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![G2
S
M
G1
pRB
The Role of CDK4/6 in Breast Cancer
Growth of HR+ MBC is
dependent on cyclin D1, a direct
transcriptional target of ER
Cyclin D1 activates CDK4/6,
resulting in G1-S phase
transition and cell cycle entry[1]
Some cell-line models of
endocrine resistance show
dependence on cyclin D1 and
CDK4/6[2,3]
ERα Mitogenic
signaling
S phase transcription
program
G1/S transition
P P P
pRB
E2F
E2F
CDK1
Cyclin B
CDK1/2
Cyclin A
CDK2
Cyclin E
CDK4/6
Cyclin D](https://image.slidesharecdn.com/hrher2neumbc-210321143728/85/Hr-her2-neu-mbc-13-320.jpg)
![20
MONARCH CLINICAL TRIALS
Footer text here. Arial 7pt font in black.
MONARCH-2
MONARCH-3
• Pre- and postmenopausal
women with HR+,
HER2– ABC
• Progression on ET
([neo]adjuvant or 1L
advanced)
N = 669
1:1
ABE + FUL
PBO + FUL
MONARCH-2 study results
All patients
ABE+FUL
n = 446
PBO+FUL
n = 223
Median PFS, mo 16.4 9.3
HR (95% CI);
P value
0.553 (0.449, 0.681);
<0.001
N = 493
1:1
ABE + NSAI
PBO + NSAI
MONARCH-3 study results
All patients
ABE+NSAI
n = 328
PBO+NSAI
n = 165
Median PFS, mo NR 14.7
HR (95% CI);
P value
0.54 (0.41, 0.72);
0.000021
N = 493
• Postmenopausal women
with HR+, HER2– ABC
• No prior systemic therapy
in the advanced setting](https://image.slidesharecdn.com/hrher2neumbc-210321143728/85/Hr-her2-neu-mbc-20-320.jpg)
![Approach to Therapy for HR+/HER2- MBC:
Move to Personalization
1L[1-4] 2L[1] 3L
AI + CDK4/6i Fulvestrant ±
everolimus
Exemestane +
everolimus[8]
Fulvestrant + CDK4/6i
Exemestane +
everolimus
4L/5L[1]
Taxane or
capecitabine
4L+[1]
Eribulin
PIK3CAm:
fulvestrant +
alpelisib[5]
BRCAm: olaparib or
talazoparib[9,10]
Sacituzumab
govitecan
(IMMU-132)[13]
ESR1m: SERD (+ CDK4/6i)[6,7]
HER2 low: trastuzumab
deruxtecan
(DS8201a)[11]
HER2m: neratinib[12]](https://image.slidesharecdn.com/hrher2neumbc-210321143728/85/Hr-her2-neu-mbc-23-320.jpg)
Uploaded bymadurai
Hr+ her2 neu mbc
This presentation discusses breast cancer, specifically hormone receptor positive/HER2 negative breast cancer. It provides statistics on the distribution of breast cancer molecular subtypes in the United States. It also discusses the evolving treatment landscape for hormone receptor positive metastatic breast cancer, including the approvals and use of targeted therapies in combination with endocrine therapy, such as CDK4/6 inhibitors. Clinical trial results are summarized that demonstrate improved progression-free survival when a CDK4/6 inhibitor is added to first-line endocrine therapy for advanced hormone receptor positive breast cancer. An approach to personalized therapy is proposed based on factors such as endocrine sensitivity and molecular alterations.
