Breast Cancer: Adjuvante Therapie

Breast Cancer: Adjuvante Therapie Ausgewählte Problemfelder anhand von einzelnen Fällen diskutieren Thomas Ruhstaller Brustzentrum St. Gallen

2 Fallbeschreibung 1 42-jährige Patientin St.n. brusterhaltender Therapie und Axilladissektion Tumorcharacteristika: pt2 (2.2cm), pn1 (1/12), G2, cmo, ER 90%, PgR 40%, HER2-, Ki-67: 24%, LVI 0 Empfehlung des Tumorboards: 4 Zyklen Chemotherapie mit TC Adjuvante endokrine Therapie Wie soll die endokrine Therapie aussehen? +/- OFS Tam oder AI Dauer der Therapie wann Start mit OFS? Adjuvante Radiotherapie der Restbrust 11.02.2015 Referent / Bereich

3 11.02.2015 Referent / Bereich

15 Zwischen 2 Polen.. Med age: 46y G 1/2 T < 2cm N0 Med age: 40y G3 T > 2cm N+ No CT indication No effect on global QoL indicators Less differences >2y Tam alone + OFS CT indication Worse endocrine symptoms and sexual functioning - Hot flushes - Loss of sexual interest - Sleep disturbance - Treatment burden 11.02.2015 Referent / Bereich

16 Fallbeschreibung 1 42-jährige Patientin St.n. brusterhaltender Therapie und Axilladissektion Tumorcharacteristika: pt2 (2.2cm), pn1 (1/12), G2, cmo, ER 90%, PgR 40%, HER2-, Ki-67: 24%, LVI 0 4 Zyklen Chemotherapie mit TC Adjuvante endokrine Therapie Adjuvante Radiotherapie der Restbrust Endokrine Therapie: +/- OFS: eher ja Tam oder AI: AI Dauer der Therapie: 5y wann Start mit OFS:? 11.02.2015 Referent / Bereich

17 Fallbeschreibung 2 62-jährige Patientin, fit und rüstig St.n. brusterhaltender Therapie und Axilladissektion Tumorcharacteristika: pt1c (1.6cm), pn1 (1/12), G2, cmo, ER 70%, PgR 50%, HER2-, Ki-67: 23%, LVI 0 Empfehlung des Tumorboards: Adjuvante endokrine Therapie Adjuvante Radiotherapie der Restbrust Diskussionen bezgl adjuvanter Chemotherapie bei möglichem, aber kleinen Gewinn Zusätzlicher Test empfohlen? OncotypeDX? Andere? 11.02.2015 Referent / Bereich

4 Schritte zur Entscheidungsfindung der adjuvanten Therapie 1) First select the target (subtype) 2) then consider the risk disease 3) The patient (Age, Comorbidities, Socio- cultural background, individual background) 4) The patient s preference Perceived risks, perceived possible benefits, non medical history and information, trustworthy person host 18

Consensus St. Gallen 2011 ER + ER -- HER2+ trastuzumab chemo endocrine trastuzumab chemo HER2 -- endocrine ± chemo chemo Selection of patients is the major challenge

22 Verteilung der Ki-67 im KSSG über die Jahre Normalverteilungen der MIB1-Werte [%] 2010-2014 2010-2014 2010 2011 2012 2013 2014 0 20 40 60 80 100 2010-2014 2010 2011 2012 2013 2014 Total 1154 178 222 247 254 253 Minimum 1 1 2 1 2 1 Maximum 95 90 86 87 95 90 Median 24,5 22,0 23,0 26,0 25,0 25,0 Mittelwert 28,3 25,6 27,4 29,5 28,7 29,4 St.abw. 18,4 17,0 17,3 18,8 18,5 19,6 11.02.2015 Referent / Bereich

