PROBLEMATICHE APERTE NELLA DETERMINAZIONE DI HER2 NEL CARCINOMA MAMMARIO: DALLA DIAGNOSI ALLA TERAPIA Trento - 19 novembre 2010

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1 Determinazione di Her2 in FISH front-line 10 anni di esperienza dr.ssa Marcella Flora U.O. ANATOMIA PATOLOGICA Oncology Department Az.Opedaliera S.Maria Nuova, Reggio Emilia, Italia. PROBLEMATICHE APERTE NELLA DETERMINAZIONE DI HER2 NEL CARCINOMA MAMMARIO: DALLA DIAGNOSI ALLA TERAPIA Trento - 19 novembre 2010

2 FISH front-line 10 anni di esperienza

3 Determinazione di Her2 in FISH front-line 10 anni di esperienza Our surgical pathology unit at Reggio Emilia Hospital receives all breast cancer samples from Reggio Emilia PROVINCE They account for about 550 new cases per year. now we know ( J Clin Oncol 27: ) that standard considerations of laboratory testing including test accuracy, reproducibility, and precision, as well as the current data favor FISH over IHC assay methods for determining HER-2 status.

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5 Determinazione di Her2 in FISH front-line 10 anni di esperienza Despite all considerations and the ASCO- CAP guidelines in J Clin Oncol 27: only few laboratories apply front- line FISH strategy to all breast cancers at the moment of first diagnosis and metastatic relapse. Our extensive practical experience in her2 FISH testing starts in 2000 when Pathvysion probes became available in Italy.

6 Determinazione di Her2 in FISH front-line 10 anni di esperienza Our oncologists stressed the FISH testing for HER2 as,at that time, IHC test accuracy, reproducibility, and precision was not satisfactory, therefore we developed a front line FISH strategy,that in our experience was easier from an organizational standpoint, than organizing an algorithm where to perform first IHC test to all samples except cytological ones from FNA S S., and only after scoring IHC samples, to run FISH on ++ samples.

7 Determinazione di Her2 in FISH front-line 10 anni di esperienza. Data from January 2004 to September 2009 : TOTAL FISH TEST 2906 HER2 AMPLIFICATION % HER2 NORMAL 2523 Chromosome 17 Polisomy %

8 Determinazione di Her2 in FISH front-line 10 anni di esperienza Ultimately, HER-2 FRONT LINE FISH testing permits the most accurate determination of whether or not an individual tumor specimen contains HER-2alteration with great enhancement of therapeutic efficacy and oncologists confidence. Last data from our Regional EMILIA ROMAGNA Tumour Registry show very encouraging results in terms of OS for breast cancer patients in REGGIO EMILIA province : 92% versus 85% of National Registry. Also encouraging is decreasing mortality trend despite increasing incidence for breast cancer

9 MAMMELLA REGGIO Determinazione di Her2 in FISH front-line 10 anni di esperienza Il trend di incidenza e mortalità APC (Annual Percent Change) incidenza mortalità * incidenza mortalita 11/58 I TUMORI A REGGIO EMILIA NEL 2007 Lucia Mangone, Registro Tumori Reggio Emilia

10 SOPRAVVIVENZA Mammella 1 0,9 0,8 femmine 92% 87% 86% 0,7 0,6. 0,5 0, /58 I TUMORI A REGGIO EMILIA NEL 2007 Lucia Mangone, Registro Tumori Reggio Emilia

11 G.SAUTER Reply to V. Arena et al JCO VOLUME 28 NUMBER 5 FEBRUARY Arena V, Pennacchia I, Carbone A, et al: FISH for HER-2 assessment in breast cancer: Is it applicable as a primary test? J Clin Oncol 27:e8, a. Arena V, Pennacchia I, Monego G, et al: Fluorescent in situ hybridization as a primary test for HER2 status in breast cancer: Controversies. J Clin Oncol 28:e83-e84, 2010.