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Hr+ her2 neu mbc
- 1. Presentation Title DR. R. RAJKUMARD.M. CONSULTANT MEDICAL ONCOLOGIST VELAMMAL MEDICAL COLLEGE & SPECIALITY HOSPITALS
- 2. BREAST CANCER: INCIDENCE 1. Distributionof BC Molecular Subtypes in United States, 2010 HR+/HER2- 73% TNBC 12% HR+/ HER2+ 10% HR-/ HER2+ 5%
- 5. AGE SHIFT –CASES SEEN IN 30’S & 40’S
- 7. Evolving Treatment Landscapeof HR-Positive MBC SOC regimens for metastatic HR+/HER2- BC based on endocrine tx Tamoxifen (Selective ER modulator) 1970-80 AIs Anastrozole Exemestane Letrozole 1990s Fulvestrant (Selective ER degrader) 2002 Fulvestrant HD 2010 Everolimus (mTOR inhibitor) 2012 Palbociclib (CDK4/6 inhibitor) 2015-17 Ribociclib, Abemaciclib (CDK4/6 inhibitors) 2017-18 Targeted Therapy + ET . Approvals
- 8. Initial Treatment ofHR+, HER2- Advanced Breast Cancer Majority of patients with HR+, HER2- metastatic BC should be treated with endocrine therapy–based regimens often in combination with targeted therapies ‒ Chemotherapy is not recommended unless patients have progressed through multiple lines of endocrine therapy or display signs of visceral crisis Treatment considerations ‒ Sites and extent of disease ‒ Organ function ‒ Prior systemic therapy ‒ Length of disease-free interval ‒ Rate of disease progression ‒ Presence of gBRCA1/2 mutation
- 9. TREATMENT GUIDELINES FORHR+, HER2– ADVANCED BREAST CANCER ESMO1 In HR+, HER2– disease, endocrine therapy is the treatment of first choice independent of metastatic site, unless rapid response is needed. Limited visceral metastases are not a contraindication for endocrine therapy ABC2 Endocrine therapy is the preferred option for HR+ disease, even in the presence of visceral disease, unless there is concern or proof of endocrine resistance or rapidly progressive disease needing a fast response ASCO3 Endocrine therapy should be recommended as initial treatment for patients with HR+ metastatic breast cancer except in patients with immediately life-threatening disease or in those with rapid visceral recurrence on adjuvant endocrine therapy. NCCN4 Endocrine therapy recommended unless there is visceral crisis, or progression with no clinical benefit after 3 sequential endocrine therapy regimens. 3
- 10. CHEMOTHERAPY VERSUS ENDOCRINETHERAPY Chemotherapy has higher response rate. 1
- 11. CHEMOTHERAPY VERSUS ENDOCRINETHERAPY 1 Wilcken et al, Cochrane System Database Review 2009 No significant differences in overall survival.
- 12. Combining Targeted andAntiestrogen Therapies to Overcome Resistance in HR+ Advanced Breast Cancer ~ 50% of advanced HR+ BCs are de novo resistant to ET, with most developing acquired resistance Mechanisms of resistance may include loss or alteration of ER expression; overexpression or activation of growth factor receptors; or activation of downstream signal transduction pathways PI3K Akt PTEN mTOR RAS Raf MEK MAPK ER Target Gene Transcription P P EGFR HER2 E E ER E ER E ER E TKI mTOR Inhibitors Everolimus Aromatase Inhibitor Nonsteroidal AIs: Anastrozole Letrozole Steroidal AI: Exemestane Selective ER Modulators Tamoxifen Toremifene ER Downregulator Fulvestrant CDK4/6 Inhibitors Palbociclib Abemaciclib Ribociclib Cell Cycle Transcription Silencing