23 Intrinsic subtypes Types based on Results Konventionelle IHC ER/PgR, HER2, Ki-67 Adapation to subtypes (St Gallen 2013) PAM 50 50 intrinsic genes Mainly driven by ER, HER2 and proliferation BluePrint Prognostic scores OncotypeDX 80-gene signature Gene function 21 genes (ER/PgR, HER2 and proliferation) Subtypes - Luminal A - Luminal B - Basal-lie - etc Subtypes - Luminal A - Luminal B - Basal-lie - etc 3 risk groups MammaPrint 70 genes 2 risk groups EndoPredict 11 genes 2 risk groups IHC4 ER/PgR, HER2, Ki-67 mit IHC 3 risk groups PAM50 ROR 50 genes plus tumor size 3 risk groups

24 Aktuelle Problematik Tests messen auf verschiedene Weise dasselbe: Prognose Indikation für adjuvante Chemotherapie Unterscheidung von good zu poor risk innerhalb der Luminaltumoren Prognostische Tests in verschiedenen Pat.populationen getestet (N0, N+, early versus late recurrence) «Risk» wird in den meisten Tests ausgeklammert, nun zunehmend implementiert (PAM50 ROR (+T), EPclin) Gentest sehr teuer, meist eine Firma, extrem grosses Marktpotential Konventionelle Tests haben «marketing-mässig» dagegen kaum eine Chance (kein Lobbying) Kosten 1800 bis 3200 Euro

25 prognostisch versus prädiktiv Prognostisch: wahrscheinliches Outcome der Erkrankung Prädiktiv: wahrscheinlicher Benefit einer Therapie Beispiele: HER2+ für HER2-targeted Therapie Triple-Negativität für das Fehlen eines Effektes einer endokrinen Therapie ER+ für endokrine Therapie Entscheidende Frage: Test prädiktiv für CT bei ER+-Tumoren?

«Test the test «26 Vorgaben des «omics framework»: «when are «omics»-based tests fit for use in clincial trials?»

27 «Test the test» für Prädiktion Behandlung A Randomisierung Testverfahren Mit allen klinischen Informationen ohne den Test Behandlung B Behandlung A Behandlung B

Breast Intergroup Trial 0100

INT 0100 Disease-Free Survival 100% 80% 60% 40% 20% 0% Log rank p = 0.002 10-year Estimate CAF T 60% CAFT 53% T alone 48% 0 5 10 15 Years from Registration 29 Albain, et al. PSABCS 2004

30 Retrospektive Analyse von SWOG-100 mit Oncotype DX Albain et al. Lancet 2009, Dez 10

31 Beispiel eines OncotpyeDX-Resultats 11.02.2015 Referent / Bereich

Disease Free Survival deso 2015 St. Gallen Adjuvante Therapie bei Brustkrebs No CAF Benefit if High ER (any N+) 0.00 0.25 0.50 0.75 1.00 Log rank p = 0.98 Tamoxifen + CAF (n=262, 104 failures)) Tamoxifen alone (n=82, 34 failures)) 0 5 10 15 Years Since Registration 32 Albain, et al. PSABCS 2004

33 Gampenrieder, DGHO 2013

34 Konklusion: molekulare Marker Molekulare Tests haben geprüften prognostischen Wert in verschiedenen Populationen Sehr teuer Prädiktiver Wert gegenüber konventionellen Angaben zusammen mit dem Risiko bisher nur retrospektiv geprüft und validiert (bisherige Vergleiche meist mit alten SG-Kriterien oder relativ undifferenzierten Methoden wie Adj!Online) prospektive Prüfung ausstehend, trotzdem auf dem Markt Vor allem ein Instrument für Messung der Proliferation Kein Allerheilweltsmittel bezgl Entscheidung für oder gegen CT

35 Fallbeschreibung 2 62-jährige Patientin, fit und rüstig St.n. brusterhaltender Therapie und Axilladissektion Tumorcharacteristika: pt1c (1.6cm), pn1 (1/12), G2, cmo, ER 70%, PgR 50%, HER2-, Ki-67: 23%, LVI 0 Empfehlung des Tumorboards: Gentests Adjuvante? endokrine Therapie Adjuvante Radiotherapie der Restbrust Oft gibt das Testresultat keinen grossen zusätzlichen Nutzen an Diskussionen bezgl adjuvanter Chemotherapie bei möglichem Information kleinen Gewinn Das Abwägen für oder gegen CT bei wahrscheinlich kleinem Benefit Zusätzlicher muss im Test Gespräch notwendig mit der? OncotypeDX Patientin evaluiert? Andere werden? 11.02.2015 Referent / Bereich

