Mechanisms of hormone drug resistance Ljiljana Stamatović Institute for Oncology and Radiology of Serbia Tenth UMOS Conference, Belgrade, 16-17 th May 2015.
Hormone receptor-positive breast cancer (HR+ BC): Most common presentation of breast cancer, 2/3 of breast cancers express ER and/or PR 40 35 30 25 20 Premenop Postmenop Premenopauza Postmenopauza 15 10 5 0 ER+/PR+ ER+/PR- ER-/PR+ ER-/PR- Elledge et al. Diseases of the Breast. 2 nd ed. 2000
Rationale for endocrine therapy in HR-positive BC Estrogen plays a critical role in the development and progression of HR+ breast cancers: ER signal transduction pathways are key promoter of tumor proliferation, survival and invasion Estrogen deprivation in breast tissue is basic rationale for endocrine therapy Endocrine therapy is an important class of target-directed therapy that blocks the growth-promoting effects of estrogen via ER
Anti-estrogen therapies in BC Timeline of approval for endocrine therapy agents Selective estrogen receptor modulators (SERMs), such as tamoxifen, which block activity of ER Third-generation aromatase inhibitors (AIs), estrogen synthesis inhibitors steroidal: anastrazole, letrozole nonsteroidal: exemestane Selective estrogen receptor down-regulators (SERDs), such as fulvestrant, which induce destabilisation/degradation of ER
Endocrine therapy in HR-positive disease Most patients with HR+ BC benefit from endocrine therapy: hormonal therapy improves clinical outcomes Endocrine therapy has become the mainstay of treatment in HRpositive early and particularly advanced disease Preserved endocrine responsiveness to first-line endocrine therapy allows successive use of several hormonal therapeutic options and thus prolongs time to introduction of chemotherapy Unfortunately, the majority of patients with HR+ advanced breast cancer will ultimately progress despite endocrine therapy: resistance is a major clinical problem de novo, intrinsic resistance acquired resistance New treatment options that restore endocrine sensitivity are needed!
ER-positive/HER2-negative ABC ET is the preferred option for HR+ disease, even in the presence of visceral disease, unless there is concern or proof of endocrine resistance or there is disease needing a fast response (LoE: 1 A) The preferred 1st line ET for postmenopausal patients is an aromatase inhibitor or tamoxifen, depending on type and duration of adjuvant ET (LoE: 1 A) Fulvestrant HD is also an alternative option (LoE: 1 B) AI + everolimus is also an option after progression on a non-steroidal AI (LoE: 1 B) Optimal post-ai treatment is uncertain. Available options include, but are not limited to, tamoxifen, another AI (with a different mechanism of action), fulvestrant HD, megestrol acetate and everolimus + AI (LoE: 1 A)
Endocrine resistance Primary endocrine resistance is defined as: relapse while on the first 2 years of adjuvant ET PD within first 6 ms of initiating 1 st line ET for mbc, while on ET Secondary (aquired) endocrine resistance is defined as: relapse while on adjuvant ET but after the first 2 years relapse within 12 months of completing adjuvant ET PD 6 months after initiating ET for mbc, while on ET (LoE: Expert opinion)
Mechanisms of endocrine resistance Upregulation of alternative signal transduction pathways ESR1 gene mutations Epihenetic modifications of the ESR1 gene Alterations in cell cycle signaling Mechanisms of endocrine resistance are a topic of active research in order to reverse resistance and improve the outcome of patients with HR+ breast tumors
Cross-talk between signal transduction pathways and ER signaling in endocrine-resistant breast cancer: Opportunities for targeted interventions Reprinted by permission from the American Association for Cancer Research: Johnston SR. Clin Cancer Res. 2005;11:889s-899s
Enhancing sensitivity to endocrine therapy: PI3K/AKT/mTOR inhibition in HR+ advanced BC mtor interacts with ER signaling as well as growth factors including IGF-1, VEGF, and ErbB1,2 RTKs: EGFR, HER2, IGF1-R ER ER PTEN Src CoA Inactivated suppressors PI3K E Aberrations of this pathway are common in multiple cancers, including BC3,4 P Ras TSC2 TSC1 Nonnuclear/ nongenomic AKT S6K1 Activation of transcription factors Proliferation Survival Invasion mtor Cellular metabolism Angiogenesis ER Nuclear/ genomic mtor inhibitor MAPK P P P P ER P ER P CoA EREs P CoA mtor is a central regulator of multiple signaling pathways involved in cancer P CoA AP-1 TFs AP-1/SP-1 TFs-REs Gene expression (GFs, RTKs) Furthermore, hyperactivation of the PI3K/AKT/mTOR pathway has been observed in endocrine-resistant BC cells4 Inhibition of the mtor pathway may enhance endocrine sensitivity by inhibiting ligand-independent activation of the estrogen receptor Dual blockade of the mtor and endocrine pathways via mtor inhibition in combination with endocrine therapy offers clinical benefits for patients progressing on NSAIs 1. Osborne CK, et al. Annu Rev Med. 2011;62:233-247; 2. Yamnik RL, et al. J Biol Chem. 2009;284(10):6361-6369; 3. Samuels Y, et al. Science. 2004;304(5670):554; 4. Miller TW, et al. J Clin Invest. 2010;120(7):2406-2413.