- 13. G2 S M G1 pRB The Role ofCDK4/6 in Breast Cancer Growth of HR+ MBC is dependent on cyclin D1, a direct transcriptional target of ER Cyclin D1 activates CDK4/6, resulting in G1-S phase transition and cell cycle entry[1] Some cell-line models of endocrine resistance show dependence on cyclin D1 and CDK4/6[2,3] ERα Mitogenic signaling S phase transcription program G1/S transition P P P pRB E2F E2F CDK1 Cyclin B CDK1/2 Cyclin A CDK2 Cyclin E CDK4/6 Cyclin D
- 14. pRB Cyclin D1 andCDK4/6 Drive Cellular Proliferation Downstream of Signaling Pathways Lange. Endocr Relat Cancer. 2011;18:C19. Kundsen. Trends Cancer. 2017;3:39. Otto. Nat Rev Cancer. 2017;17:93. Corona. Drug Des Devel Ther. 2018.12:321. Tripathy. Clin Cancer Res. 2017;23:3251-3262. Gene transcription G2 S M G1 Inactive Active tumor suppressor E2F E2F Restriction point p16 p21 p53 CDK4/6 Cyclin D CDK2 Cyclin E pRB P P P G0 Pl3K/Akt STATs MAPKs ER/PR/AR Wnt/β-catenin NF-κB FGFR
- 15. Pan-CDK Inhibitors: Early ClinicalTrial Experience Both agents showed low therapeutic index resulting in toxicities at doses sufficient to inhibit target CDKs Agent Primary Targets Antitumor Activity Notable Grade 3/4 Toxicities Alvocidib (flavopiridol) CDKs 1, 2, 4, 6, 7, 9 Solid tumors: minimal CLL (relapsed/ refractory): ORR ≈ 25% to 50% Neutropenia, gastrointestinal/diarrhea, tumor lysis syndrome, infections Seliciclib CDKs 1, 2, 5, 7, 9 Solid tumors: minimal, if any Nausea, vomiting, fatigue, hepatic dysfunction
- 16. CDK4/6 Inhibitors: Comparisonof Key Clinical Characteristics Characteristic PALBOCICLIB RIBOCICLIB ABEMACICLIB Target (IC50, nM) CDK4 (11); CDK6 (15) CDK4 (10); CDK6 (39) CDK4 (2); CDK6 (10) Route PO PO PO Dose, mg 125 QD 600 QD Monotx: 200 BID Combo w/ET: 150 BID Schedule 3 wks on/1 wk off 3 wks on/1 wk off Continuous Half-life, hr 27 32.6 17-38
- 17. PALOMA-1 PALOMA-2 MONALEESA-2MONARCH-3 MONALEESA-3 Study design Phase II 1st line Phase III 1st line Phase III 1st line Phase III 1st line Phase III 1st and 2nd line Endocrine partner Letrozole Letrozole Letrozole Letrozole or anastrozole Fulvestrant CDK4/6 inhibitor Palbociclib Palbociclib Ribociclib Abemaciclib Ribociclib Patients, N 165 666 668 493 367 HR 0.49 0.58 0.56 0.54 0.57 PFS, mos 20.2 vs 10.2 24.8 vs 14.5 25.3 vs 16 NR vs 14.7 NR vs 18.3 ORR, % 56 vs 39 55.3 vs 44.4 52.7 vs 37.1 59 vs 44 40.9 vs 28.7* Impact of CDK4/6 Inhibition on PFS: First-Line Setting 1
- 18. 18 PALOMA CLINICAL TRIALS Footertext here. Arial 7pt font in black. • Postmenopausal women with HR+, HER2– ABC • No prior treatment for advanced disease N = 666 PALOMA-2 2:1 PBO + LET PAL + LET PALOMA-2 study results All patients PAL+LET (n = 444) PBO+LET (n = 222) Median PFS, mo 24.8 14.5 HR (95% CI); P value 0.58 (0.46, 0.72); < 0.001 • Pre- or postmenopausal women with HR+, HER2– ABC • Relapsed/progressed during prior ET N = 521 PALOMA-32 2:1 PBO + FUL PAL + FUL PALOMA-3 study results All patients2 PAL+FUL (n = 347) PBO+FUL (n = 174) Median PFS, mo 9.5 4.6 HR (95% CI); P value 0.46 (0.36, 0.59); < 0.0001
