; the tumoral marker PSA, and the risk- of trisomy 21. PIK3CA The patientEffective disease must be providedSirolimus in MeSH ontologyOther format for correct interpretation of patient66.67% data. Other disease ontologies2) such Preclinical as ICD must be 0 converted to the correct MeSH term by the certified physician. p.E545A (SNV) Any genetic findings outside of the intended use of treatment decision support in cancer care, e.g., risk factors for potential future diseases of a patient or variants that indicate that the patient is a genetic carrier for hereditary diseases are not annotated and reported,- even though corresponding variants or risk PIK3CA lneffective Trastuzumab Approved* 66.67% 4) Clinical factors may be identified as a result of an MH Guide analysis. p.E545A (SNV) 1 � The identification of a genomic biomarker does not necessarily imply pharmacological effectivenessor ineffectiveness.The medications identified by the * the drug is approved for the cancer type but either none of the currently approved biomarkers for this- drug were identified, or an approved resistance treatingbiomarker physician for the may drug or maywas identifiednot be suitable in this for patient. use on Therefore, a particular the patient. drug labe[ Thus, may the not clinical cover report the analyzed does not patient; guarantee VAF that= Variant any particular allele frequency agent will be effectiveBiomarkerin the treatmentscore: AMP of score any particular and CVI score. condition. Clinically Also, theapproved: absence Approved of a recommendation biomarker (by for the a medication FDA, EMA, or by NCCN) MH Guide to predict does not a specific determine effect thein the patient's effectivenessdisease. Clinical:or predict Not an yet ineffective approvedor biomarker safety-relevant for the effect patient'sof a medication disease. Observed selected in by clinical the treating studies physician. as a potential biomarker to predict a specific effectof the Thedrug. contents Preclinical: of the clinical This biomarker report, a result has not of mappingyet been observed/testedpatient data against in patients the MH to Guide predict database, a specific and effect selectionof the of drug. treatment-relevant lt is supported byinformation preclinical by evidence the or MH-certifiedtranslational physician data. are to be used only as an additional aid to the clinical decision by the treating physician. Interpretation of the report contents must occurYou in can consultation find more withdetails a medical on the biomarker expert. Decisionsscore (AMP on patient and CVI care score) and in treatment the glossary. 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 applicable standard of care. Decisions regarding care and treatment should not be based solely on the information contained in this report. MH Guide can detect single nucleotide variants (SNVs), insertions and deletions (indels), fusion gen es (from DNA or RNA data in unpaired analyses or from RNA data in paired analyses), copy number alterations (paired analyses only), microsatellite instability (MSI-H, paired analyses only) and tumor mutational burden (TMB) from NGS data. The clinical validity of TM B defined by the underlying lab test has not been established. The detection methods for indels, fusion genes and copy number alterations from FASTQ and BAM were validated using synthetic data only. Therefore, indel, fusion gene, and CNA detection in MH Guide must be validated with an orthogonal method (e.g., Sanger sequencing) before a treatment is recommended. MSI status of unclassified cases or MSS cases should be assessed with orthogonal methods before a treatment decision is made based on the MSI status. lt is the responsibility of the MH-certified physician to assess the pre- and post-alignment QC results within MH Guide and to communicate with the treating physician any data which are of suboptimal quality. lf genetic aberration signals are submitted in the format of a VCF file for processing in MH Guide, the quality of the results from MH Guide depends on the quality of the input data submitted by a lab on behalf of the MH-certified physician. The accuracy, analytic sensitivity and specificity of the variant lists is the sole responsibility of the MH-certified physician.

TheodorTheodor Stern Stern Kai 7, Kai 7, SignedSigned by: by: MolecularMolecular Health Health GmbH GmbH 6059060590 Frankfurt Frankfurt ReportReport date:date: 08 Mar 08 2021 Mar 202116:5816:58 (UTC+Ol:00) (UTC+Ol:00) Kurfürsten-AnlageKurfürsten-Anlage 21, 21, ReportReportversion: version: 3 3 6911569115 Heidelberg Heidelberg OrderOrder date: date: 08 Mar 08 2021 Mar 2021

Page Page12 of 113 of 13 PatientPatient name name ***** ***** DiagnosisDiagnosis MammakarzinomMammakarzinom • DR. SENCKENBERGISCHESDR. SENCKENBERGISCHES R PATHOLOGIER PATHOLOGIE PatientPatient 1D 1D Testl234Testl234 ICD-10-CMICD-10-CM code code ;;;;;;:; spsp CaseCase 1D 1D EU001930EU001930 MeSHMeSH ID/term ID/term D001943D001943 (Breast (Breast Neoplasms) Neoplasms) W1ldlabW1ldlab DateDate of birth of birth AdditionalAdditional MeSH MeSH IDs IDs - -

For ethnicitySex JapaneseFemale (J PT) populationSample type frequencies FFPE from ToMMoLabtest 3.5KJPNv2 (MAF>=l %)VCF-complete are available inimport the application (paired) for displayGeneral and dataset filtering. 1D 105685598965 MH GuideEthnicity uses andEUR contains dataTumor and cellularity information 100% obtained fromOrganizational third-party sources. unit MHSIPV2TEST uses reasonable effortsto ensure thatCVI thisdataset information 1D is105685598965 as accurate as possibleCountry in a tightlyDE controlled curation process. However, MH cannot guarantee that data from any third party are accurate,Software comprehensive,version and4.3.3 complete. Thus, MH Guide may not contain all relevant or all up-to-date information. Third-party databases or other sources in MH Guide may only be updated from timeMutational to time with status new of or commonly revised information. mutated genes in the patient disease MH GuideATM has not BRCAlbeen cleared BRCA2or approved byCDK4the U.S. FoodCDKN2A and Drug AdministrationCHEK2 EGFR (FDA). However,ERBB2 MH GuideESRl using VCF asPALB2 input is offeredPIK3CAas a bioinformaticsnot servicenot under CLIA.not not not not not not not not 1 SNV In theidentified European Union,identified Molecular identified Health Guideidentified (MH Guide) identified is registered identified as an in vitro identified diagnostic medicalidentified device identified (IVD). The reportsidentified MH Guide and MH Guide Premium are covered by the IVD registration. MH Guide Onco Report, MH Guide Onco Report+ and MH Guide Onco Report Premium are for non-clinical use. MH isPTEN the legal manufacturerTP53 of MH Guide as a stand-alone software,and the statutory provisions of the German Medical Devices Act (MPG) and the European Directivenot 98/79/ECnot apply to MH. We therefore maintain a quality management system according to EN ISO 13485 for the scope of "Design, Development and Manufactureidentified of softwareidentifiedsystems for the integrated analysis of clinical and genomic patient data to support treatment decisions and provision of related services". MH has also received CLIA certification and CAP accreditation for the provision of MH Guide as a dry lab service to clinical laboratories in the US. MH Guide is a registered trademark of Molecular Health GmbH. SUMMARY

Overview of potential treatment impacts Overview of prognostic and diagnostic findings Clinical trials found 3 Effective 1 lneffective o Safety O Prognostic O Diagnostic 6 Trials

VAF/Copy Potential impact Treatment Drug approval Biomarker Biomarker score Trials Number

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