Systemic Treatment of Luminal Early and Advanced Breast Cancer Alexandru ENIU, MD, PhD Medical Oncologist Department of Breast Tumors Cancer Institute Ion Chiricuţă Cluj-Napoca, Romania Coordinator, ESO Eastern Europe and Balkan Region programme (EEBR) ESO-ESMO EEBR Masterclass 2019
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Systemic Treatment of Luminal Early and Advanced Breast ......Systemic Treatment of Luminal Early and Advanced Breast Cancer Alexandru ENIU, MD, PhD. Medical Oncologist. Department
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Sys te m ic Tre a tm e nt of Lum ina l Ea rly and Advance d Bre as t
Cance r
Alexandru ENIU, MD, PhDMedical Oncologist
Department of Breast TumorsCancer Institute Ion Chiricuţă
Cluj-Napoca, Romania
Coordinator, ESO Eastern Europe and Balkan Region programme (EEBR)
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Adjuvant Tamoxifen: EBCTCG Oxford Meta-analysis
38% RR
RR 30%
EBCTCG, Lancet 2011
Effect on Recurrence Rate and Survival Irrespective of Age, Stage, Grade, PR and Tumor Diameter.
N>10,000, 44% N+, 51% chemotherapy
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Δ 8%Δ 8.8%
Δ 14.2%
The longer – The better
1 year of tamoxifen
5 years of tamoxifen
2 years of tamoxifen
EBCTCG Metaanalysis, Lancet , 2011
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MAJOR PUBLISHED STUDIES OF ADJUVANT ENDOCRINE THERAPY WITH AN AI IN
POSTMENOPAUSAL WOMEN
« STANDARD THERAPY »
Challenged by
• 1) Upfront AI ATAC
BIG 1-98
• 2) Earlysequential AI
IES (BIG 2-97)
ABCSG + ARNO
• 3) Latesequential AI
MA17 (BIG 1-97)ABCSG – 6A
N=8010
N=4742
N=5187andN=856
N=28177
Tamoxifen x 5y
Anastrozole x 5 years
Tamoxifenx 2-3y
Exemestanex 3-2y
Tamoxifen x 5yLetrozole x 5y
Anastrozole* x 3y
Tam x 2y
Anastrozole x 3y
N=3123Letrozole x 5 years
N=6241
*Anastrozol is not approved for extended therapy
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Aromatase inhibitors vs. Tamoxifen meta-analysisAI (5y) vs. Tam (5y)Tam→AI (5y) vs. Tam (5y)
Dowsett et al, JCO, 2010
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Presented by: Honghchao Pan, EBCTCG
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MA.17R Trial DesignAI x 5 yrs - Following Prior 5 years of AI - preceded or not by Tamoxifen
•1900 pts•54% N+ve•58% Adjuvant chemotherapy
RANDOMIZE
Placebo
4.5-6 yrs of Aromatase Inhibitor Letrozole 2.5 mg po od
2. Is an OS + AI superior to OS + Tamoxifen?ESO-ESMO E
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No chemo group: low risk clinicopthologic features: 90% >40y, 91% N0, 85% T<2 cm, 41% Grade 1
Francis, NEJM, 2015, 2018(SOFT trial)
For women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal,
the addition of ovarian suppression improved disease outcomes
SOFT: Ovarian ablationor not?
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Francis, NEJM, 2018(TEXTtrial)
TEXT: If Ovarian ablation,TAM or AI?