- 19. 19 MONALEESA CLINICAL TRIALS Footertext here. Arial 7pt font in black. ML-2 ML-7 • Postmenopausal women with HR+, HER2– ABC • No prior therapy for ABC N = 668 ML-3 • Men and postmenopausal women with HR+, HER2– ABC • No prior CT for ABC N = 726 • Premenopausal women with HR+, HER2– ABC • No prior ET for advanced disease • ≤ 1L prior CT allowed N = 672 ML-2 study results All patients RIBO+LET (n = 334) PBO+LET (n = 334) Median PFS, mo 25.3 16.0 HR (95% CI); P value 0.568 (0.457, 0.704); 9.63×10–8 ML-3 study results All patients2 RIBO+FUL (n = 484) PBO+FUL (n = 242) Median PFS, mo 20.5 12.8 HR (95% CI); P value 0.593 (0.480, 0.732); <0.001 ML-7 study results All patients RIBO+ET+GOS (n = 335) PBO+ET+GOS (n = 337) Median PFS, mo 23.8 13.0 HR (95% CI); P value 0.55 (0.44, 0.69); <0.0001 1:1 RIBO + LET PBO + LET 2:1 RIBO + FUL PBO + FUL 1:1 RIBO + ET + GOS PBO + ET + GOS
- 20. 20 MONARCH CLINICAL TRIALS Footertext here. Arial 7pt font in black. MONARCH-2 MONARCH-3 • Pre- and postmenopausal women with HR+, HER2– ABC • Progression on ET ([neo]adjuvant or 1L advanced) N = 669 1:1 ABE + FUL PBO + FUL MONARCH-2 study results All patients ABE+FUL n = 446 PBO+FUL n = 223 Median PFS, mo 16.4 9.3 HR (95% CI); P value 0.553 (0.449, 0.681); <0.001 N = 493 1:1 ABE + NSAI PBO + NSAI MONARCH-3 study results All patients ABE+NSAI n = 328 PBO+NSAI n = 165 Median PFS, mo NR 14.7 HR (95% CI); P value 0.54 (0.41, 0.72); 0.000021 N = 493 • Postmenopausal women with HR+, HER2– ABC • No prior systemic therapy in the advanced setting
- 21. Do CDK4/6 inhibitorsresult in an improvement in overall survival? YES
- 22. MONALEESA-3: OVERALL SURVIVALBY LINE OF THERAPY OS by line of therapy was consistent with overall population Slamon. ESMO 2019. Abstr LBA7_PR. RIBO + FULV PBO + FULV Events/N 102/237 60/109 Median OS, Mos 40.2 32.5 RIBO + FULV PBO + FULV Events/N 63/237 47/128 Median OS, Mos NR 45.1 RIBO + FULV PBO + FULV RIBO + FULV PBO + FULV 237231222218213210199188184179172167158152145135 109103 98 97 93 90 88 83 81 78 77 72 69 63 61 59 54 49 35 23 15 6 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 129122 94 63 36 17 7 1 0 1 0 0 0 20 40 60 80 100 Mos 237229222217214210207206205202194190182174173166163157138 92 54 22 0 6 1 128126 122121119116113110106104 99 97 93 91 85 84 82 70 40 21 8 2 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 Mos 0 20 40 60 80 100 First line Early relapse + Second line OS, % Patients Atrisk,n PBO RIBO Patients Atrisk,n PBO RIBO HR: 0.700 (95% CI: 0.479-1.021) HR: 0.730 (95% CI: 0.530-1.004) 125
- 23. Approach to Therapyfor HR+/HER2- MBC: Move to Personalization 1L[1-4] 2L[1] 3L AI + CDK4/6i Fulvestrant ± everolimus Exemestane + everolimus[8] Fulvestrant + CDK4/6i Exemestane + everolimus 4L/5L[1] Taxane or capecitabine 4L+[1] Eribulin PIK3CAm: fulvestrant + alpelisib[5] BRCAm: olaparib or talazoparib[9,10] Sacituzumab govitecan (IMMU-132)[13] ESR1m: SERD (+ CDK4/6i)[6,7] HER2 low: trastuzumab deruxtecan (DS8201a)[11] HER2m: neratinib[12]
- 24. *De novo stageIV disease appears to be enriched in relative endocrine resistant disease. †No data comparing CDK4/6i combined with AI vs fulvestrant in first line setting. HR+/HER2- Advanced BC: Changing Paradigms CT Poor Endocrine Sensitivity Progression within 2 yrs from start of adj ET Fulvestrant + CDK4/6i High Endocrine Sensitivity NSAI + CDK4/6i ET naive* Progression > 1 yr after adj ET Fulvestrant† (bone only, no prior ET) EXE + EVE PIK3CA WT FULV (± EVE) FULV + Alpelisib PIK3CA MUT FULV + CDK4/6i EXE + EVE Progression between 2-3 yrs from start of or < 1 yr from end of adj ET Moderate Endocrine Sensitivity AI + Alpelisib PIK3CA WT PIK3CA MUT EXE + EVE AI + alpelisib PIK3CA WT PIK3CA MUT