BOLERO-2: Everolimus + Exemestane in HR+ advanced breast cancer progressing during/after NSAI therapy N = 724 Postmenopausal ER+ Unresectable locally advanced or metastatic BC Recurrence or progression after letrozole or astrozole R 2:1 Breast cancer trials of OraL EveROlimus-2 Phase 3 trial EVE 10 mg daily + EXE 25 mg daily (n = 485) Placebo + EXE 25 mg daily (n = 239) Stratification 1. Sensitivity to prior hormonal therapy 2. Presence of visceral disease Endpoints Primary: PFS (local assessment) Secondary: OS, ORR, QOL, safety, bone markers, PK. Baselga J et al. N Engl J Med. 2012;366:520-529
Probability of Event (%) BOLERO-2: Everolimus + Exemestane improves PFS in HR+ mbc 100 90 80 70 60 50 40 30 20 10 0 Patients at Risk, n Everolimus Placebo 0 6 12 18 24 30 36 42 48 54 60 66 72 78 485 239 HR: 0.36 (95% CI: 0.27-0.47) log-rank P <.001 385 168 281 94 201 55 132 33 Central Assessment 102 20 67 11 Wks 43 11 28 6 18 3 Everolimus + exemestane (median PFS: 10.6 mos) Placebo + exemestane (median PFS: 4.1 mos) 9 3 3 1 2 0 0 0 PFS Local Assessment: 7.8 mos vs 3.2 mos, HR: 0.45 (95% CI: 0.38-0.54) log-rank P <.0001 Baselga J et al. N Engl J Med 2012;366:520-529
BOLERO-2: Final OS analysis (39-mo follow-up)
ER mutations in HR+ breast cancer Resistance in BC is characterized by loss of ER (Erα isoform) expression and ER gene mutations Current studies: Identify types of ER mutations with patient-derived xenograft models [1] Explored prevalence of ER mutations throughout natural history of ER+ breast cancer, emphasizing endocrine-resistant disease state [2] 1. Shao J et al. SABCS 2013. Abstract S3-05 2. Jeselsohn RM et al. SABCS 2013. Abstract S3-06
TP53 PIK3CA CCND1 MCL1 MYC FGFR1 ESR1 ERBB2 AKT1 NF1 PTEN Alteration Percentage Patients With LBD Mutations, % Effects of ER mutational status 40 Genomic Alterations in ER+ Tumors 50 Disease Progression and LBD Mutation Frequency 35 30 Primary Metastasis 40 25 20 15 P < 0.05 30 20 20 10 5 0 10 0 0 Primary 12 Early Metastatic Disease Late Metastatic Disease Primary tumors very rarely have ER mutations, whereas ESR1 alterations were significantly more frequent in metastatic samples after endocrine treatment As the disease progresses from primary to early to late metastatic disease, the percentage of patients with LBD mutations increases LBD, ligand-binding domain Jeselsohn RM et al. SABCS 2013. Abstract S3-06
ER mutations in HR+ breast cancer Mutation of ESR1 found in tumors in patients with ER+ mbc Mutations led to resistance to endocrine therapy [1,2] Type of mutation leads to differential treatment resistance [1] Ligand-binding domain mutations: resistance to AIs; potentially treatable with high-dose fulvestrant or antiestrogens Gene translocations: resistance to classic endocrine treatment Gene amplifications: resistance to AIs; potentially treatable with estradiol or antiestrogens Mutations of ESR1 mostly absent in primary tumors, and correlate with increasing number of endocrine therapies [2] Mutations potential driver of endocrine resistance 1. Shao J et al. SABCS 2013. Abstract S3-05 2. Jeselsohn RM et al. SABCS 2013. Abstract S3-06
Breast cancer genome sequencing results Ellis MJ et al. Nature 2012;486:353 360
Targeting cell cycle progression downstream of the activated ER: An efficient strategy for antagonizing constitutive ERα signaling? Rationale for CDK4/6 inhibitors in ER+ BC
PALOMA-1/TRIO-18 (Phase 2): Palbociclib (PD0332991) + LET vs LET, 1st-line ER+/HER2 ABC Finn RS et al. SABCS 2012; Abstract S1-6
PALOMA-1/TRIO-18: Interim PFS Aromatase Inhibitor + CDK4/6 Inhibitor improves PFS in ER+ mbc Finn RS et al. SABCS 2012; Abstract S1-6
PALOMA-1/TRIO-18: Final survival results Finn RS et al. AACR 2014; Abstract CT101
Ongoing phase 3 studies assessing CDK 4/6 inhibition
Epigenetics mechanisms regulating ER expression Epigenetics: refers to reversible changes in gene expression secondary to histone hypoacetylation and abnormal DNA methylation in the promoter region of important genes Epigenetic modifications: might be modulated with the use of agents such as histone deacetylase (HDAC) inhibitors or demethylating agents HDAC inhibitors are of great interest because of the frequency of detection of epigenetic alterations in ER-positive BC
ENCORE 301: Entinostat + EXE vs EXE 2nd-line ER+ ABC, Randomized Phase 2 ENtinostat Combinations Overcoming Resistance Entinostat: histone deacetylase (HDAC) inhibitor Yardley DA et al. J Clin Oncol 2013;31:2128-2135 ENCORE 301 trial: NCT00676663. http://www.clinicaltrials.gov/ct2/show/nct00676663?term=encore+301&rank=1
ENCORE 301: PFS and OS* *Overall survival was an exploratory endpoint Yardley DA et al. J Clin Oncol 2013;31:2128-2135
Updates on systemic endocrine treatments for breast cancer Numerous clinical trials are ongoing to address the unmet therapeutic needs in postmenopausal patients with HR+ mbc progressing on existing therapies Studies investigating therapeutic strategies that combine sequential endocrine therapies with targeted agents such as PI3K/mTOR, CDK4/6 and HDAC inhibitors are particularly promising Further understanding of the signaling/crosstalk pathways should lead to identification of additional targets and development of more targeted agents that can combine with sequential endocrine therapy to overcome the mechanism of progression and improve outcomes