36 Fallbeschreibung 3 83-jährige Patientin St.n. brusterhaltender Therapie und Axilladissektion Tumorcharacteristika: pt2 (2.2cm), pn1 (3/12), G3, cmo, ER 90%, PgR 0%, HER2-, Ki-67: 33%, LVI 0 RT und endokrine Therapie, aber auch klare Indikation für adjuvante Chemotherapie Soll adjuvante CT empfohlen werden? Wenn ja welche? 11.02.2015 Referent / Bereich

37 Systemic therapy in elderly patients Old (>80y) or elderly and frail

38 Reasons to balance decisions differently. Missing evidence 50% >64y women, but only 9% > 64y in clinical trials included (Hutchins LF, N Engl J Med 1999; 2061) Most studies investigating systemic therapy until 70y If not, barriers of accrual are bias of physician, patients and the family members Stringent exclusion criteria Judging the benefit of therapy Adjuvant therapy against natural life expectancy Adjuvant and metastastic: toxicity higher? Estimation of «frailty» is difficult Geriatric assessments could be helpful Biologic and prognostic different tumors?

39 The tumor of the elderly woman More advanced stage by diagnosis (Freyer, Ann Oncol 2006, 211) Different biology or different attitude? Retrospective analysis of 3814 pts (Molino A, Crit Rev Oncol Hematol 2006: 226) Elderly pts: larger tumors, more axillary node involvement and lymphovascular invasion more ER/PgR-pos. tumors, lower grades and proliferative indices, and less likely HER2-positive Differences in prognosis? (Singh, Cancer 2004:1807) 2136 pts with mastectomy without any systemic treatment (1927-87) Med F-u: 12.3y 10-DDFS in the N0-group higher in the group < 70y 10-DDFS in the N+-group similar 20-30% of older pts aggressive biologic phenotype (ER-)

40 Estimation of life expectancy very important for recommendation of adjuvant therapy = helpfull tool 70y, healthy 15y+ life expectancy 70y, relevant comorbidities 3-5y life expectancy

41 Adjuvant endocrine therapy

42 Adjuvante chemotherapy SEER registry: 23053 pts >65y 20%: N1-3 15%: N4+ 10-24% with poor prognostic factors (large tumor size, ER-, high proliferation) there is a population with a high risk of recurrence and an indication for adjuvant chemotherapy Little evidence about benefits and risks of CT >70y

43 A lot of evidence: Elderly patients get less intensive therapy EBCTCG Lancet 2011 Few women over 70 years (4.3%) of age entered these trials; they may have had somewhat greater immediate hazards from chemotherapy, but appear to have had as great a reduction as younger women in breast cancer recurrence and mortality

44 SEER database (Elkin EB et al., JCO 2006; 2757) 1711 women, ER-, stage l-lll, 92-99 Reduction of adjuvant CT with age: 66-69y: 52% > 85y: 5% 15% reduction in all-cause-mortality with chemotherapy, driven by the N+-cohort Adjuvant CT over time: 1991: 7.4% 1999: 16.3%

45 Benefit of chemotherapy in the elderly Comparison with younger patients should be taken with caution: small minority of elderly pts highly selected «Benefits of CT did not differ across age groups» in studies but.older pts have worse OS due to competing causes of death higher rate of treatment related mortality (~1.5%) Reasons for higher toxicity: - changes in pharmacokinetics of drugs - polypharmacy and potential drug interactions - poor compliance (oral therapies)

46 Less intensive adjuvant chemotherapy? 600 pts >65y (60% 70-79y), stage l-lllb, 67% ER+, >70% N+ R JCO 2011; 1022 QUALITY OF LIFE: Capecitabine was associated with better QoL during treatment, QoL was similar for both groups at 1 year Breast Cancer Res Treat 2013; 607 COGNTIVE FUNCTION: Over 24 months, women reported minimal 6xCMF / 4x AC changes at each time point and insignificant differences by treatment arm were observed 6x Capecitabine (2g/m2 d1-14 q3w)