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13 Determinazione di Her2 in FISH front-line 10 anni di esperienza PROBLEMATICHE APERTE in FISH FRONT LINE : STRATEGIA POCO USATA :PERCHE? PROBLEMATICHE GESTIONALI : ORGANIZZAZIONE FRAMMENTAZIONE LABORATORI COSTI STRUMENTAZIONE Tempi di RISPOSTA

14 Determinazione di Her2 in FISH front-line 10 anni di esperienza PROBLEMATICHE APERTE in FISH FRONT LINE : STRATEGIA POCO USATA :PERCHE? PROBLEMATICHE SCIENTIFICHE : TEST QUANTITATIVO CASI BORDERLINE ETEROGENEITA GENETICA CONTROLLI DI QUALITA INTERLAB QUANTI PAZIENTI SI ARRUOLANO?

15 Determinazione di Her2 in FISH front-line 10 anni di esperienza. Data from January 2004 to September 2009 : TOTAL FISH TEST 2906 HER2 AMPLIFICATION % HER2 NORMAL 2523 Chromosome 17 Polisomy %

16 FONDAZIONE MICHELANGELO 23 Ottobre Seminario: Up-date on HER2-directed therapies in early breast cancer

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19 FONDAZIONE MICHELANGELO 23 Ottobre Seminario: Up-date on HER2-directed therapies in early breast cancer Edith Perez

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21 Controlli di Qualità FISH HER2 DIP.SC.BIOMEDICHE e ONCOL.UM.UNIV.TORINO U.PATOL.SENOL. A.O.U S.G.Battista TORINO GRUPPO B Elenco centri: 1) IRCC Candiolo (TO) 2) Treviso 3) Piacenza 4) San Luigi Orbassano (TO) 5) Trento 6) Reggio Emilia 7) Belluno 8) Bergamo 9) Torino

22 SAUTER G. et al GUIDELINES for HER-2 TESTING :BIOLOGIC and METODOLOGIC CONSIDERATIONS JCO 2009 HER2 BORDERLINE in FISH 2% POLISOMY 2-9% 2 FALSE POSITIVE in IHC 5-22% 5 FALSE NEGATIVE in IHC 2-8% 2 IHC % HER-2 2 AMPLIFICATION 20-25% 25%

23 Optimal Testing Algorithm. Result Category IHC Score HER2 Protein Expression Testing Method FISH Score HER2 Gene Amplification HER2/CEP 17 ratio >2.2 Positive 3+ ** or Average HER2 gene copy number >6 Equivocal 2+ Negative 0 1+ HER2/CEP 17 ratio of or Average HER2 gene copy number 4 6 HER2/CEP 17 ratio <1.8 or Average HER2 gene copy number <4 ** Defined as uniform intense membrane staining of >30% of invasive tumor cells Signals/nucleus for those test systems without an internal central probe ASCO-CAP2007

24 Optimal Testing Algorithm HER2 analysis must be preformed on the invasive component of breast cancer since HER2 overexpression and/or amplification is frequently increased in situ Equivocal results require additional action: Equivocal Samples Confirm by IHC FISH* FISH analysis of original sample Counting additional cells or Repeating FISH test * Confirmatory IHC is recommended if FISH remains equivocal so that HER2 protein expression is known for the sample with true equivocal gene amplification status ASCO-CAP2007

25 Optimal Testing Algorithm. FISH Breast cancer specimen (invasive component) HER2 testing by validated FISH assay for HER2 gene amplification Positive for HER2 gene amplification (FISH ratio >2.2 or HER2 gene copy >6.0) Equivocal for HER2 gene amplification (FISH ratio or HER2 gene copy ) Count additional cells for FISH or retest, or test with HER2 IHC Negative for HER2 gene amplification (FISH ratio <1.8 or HER2 gene copy <4.0) ASCO-CAP2007 Equivocal HER2 gene amplification result (Patients with HER2/CEP17 ratio 2.0 were eligible for the adjuvant trastuzumab trials)

