Lecture 5 Primary systemic therapy: clinical and biological endpoints Valentina Guarneri, M.D., Ph.D.
Primary systemic therapy in breast cancer Firstly introduced d into clinical i l practice in 70s for inoperable LABC and IBC Preoperative chemotherapy is the standard of care in locally advanced and inflammatory breast cancer: achievement of operability in large, bulky tumors improvement of survival in IBC Preoperative chemotherapy has been introduced in large, operable primaries, to increase the chance for breast conserving surgery
Preoperative chemotherapy for women with operable breast cancer (Review) Preoperative vs postoperative, ti Overall Survival The Cochrane Library, Issue 3, 2008
Preoperative chemotherapy for women with operable breast cancer (Review) Preoperative vs postoperative p chemotherapy, mastectomy rate
Primary systemic therapy (PST) in breast cancer ESMO 2011: Primary systemic therapy is indicated for locally advanced breast cancer (stages IIIA B) including IBC [III, B] and for large operable tumors for reducing tumor size in order possibly to perform breast conserving surgery NCCN 2012: - LABC -IBC - stage IIA, IIB, IIIA and fullfills the criteria for breast conservation except for size According to these recommendations, PST should not be given to: - Patients eligible upfront to BCS - Patients with multicentric tumors - Patients for whom BCS would not guarantee satisfactory cosmetic results - Patients not eligible for or unwilling to receive RadiationRx
Breast conservation Mastectomy
pcr No-pCR
Pathologic complete response (pcr) vs residual disease DFS Overall Survival OS The Cochrane Library, Issue 3, 2008
Untch M et al, J Clin Oncol 2011
Response to neoadjuvant therapy and long-term survival in triple negative BC C Liedtke et al, J Clin Oncol 2008
Different definitions of pcr Definition of pcr NSABP: Absence of invasive cancer in the breast MDACC: Absence of invasive cancer in the breast and in the axillary lymph nodes. GBG: Absence of invasive and in situ cancer cells in the breast and din the axillary nodes The prognostic value of pcr is maintained irrespectively of the definition
Hormone receptor status and pcr % pcr Ti Trial/author pts # Regimen pcr % HR- HR+ Ring 435 CMF, A/E 12 21.6 8.1 Bear 1211 AC 10 13.6 5.7 Bear 565 AC+T 19 22.8 14.1 GEPARDUO 913 ddad/ca-d 11 22.8 6.2 GEPARTRIO 286 TAC/TAC-NX 17 36.6 10.1 Guarneri 1731 FAC+/-P 13 23.8 7.8 Gianni 448 A+/P/CMF 20 42.2 11.6 Guarneri 201 FEC/ET/GET 9 15% 5% Colleoni 399 ECF/EC/ET/ViFuP 16 33.3 7.6
Hormone receptor status and pcr % pcr Ti Trial/author pts # Regimen pcr % HR- HR+ Ring 435 CMF, A/E 12 21.6 8.1 Bear 1211 AC 10 13.6 5.7 Bear 565 AC+T 19 22.8 14.1 GEPARDUO 913 ddad/ca-d 11 22.8 6.2 GEPARTRIO 286 TAC/TAC-NX 17 36.6 10.1 Guarneri 1731 FAC+/-P 13 23.8 78 7.8 Gianni 448 A+/P/CMF 20 42.2 11.6 Guarneri 201 FEC/ET/GET 9 15 5 Colleoni 399 ECF/EC/ET/ViFuP 16 33.3 7.6
pcr No-pCR Histology KI67 Grade HR HER2
NEOADJUVANT P-FEC TRASTUZUMAB IN HER2+ OPERABLE BREAST CANCER T-FEC 19 pts T-FEC + H 23 pts pcr 26.3 % 65.2 % pcr ER pos 27 % 61 % pcr ER neg 25 % 70 % pn0 78.9 % 86.9 % Buzdar, J Clin Oncol 2005 Buzdar AU, Clin Cancer Res 2007
