Endocrine treatment might NOT be the preferred option in Hrpos MBC Dr. Mircea Dediu Sanador Hospital Bucharest Summer School Bucharest 2015
Overall survival not improved by the AI treatment
Benefit in OS during the last decade was due to CT development, despite the fact that the majority of BC are ER+
et al. Systemic therapy ER+ Visceral mets included Endocrine resistance Need for fast response Endocrine therapy Cytotoxic therapy Cardoso F et al. Ann Oncol 2014; 00; 1-18
ER+ disease is a heterogenous disease Estrogen Receptor positive Reis-Filho et al. Lancet 2011;378:1812-1823
Proliferation cluster as a prognostic factor for ER-positive cancers (adjuvant setting) Reis-Filho et al. Lancet 2011;378:1812-1823
Does the primary tumor and the metastases have the same biologic profile?
Meta-analysis of individual data for 289 patients Change in therapy due to modification of the receptor profile in the metastasis as compared with the primary Amir E. et al, Cancer Treat Rev (2011), doi:10.1016/j.ctrv.2011.11.006
Take home message Up to 30% of patients will experience ER+ to ER- conversion during the metastatic process Up to 30 % of patients will be treated wrong with ET upfront as per ESMO guidelines Rebiopsy is recommended nowadays to guide therapy in advanced MBC
Do we have reliable predictive factors for the endocrine treatment benefit? - ER/PR [+] - Long DFI - CB to prior ET - No/Low symptoms - Indolent disease course ET?
Capecitabine following taxanes and anthracyclines in MBC ER+ ER- ER+ Gilabert M et al. Anticancer Res. 2011; 31:1079-1086
Capecitabine : predictive factors influencing OS Grading DFS Disease Course ER 1 long slow + M1 burden low
Take home message Same predictive factors for both ET and CT ( capecitabine)
et al HER 2 positive ABC For patients with ER+/HER+ MBC anti-her-2 therapy in combination with ET has shown substantial PFS benefit compared with ET alone
aufman B, et al. J Clin Oncol 2009; 27:5529-5537 ohnston S, et al. J Clin Oncol 2009; 27:5538-5546; ER/HER+ subtype TAnDEM EGF30008 PFS PFS Study Agents AI AI+anti-HER2 p Value TANDEM Anastrazole,trastuzumab 3.8 5.6 0.005 30008 Letrozole,lapatinib 3.0 8.2 0.019
Progression free survival: Strong differences on letrozole by HER2 status Johnston S, et al. J Clin Oncol 2009; 27:5538-5546;
Trastuzumab single agent vs. Trastuzumab + Anastrozole Trastuzumab 1 Trastuzumab+ Anastrozole 2 RR% 35 20 CB% 48 57 PFS 4.9 mo 5.6 1 Vogel C L et al. JCO 2002;20:719-726 2 Kaufman B, et al. J Clin Oncol 2009; 27:5529-5537
Role of hormonal therapy in ER/HER positive breast cancer is highly questionable HER2 is the dominant receptor Blocking HER2 is more important than ER
et al Endocrine treatment after CT to maintain benefits is a REASONABLE OPTION.. although this approach has not been assessed in randomized trials!
Gennari A., JCO 2011; 29: 2144-2149
Clinical implications First line chemotherapy should be as long as possible Second line chemotherapy is currently recommended after PD Role of maintenance hormonal therapy for ER+ patients remains questionable.
Hormonal therapy resistance is a major issue in the management of MBC (ER+) Primary resistance (de novo) Secondary resistance
Around 50% of ER+ patients are hormone refractory to initial therapy (de novo resistance) ANA vs TAM ANA vs TAM LET vs TAM EXE vs TAM PD % 41 vs 54 44 vs 44 50 vs 62 34 vs 51
All hormonal sensitive tumors eventually become resistant lizabeth A. Musgrove, et al. Nat Rev Cancer. 2009;9(9):631-643.
Exemstane vs. Exemestane + Everolimus José Baselga, et. al., December 7, 2011 (10.1056/NEJMoa1109653)
Baselga J et al. N Engl J Med 2012 : 366:520-529
Overall Survival : no benefit! Piccart M et al. Ann Oncol 2014 ; 25:2357-2362
Letrozole +/-Palbociclib (CDKs 4/6 inhibitor) mpfs= 26.1 vs 5.7 mo HR=0.29,p<0.0001 Finn R et al. Lancet Oncol 2015; 16:25-35
Finn R et al. Lancet Oncol 2015; 16:25-35 No OS benefit!