26 Optimal Performance, Interpretation & Reporting Laboratories that test for HER2 are required to participate in proficiency testing HER2 status should be used for patient management only if the testing laboratory is CAP-accredited or has met accreditation requirements outlined in the ASCO/CAP guideline Oncologists are encouraged to verify the laboratory accreditation status as well as confirm standardized reporting elements for IHC and/or FISH when reviewing HER2 test assessments ASCO-CAP2007

27 REFERTO REGGIO EMILIA RICERCA dell AMPLIFICAZIONE GENICA DI HER-2/ neu in FISH (Fluorescence In Situ Hybridization ) ANALYSIS.* Su sezione istologica di CARCINOMA MAMMARIO *IBRIDAZIONE effettuata con DUAL COLOR PROBE LSI HER-2/ 2/neu Spectrum Orange/ CEP 17 Spectrum Green. PathVysion kit VYSIS. Sono stati esaminati 60 nuclei neoplastici in interfase di carcinoma mammario che hanno evidenziato il seguente risultato : La media dei segnali HER2/neu è 2.4 La media dei segnali CEP 17 è 2.1 Rapporto HER2/neu : CEP 17 = 1.1 CONCLUSIONE : HER-2/ neu NON AMPLIFICATO HER-2/NEU AMPLIFICATO

28 G.SAUTER Reply to V. Arena et al JCO VOLUME 28 NUMBER 5 FEBRUARY From a therapeutic perspective, it is rare that there is a medical time constraint that cannot be accommodated by the additional time that may be needed to repeat the assay. Given the significant difference in therapeutic approaches for HER2-positive versus HER2-negative breast cancers as well as the dramatic difference in cost of therapy, it is much more important to obtain the correct test result than a result within 72 to 96 hours. Our reported 98.4% success rate in Cancer International Research Group (CIRG) clinical trials was conducted under conditions requiring us to communicate thefishassay report to the clinical site within 5 days of receiving the specimen.

29 Background Agents that target the HER2 pathway have been developed for use in the metastatic and adjuvant settings Trastuzumab (anti-her2 therapy) was FDA-approved in 1998 for treatment of metastatic disease Adjuvant trastuzumab reduces the risk of recurrence and mortality by ½ and 1 / 3, respectively, in patients with early stage, high-risk breast cancers that overexpress HER2 Costs for one year of trastuzumab range from $70,000-$110,000 $110,000 Trastuzumab correlates with asymptomatic cardiac dysfunction (5-15% of patients) and symptomatic congestive heart failure (2-4% of patients) ASCO-CAP2007

30 SAUTER G. et al GUIDELINES for HER-2 TESTING :BIOLOGIC and METODOLOGIC CONSIDERATIONS JC Some have argued that FISH is a more expensive method thanihcfor HER-2 determination. However, an analysis of total cost and benefits supports primary FISH testing as the most costeffective approach for patient management.to best inform policy makers,her-2testing guidelines should also consider an economic evaluation that assesses the clinical benefits and adverse effects of therapy measured in qualityadjusted life-years; the observed response to therapy with various testing methods; and the cost of testing, monitoring, and treatment.

31 SAUTER G. et al GUIDELINES for HER-2 TESTING :BIOLOGIC and METODOLOGIC CONSIDERATIONS JCO2009 This is especially important when considering that the cost of trastuzumab is approximately $1,000 per treatment once a week for 52 weeks and the cost of lapatinib is approximately $120 per daily treatment for 6 months. In addition, trastuzumab administered either concurrently with or after anthracycline chemotherapy has significantly increased anthracycline-associated cardiac toxicity rates. In a recent review of economic models, adjuvant therapy seems cost effective,

32 G.SAUTER Reply to V. Arena et al JCO VOLUME 28 NUMBER 5 FEBRUARY FISH COST One must also be careful not to confuse reimbursement with cost. Economic analyses of HER2 testing document costs of IHC ranging from $61 to $285 ( 43 to 200) and FISH ranging from $250 to $782 ( 175 to 548), but those are often based on a payer perspective.barberis et al compare several HER2 testing methods basedona laboratory perspective.ihccosts per case (HercepTest, DAKO,Carpinteria,CA)ranged from $151downto $71 ( 106 to 50) for the processing of from 1 to 40 cases, respectively..