NOAH (n=115) H + AT q3w x 3 cycles H + T q3w x 4 cycles H q3w x 4 cycles + CMF q4w x 3 cycles HER2-positive LABC (IHC 3+ or FISH+) (n=113) AT q3w x 3 cycles T q3w x 4 cycles CMF q4w x 3 cycles HER2-negative LABC (IHC 0/1+) (n=99) AT q3w x 3 cycles T q3w x 4 cycles CMF q4w x 3 cycles Surgery followed by radiotherapy a H continued q3w to week 52 Surgery followed by radiotherapy a 19 crossed over to H Surgery followed by radiotherapy a
Gianni L, Lancet 2010
HER2+ BC: looking for a new gold standard Phase III NeoALLTO study Phase II CHER-LOB study
Dual Anti-HER2 blockade significantly increases the pcr rate 60 50 Exploratory p=0 0.01870187 40 30 20 10 0 Arm A: CT + T Arm B: CT + L Arm C: CT + T + L pcr (breast & axilla) Baselga J et al. Lancet 2012 Guarneri V et al, J Clin Oncol 2012
ALTTO study design (8000 patients)
Primary systemic therapy should be tailored on molecular subtypes In vivo assessment of treatment effect, being pcr a powerful predictor of long-term outcome for HER2 positive and triple negative disease This is less true for HR positive tumors for the following reasons: Very low pcr rate Rescue from adjuvant a HT
Primary systemic therapy for HR+ Study P024 IMPACT Semiglazov GEICAM L T A T A+T Chemo AIs Chemo AIs Clinical OR % 55 36 37 36 39 63.6 64.5 - - US response % 35 25 24 20 28 46 40 66* 48* BCS % 45 35 46 22 26 24 33 47 56 pcr % 2 3 - - - 6 3 6 0 *MRI response
IMPACT Trial 330 Intent to Treat patients Randomise Pretreatment surgical assessment for Mastectomy or BCS* Anastrozole 113 Tamoxifen 108 Combination 109 3 months Major violations/ deviations 34 (10%) Surgery 292 Per Protocol patients * Breast conserving surgery
ACOSOG Z1031 COHORT B Postmenopausal patient with clinical Stage II or stage III ER+ Breast Cancer R A N D O M I Z E Exemestane Letrozole Anastrozole 2 4 week biopsy for Ki67 testing Ki67 > 10% Chemotherapy or Immediate Surgery Ki67 10% Continue AI therapy S U R G E R Y PEPI score 0 Path stage 1/0 No Chemotherapy PEPI > 0 Path Stage > 1 treatment t t discretionary F O L L O W SURGERY FOLLOW Amendment 6 Activated October 1 st 2009 http://www.ctsu.org/ p// PEPI: Preoperative Endocrine Prognostic Index
S C R E E N I N G R A N D O M N = 138 N = 132 Letrozole 2.5 mg/d RAD001 10 mg/d Letrozole 2.5 mg/d Placebo 16 weeks Surgery Tumor biopsy (pretreatment) Tumor biopsy (15 days) OR (CR+PR) E+L (n=138) P+L (n=132) p Palpation 68.1 59.1.062* USG 58.0 47.0.035* *1-sided chi-square level of significance is 10%. Baselga J et al. J Clin Oncol 2009
Baselga J et al. J Clin Oncol 2009
Tailoring anti-her2 therapy: the p95her2 story p95her2 is an NH(2)-terminally truncated form of HER2 that lacks the trastuzumab binding site p95her2 is expressed in approximately 30% of HER2 positive breast cancer patients Preclinical and initial clinical evidence suggest that p95her2 confers resistance to trastuzumab p95her2 might retain sensitivity to kinase inhibitors Molina, et al. Clin Cancer Res 2002;8:347-53; Scaltriti, et al. J Natl Cancer Inst 2007; 99(8):628-38