Palbociclib: High toxicity and no OS benefit Gr 3-4 AE Palbociclib +LET LET Any 76% 21% Neutropenia 54% 1% Anemia 6% 1% Fatigue 4% 1% Finn R et al. Lancet Oncol 2015; 16:25-35
Conclusions(1) ER expression per se does not necessary recommend HT in advanced BC ER+ tumor is a heterogeneous entity. Some particular genetic patterns may recommend the CT up front. Slow progressing tumors, long DFS interval, low tumor burden are indicatives for a substantial CT benefit even if ER+
Conclusions(2) Whenever possible, the pathologic discordance between the primary and the metastatic sites should be questioned Primary resistance to HT is encountered in 50%. Ultimate developments of ET were not able to induce an OS improvement Virtually all hormonal sensitive tumors become resistant. CHEMOTHERPY remains the sole rescue medication for these patients.
Thank You Mircea Dediu
No difference in effect on OS between subgroups treated with or without concurrent hormone therapy Gennari A., JCO 2011; 29: 2144-2149
Gennari A., JCO 2011; 29: 2144-2149
Factors predicting capecitabine effect PFS OS HR+ HR- Gilabert M et al. Anticancer Res 2011; 31:1079-1086
Gilabert M et al. Anticancer Res. 2011; 31:1079-1086 Capecitabine : variables influencing PFS
Letrozole +/-Palbociclib (CDKs 4/6 inhibitor) ER +, HER - Cyclin D1 amp, loss of p16 mpfs= 26.1 vs 5.7 mo HR=0.29,p<0.0001 mpfs= 18.1 vs 11.1 mo HR=0.50,p=0.0046 Finn R et al. Lancet Oncol 2015; 16:25-35
Luminal A and luminal B are both ER+, but biologically are different Reis-Filho et al. Lancet 2011;378:1812-1823
Patients with luminal-type breast cancer (HR positive BC, irrespective of HER2 status) Endocrine therapy is the preferred option except if clinically aggressive disease mandates a quicker response or if there are doubts regarding the endocrine responsiveness of the tumor Cardoso F et al. Ann Oncol 2011; 22:vi25-vi30
Factors to consider in treatment decision making for MBC Cardoso F et al. Ann Oncol 2011; 22:vi25-vi30
Capecitabine : predictive factors influencing OS Grading DFS Disease Course ER 1 + M1 burden
The metastatic deposits may change their biology 3-28% of metastatic regions will either lose or acquire ER expression 3-25% of the cases will either lose or acquire HER2 amplification Viale G. Personal communication, ECCO 2011
Therapy induced changes PgR downregulation by endocrine therapy Aquired resistance to endocrine treatments with HER 2 overexpression (Re-)Induction of ER expression by trastuzumab Extensive degradation of HER 2 protein by trastuzumab Viale G. Personal communication, ECCO 2011
Intratumoral heterogeneity
Why the metastases might be different?
Gilabert M et al. Anticancer Res. 2011; 31:1079-1086 Capecitabine : variables influencing PFS
Major clinical advances 2011 Exemstane vs. Exemestane + Everolimus José Baselga, et. al., December 7, 2011 (10.1056/NEJMoa1109653)
Breast cancer is heterogenous
Gennari A., JCO 2011; 29: 2144-2149
Meta-analysis of individual data for 289 patients Change in receptor expression between primary tumor and recurrence Change in therapy based on receptor profile of primary tumor. Receptor Primary Recurrence % p ER Positive Negative Negative Positive 12.4% 13.2% < 0.001 < 0.001 PgR Positive Negative Negative Positive 42.7% 16.0% < 0.001 < 0.001 HER2 Positive Negative Negative Positive 12.5% 4.6% < 0.001 < 0.001 Amir E. et al, Cancer Treat Rev (2011), doi:10.1016/j.ctrv.2011.11.006
Meta-analysis of individual data for 289 patients Change in receptor expression between primary tumor and recurrence Change in therapy based on receptor profile of primary tumor. Receptor Primary Recurrence % p ER Positive Negative Negative Positive 12.4% 13.2% < 0.001 < 0.001 PgR Positive Negative Negative Positive 42.7% 16.0% < 0.001 < 0.001 HER2 Positive Negative Negative Positive 12.5% 4.6% < 0.001 < 0.001 Amir E. et al, Cancer Treat Rev (2011), doi:10.1016/j.ctrv.2011.11.006
Cross-talk between receptor pathways Di Cosimo et. al, Nature Reviews Clinical Oncology 7, 139-147
No Hormonal Therapy Chemotherapy
Yes! Hormonal Therapy Chemotherapy
There are few proven standards of care in MBC management.; therefore, well-designed,independent prospective randomized trials are a priority.
Breast cancer is heterogenous
Breast cancer is heterogenous
ER+ is a heterogenous disease ER status in the primary may not be the same in the metastatic sites
Viale G. ECCO 2011.
(A) Progression-free and (B) overall survival. Paridaens R J et al. JCO 2008;26:4883-4890 2008 by American Society of Clinical Oncology
Treatment algorithms for advanced breast cancer ER/PR [+] Long DFI CB to prior ET No/Low symptoms Endocrine therapy Systemic therapy HER2[+] Anti-HER2 therapy OSS ER/PR [-] Short DFI Rapidly progressing Visceral disease Refractory to ET Cytotoxic therapy Biophosphonates