47 Adjuvant trastuzumab in elderly Systematic review of RCT: (Brollo J, Cancer Treat Rev 2013; 44) PACS04: <65y BCIRG 006: 48% >50y, no subgroup analysis acc to age FinHer: <66y HERA: 549 (16%) > 60y NSABP/NCCTG: 535 (16%) > 60y The pooled proportion of cardiac events was 5%: HERA 3.75% (0.06%) N9831 6.6% (3.5%) B-31 5.2% (4.1%)

48 Conclusion The term «old» or «elderly» not clearly defined It is changing over time! Additional difficulties for decisions: It is a kind of art to treat old breast cancer patients! missing evidence >70y Benefits balanced in relation to life expectancy Frailty difficult to estimate (geriatric assessments) Compared to younger pts: More advanced stages by diagnosis more ER+ /good risk tumors but 20-30% with aggressive biology Decisions about therapy: The same benefits can be reached, but we have to consider other conditions: Life expectancy, competing causes of death, higher toxicity Pts and relatives may have different goals than younger pts Use the best drugs, but an adaption of the dose maybe justified

49 Fallbeschreibung 3 83-jährige Patientin St.n. brusterhaltender Therapie und Axilladissektion Tumorcharacteristika: pt2 (2.2cm), pn1 (3/12), G3, cmo, ER 90%, PgR 0%, HER2-, Ki-67: 33%, LVI 0 RT und endokrine Therapie, aber auch klare Indikation für adjuvante Chemotherapie Soll adjuvante CT empfohlen werden? Wenn ja welche? 11.02.2015 Referent / Bereich

50 No relevant comorbidites Relevant comorbidities

51 Fallbeschreibung 4 75-jährige Patientin St.n. brusterhaltender Therapie Tumorcharacteristika: pt1c (1.2cm), pn0 (0/1 sn), G2, cmo, ER 100%, PgR 80%, HER2: ICH( Oracle) 3+, Ki-67: 24%, LVI 0 Empfehlung des Tumorboards: Chemotherapie, Trastuzumab für ein Jahr, Adjuvante endokrine Therapie Adjuvante Radiotherapie der Restbrust Wie soll die Chemotherapie aussehen? Dauer, Art? 11.02.2015 Referent / Bereich

Adjuvant Trastzumab

65 Fallbeschreibung 4 75-jährige Patientin St.n. brusterhaltender Therapie Tumorcharacteristika: pt1c (1.2cm), pn0 (0/1 sn), G2, cmo, ER 100%, PgR 80%, HER2: ICH( Oracle) 3+, Ki-67: 24%, LVI 0 Empfehlung des Tumorboards: Chemotherapie, Trastuzumab für ein Jahr, Adjuvante endokrine Therapie Adjuvante Radiotherapie der Restbrust SG Policy: kurze CT zum Beispiel 4 x TC zusammen mit Trastuzumab 11.02.2015 Referent / Bereich

66 Fallbeschreibung 5 53-jährige Patientin St.n. brusterhaltender Therapie und Axilladissektion Tumorcharacteristika: pt2 (2.5cm), pn1 (3/14), G3, cmo, ER 0%, PgR 0%, HER2-, Ki-67: 44%, LVI 1 Empfehlung des Tumorboards: Chemotherapie über 6 Monate Adjuvante Radiotherapie der Restbrust und Lymphabflusswege Wie soll die Chemotherapie aussehen? +/- Platine 11.02.2015 Referent / Bereich

67 The term «triple-negative BC» describes what it is not: ER-,PgR-, HER2- Immunhistochemical phenotyp first mentioned 2005, since then hundreds of publications 15% of all BC: younger patient high proliferation visceral and cerebral metastases msurvival 12ms often early relapses, after 5y nearly no relapses..but, TNBC is molecularly heterogenous!!