CHER LOB p95her2 testing: methodology Assay Format: IHC assay developed by biotheranostics and biomerieux to detect p95, a C-terminal fragment (CTF) of the full-length HER2, by using a monoclonal antibody that specifically recognizes the 611 CTF Scoring system: p95her2 score 0,1+,2+,3+ based on membrane staining. Different cut offs for binary score of positive or negative were tested, from 30% to 80% of tumor cells with strong immunoreactivity No staining Faint/barely perceptible membrane staining Weak to moderate complete membrane staining A strong complete membrane staining in 80% of tumoral cells P95 scoring was independently completed by two pathologists. A third independent pathologist examined discordant p95her2 scores p95her2 was expressed in 27 patients (30.7%) Guarneri V et al, SABCS 2011 (PD-05-01)
CHER-LOB: Biomarkers analysis No correlation between baseline expression of p95-her2 and pcr 50 45 40 35 30 25 20 15 10 5 0 Arm A:CT + T Arm B: CT + L Arm C: CT + T+L p95 <80% p95 80%
CHER-LOB: DFS by yp95her2 Poster presentation, ESMO 2012
HR negative, or HR+ with cn+
(N=145 patients treated with EC+T Doc+T) Loibl S et al, ASCO 2011 Abstr #530
LET-LOB: Study Plan HR+/HER2 -, postmenopausal operable BC (Stage II-IIIA) Letrozole 2.5 mg daily for 6 months Lapatinib 1500 mg daily for 6 months R Letrozole 2.5 mg daily for 6 months Placebo daily for 6 months S U R G E R Y Sample size: 91 pts
US response (RECIST) 70 60 50 40 30 letrozole-lapatinib letrozole-placebo 20 10 0 CR PR SD PD Conte P, et al, ASCO 2011
Molecular response (KI67) 70 60 50 40 30 20 10 Arm A: Letrozole-lapatinib Arm B: Letrozole-placebo 0 Pre ki67 Post Ki67 Pre ki67 Post Ki67 Conte P, et al, ASCO 2011
100 80 Arm A: letrozole placebo 60 40 20 0-20 -30-40 PIK3CA WT PIK3CA mut PIK3CA NA -60-80 -100 100 80 Arm B: letrozole lapatinib 60 40 20 0-20 -30-40 -60-80 -100
Ki-67 Prognostic significance after PCT DFS by post-therapy Ki 67 and nodal status Low Ki67 and N- High Ki67 or N+ 0.75 1.00 Post-therapy Ki-67<15% High Ki67 and N+ Probability 0.50 Post-therapy Ki-67>/=15% 0.00 0.25 0 1 2 3 4 5 6 7 8 9 10 Time (years) V Guarneri et al, Ann Oncol 2009 V. Guarneri, ASCO 2010
Patients at high risk after PST: target for accelerated adjuvant studies Patients still at high risk of relapse after receiving the best neoadjuvant therapy are the optimal candidates for testing new agents/strategies High rate of events in a short period of time minimal residual disease with no organ dysfunction and excellent performance status no approved therapies (an part from endocrine therapy for HR+ pts and/or trastuzumab in HER2+) availability a ab of tumor tissue to study mechanisms s of resistance sta to conventional drugs.
Conclusions Breast conservation is a clinical end-point, but should not be considered the only reason to offer primary systemic therapy pcr is a powerful predictor of long-term outcome, and in HER2+ and triple negative disease is a clinically i ll relevant end-point In HR+/HER2- patients primary endocrine therapy is not inferior to PCT, and molecular l response is a surrogate markers of efficacy for combined endocrine+targeted agents Patients t at high-risk h i after PST are the optimal candidates for testing ti new agents/strategies Histology, HER2 and HR remain the main drivers for treatment t t selection More recent neoadjuvant studies routinely include correlative biomarkers studies which h hopefully will add to our present knowledge