33 G.SAUTER Reply to V. Arena et al JCO VOLUME 28 NUMBER 5 FEBRUARY FISH COST For FISH (Path-Vysion, Abbott Molecular, Abbott Park, IL), costs per case ranged from $652 to $250 ( 457 to 175) for processing 1 to 40 cases, respectively. Becasue both reagent and technical staff costs are included for both IHC and FISH, the cost differential between FISH and IHC declines from approximately $500 to $179 ( 351 to 125) with increasing numbers of samples processed, further suggesting that centralized laboratory testing may both improve quality and reduce medical expenditures independent of HER2 testing algorithms. We fully understand the challenges of operating within a laboratory

34 SAUTER G. et al GUIDELINES for HER-2 TESTING :BIOLOGIC and METODOLOGIC CONSIDERATIONS about FISH costs : Many studies in the past have shown (LIDGREN M. Acta Oncologica,, 2008; 47: 1018_1028) that trastuzumab and chemotherapy treatment for FISH positive patients is a cost-effective treatment option from a social perspective

35 G.SAUTER Reply to V. Arena et al JCO VOLUME 28 NUMBER 5 FEBRUARY FISH costs FISH costs We fully understand the challenges of operating within a laboratory budget, but one must avoid reducing laboratory costs at the expense of even larger costs related to increased pharmaceutical, outpatient, and inpatient costs for therapies that might not be effective in a given patient. The drug costs alone (approximately $40,000 { 28,040} excluding infusion costs and chair/nursing time) to treat even one patient with a full course of trastuzumab, who was incorrectly identified as HER2 positive, would cover the increased cost of testing approximately 223 patients by FISH.

36 G.SAUTER Reply to V. Arena et al JCO VOLUME 28 NUMBER 5 FEBRUARY When QALY is appropriately integrated, the cost effectiveness of going from the least cost strategy to primary FISH is less than $28,000 ( ) per QALY, well below established thresholds for commonly provided health interventions in developed countries. For example, in Making Choices in Health: WHO Guide to Cost-Effectiveness Analysis, three broad categories of cost-effectiveness are defined: interventions that gain each year of healthy life at a cost less than the per capita gross domestic product (GDP) are defined as very cost effective; at a cost between one and three times gross domestic product per head are cost effective; and the remainder are not cost effective.

37 G.SAUTER Reply to V. Arena et al JCO VOLUME 28 NUMBER 5 FEBRUARY WHO. Guide to Cost-Effectiveness Analysis, According to the International Monetary Fund, the per capitagdpfor Italy in 2008 was approximately ($39,000). For the United States, the figure is $46,859 ( ). Accordingly, primary FISH is between cost effective and highly cost effective for both Italy and the United States.

38 SOFTWARE IMAGING

39 . G.SAUTER Reply to V. Arena et al JCO VOLUME 28 NUMBER 5 FEBRUARY

40 G.SAUTER Reply to V. Arena et al JCO VOLUME 28 NUMBER 5 FEBRUARY Guido Sauter Department of Pathology, University Medical Center Hamburg-Eppendorf,University of Hamburg, Germany James A. Lee Health Quality Research, Altarum Institute, Ann Arbor, MI Dennis J. Slamon Division of Hematology and Oncology, Department of Medicine,University of California at Los Angeles Michael F. Press Department of Pathology Cancer Center, University of Southern California, Los Angeles,

41 Determinazione di Her2 in FISH front-line 10 anni di esperienza GRAZIE!!!

42 I COME TO PRISE FISH NOT TO BURY IT WILLIAM SHAKESPEARE GIULIO CESARE