- 25. THERAPEUTIC OPTIONS FORHR+, HER2– ABC ARE EVOLVING • ET-based therapy remains the basis of treatment for HR+, HER2– ABC1 • CDK4/6 inhibitors in combination with ET have resulted in a paradigm shift for treating HR+, HER2– ABC2 ─ A meta analysis of 50,029 patients with HR+, HER2– MBC across 140 phase 2 and 3 studies found that the combination of CDK4/6 inhibitors plus hormone therapies is associated with better PFS than standard hormone therapies as first- or second-line treatments for postmenopausal patients3 Oestrogen ER SRC Me/Ac EGFR/HER2/HER3 Inhibitors FGFR Inhibitors IGFR Inhibitors EGFR/HER3 FGFR IGFR MET E2F CDK Cyclin D p21WAF1/CIP1 SRC Inhibitor SRC STAT3 RAF MEK ERK CDK Inhibitors MAPK/MEK Inhibitors RAS PI3K PIP2 PI3K Inhibitors mTOR Inhibitors PIP3 mTORC2 AKT TSC p53 Rheb Rheb mTORC1 P AKT Inhibitors HDAC Inhibitors MDM2 ER SERDs/ SERMs 25
Editor's Notes
- #3 BC, breast cancer; TNBC, triple-negative breast cancer.
- #8 BC, breast cancer; CDK, cyclin-dependent kinases; ER, estrogen receptor; ET, endocrine therapy; HD, high dose; mTOR, mammalian target of rapamycin; SOC, standard of care; tx, therapy. References Anastrozole [package insert]. 2014. Exemestane [package insert]. 2018. Letrozole [package insert]. 2018. Fulvestrant [package insert]. 2018. Everolimus [package insert]. 2018. Palbociclib [package insert]. 2018. Ribociclib [package insert]. 2018. Abemaciclib [package insert]. 2018. Brufsky AM. Cancer Treat Rev. 2017;59:22-32. Lim E, et al. Oncology (Williston Park). 2012;26:688-694. Croxtall JD, et al. Drugs. 2011;71:363-380. Cohen MH, et al. Oncologist. 2001;6:4-11.
- #9 BC, breast cancer; HR, hormone receptor.
- #13 AI, aromatase inhibitor; BC, breast cancer; E, estrogen; ER, estrogen receptor; ET, endocrine therapy; HR, hormone receptor; MAPK, mitogen activated protein kinase; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; RAS, renin-angiotensin system; TKI, tyrosine kinase inhibitor. References Johnston SR. Clin Cancer Res. 2010;16:1979-1987. Brufsky AM. Cancer Treat Rev. 2017;59:22-32. AlFakeeh A, et al. Curr Oncol. 2018;25(suppl 1): S18-S27.
- #14 CDK, cyclin-dependent kinase; ER, estrogen receptor; HR, hormone receptor; MBC, metastatic breast cancer.
- #15 CDK, cyclin-dependent kinase.
- #16 CLL, chronic lymphocytic leukemia.
- #17 CDK, cyclin-dependent kinases; ET, endocrine therapy.
- #18 CDK, cyclin-dependent kinase; NR, not reached.
- #20 The MONALEESA-3 first line patient population PFS analysis was not reached
- #22 CDK, cyclin-dependent kinase.
- #23 FULV, fulvestrant; PBO, placebo; RIBO, ribocliclib.
- #24 AI, aromatase inhibitor; HR, hormone receptor; MBC, metastatic breast cancer; SERD, selective estrogen receptor degrader.
- #25 Adj, adjuvant; AI, aromatase inhibitor; BC, breast cancer; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; CT, chemotherapy; ET, endocrine therapy; EVE, everolimus; EXE, exemestane; FULV, fulvestrant; HR, hormone receptor; MUT, mutant; NSAI, non-steroidal aromatase inhibitor; WT, wildtype.