TNBC and gene expression signature 70-90% overlapping with basal-like BC non-triple-neg. BLBC: (25%) - mainly HER2+ - seldom ER+ TNBC BLBC Non-basal-like TNBC: - claudin-low tumors - medullary tumors - metaplastic tumors - others BLBC: genetically instable BRCA Mutation 16-42% of TNBC have BRCAmutation

69 Cornerstone of therapy: Chemotherapy but mixed results. Retrospective review (MDACC): 1118 pts, 85-04, stage l-lll, complete receptor information available no trastuzumab, all neoadjuvante chemotherapy 255 TNBC (<10% ER) pcr TNBC: 22% pcr non-tnbc: 11%

70 Conventional chemotherapy and TNBC Retrospective subgroup analysis: Anthracyclines versus CMF: conflicting results Anthracyclines +/- Taxanes: adjuvant BCIRG 001: TAC vs FAC (J. Hugh, J Clin Oncol, 2009) Standard: TNBC (n=192), 3y-DFS 73.5% vs. 60% (p=0.051) Anthracyclines and taxanes-based BLBC (ICH) sig. better survival with FEC/DOC combination CT PACS01: 6x FEC vs 3x FEC/3x DOC (J Jacquemier, J Clin Oncol, ab. 509) TACT Trial: 8xFEC or 4xFEC/4xCMF vs 4xFEC/4xDOC No differences (P. Ellis, Lancet 2009)

71 Chemotherapy responses dependent on molecular subtypes? H. Masuda, ASCO 2013

72 Predictive factors for therapy? «targets? BRCA function: 1. BRCA responsible for development of stem cell to ER+-Luminal A cell 2. DNA-Repair Mutation Cancer Germline BRCA1/2 and sporadic mutations in unselected TNBC about 20% Mutation in BRCA: Platinums PARPi sensitive to DNA-damaging substances Also true for BRCAness (Function loss of BRCA)?

73 DNA-repair-defects of TNBC as target for platinum therapy Unselected TNBC: Small, single center ph-ll trial Neoadjuvant:

74 gbrca 1/2 and Platinums Proof of concept study: 25 BRCA1 carrier: 4x Cisplatin neoadjuant: pcr 72%! Gronwald, J Clin Oncol 2009, abstr. 502 Cisplatin neoadjuvant (n=28) in unselected pts: 22% pcr, 64% PR, 14% PD 2 BRCA1 carrier: both pcr J Clin Oncol 2010; 28(7):1145-53 PrECOG 0105: phase II study of gemcitabine (G) and carboplatin (C) plus iniparib (BSI-201) as neoadjuvant therapy for TNBC and BRCA1/2 mutation-associated breast cancer. Overall pcr 36% gbrca 1 or 2 56% Loss of heterozygosity (measurement of genomic instability): ~ pcr (gbrca1/2 and wild-type pts!)

TNT: Carboplatin vs Taxotere Primary endpoint: Secondary endpoint: ORR PFS, OS, ORR (crossover treatment), toxicity Median follow-up in all patients: 11.0 months

TNT: Carboplatin vs Taxotere

TNT: Konklusion Kein Vorteil von Carbo vs Taxotere in unselektionierten triple-neg Patientinnen Verbesserte responses und PFS bei BRCA1/2-mutierten Patientinnen von Carbo vs Taxotere BRCA1/2 genotyping empfohlen für Indikation von Platinen

PARP Inhibitors Proof-of-concept in BRCA 1/2 BC 400mg 100mg A. Tutt, Lancet, 2010

BRCAness also a target of PARPi for - high-grade, serous ovarian cancer? - TNBC? Lancet Oncol 2011, 852-861

Ovarian Cancer: gbrca-mut: single agent PARPi sufficient for response BRCA-ness: single agent PARPi sufficient for response J Clin Oncol 28:15s, 2010 (suppl; abstr 3002)

Breast Cancer: BRCA-Mutation: single agent PARPi sufficient for response BRCA-ness (TNBC): single agent PARPi not sufficient for response TNBC as a surrogate for BRCAness is not predictive for PARPi response! J Clin Oncol 28:15s, 2010 (suppl; abstr 3002)