In premenopausal women with hormone-receptor–positive early breast cancer, adjuvant treatment with exemestaneplus ovarian suppression, as compared with a tamoxifen
plus ovarian suppression, significantly reduced recurrencePagani, NEJM, 2014(TEXT trial)
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Risk Hormone therapy Chemotherapy Factors to consider
Low risk T1, N0, Grade 1,or low “gen risk”
PRE TAM No chemo No Ovarian Sup.5 years enough
POST TAM or AI No chemo 5 years enough AI in Lobular C
Interm risk, pN0High/interm HR
pT1c, pT2, pN0 or G2/G3, interm “gen risk”
PRE OFS+TAMor OFS+AI
Consider chemo for some 10 years of TAM for some
POST AI upfront Chemo in many cases Bisphosphonates
Interm risk, pN1High/interm HR
pT1c, pT2, pN1 (1-3) or G2/G3, interm “gen risk”
PRE OFS +AI (benefit larger
<35y)
Chemo in many cases Extended HT with TAM
POST AI upfront for 3-5 years
Chemo in many cases Extended HT with AI Bisphosphonates
High risklow/interm HR
pT3,pN2-3High grade
Younger
PRE OFS +AI Chemotherapy for most Consider Extended HT with AI
POST AI Chemotherapy for most Extended HT with AI Bisphosphonates
ER+ breast cancer- circa 2019
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If the results of tumour biology in the metastatic lesion differ from the primary tumour, it is currently unknown which result should be used for treatment-decision making. Since a clinical trial addressing this issue is difficult to undertake, we recommend considering the use of targeted therapy (ET and/or anti-HER-2 therapy) when receptors are positive in at least one biopsy, regardless of timing(LoE: Expert opinion) (87%).
PRIMARY ENDOCRINE RESISTANCE is defined as:Relapse while on the first 2 years of adjuvant ET, orPD within first 6 months of 1st line ET for MBC, while on ET
SECONDARY (ACQUIRED) ENDOCRINE RESISTANCE is defined as:Relapse while on adjuvant ET but after the first 2 years, orRelapse within 12 months of completing adjuvant ET, orPD ≥ 6 months after initiating ET for MBC, while on ET
(LoE: Expert opinion) (67%%)
3rd ESO-ESMO International ConsensusGuidelines for Advanced Breast Cancer (ABC3)
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First line Hormonal therapy
Hong-Bin Xu et al Clinical Breast Cancer 11 (4); 246, 2011
Significant difference in favouring AIs over TAM ORR (OR, 1.56; 95% CI, 1.17-2.07; P .002) and CB (OR, 1.70; 95% CI, 1.24-2.33; P .0009)
Trend toward an improved OS not significant (OR, 1.95; 95% CI, 0.88-4.30; P .10)
ORR
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Robertson, Lancet, 388:10063
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Combining Other Targeted Agents and Endocrine Therapy
SOSRAS
RAF
BasalTranscription
Machineryp160
ERE ER Target Gene Transcription
ER CBPPP P P
ER
Pp90RSK
Akt P
MAPK P
CellSurvivalTam
Cytoplasm
Nucleus
ER
AI
P13-KPP
PPP
P
CellGrowth
MEKP
PlasmaMembrane
EGFR/HER2
IGFRGrowth FactorEstrogenTamoxifen
EGF30008
mTOR
CellCycle
CDK 4/6 Inhibitors HDAC InhibitorEntinostat
Transcription Silencing
BOLEROTAMRAD
HORIZON
TANDEMeLEcTRA
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Baselga et al. NEJM. Epub
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CDK4 & 6 in Breast Cancer
• D type cyclins activate CDK4 & 6 which phosphorylate Rb resulting in G1 to
S progression
• Estrogen stimulates cyclin D1 in HR+ breast cancer1
Second line: Fulvestrant vs CDK4/6 inh + Fulvestrant
PALOMA 3
MONARCH 2
MONALEESA 3- second line
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FDA pooled CDKi Analysis
Average cost of CDK inh: 13.500 USD per month=162.000 USD per yearAI: 500 USD/monthTAM: 150 USD/month
• Clearly there are subgroups of patients that do very well with HT alone
• No predictive biomarkers- we are unable to select patients
• We have the option ( if reimbursed) to offerCDK4/6 inhibitors to all our first and secondline NOW
• What will happen when they progress?-
• Which sequence?ESO-ESMO E
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SOLAR-1
PIK3CA-non-mutant cohort
(n=231)
ALP 300 mg QD PO + FUL 500 mg IM*
n=115
PBO+ FUL 500 mg IM*
n=116
• Men or post-menopausal women with HR+, HER2– ABC
• Received prior AI• Identified PIK3CA status
(in archival or fresh tumor tissue)
• Measurable disease or ≥1 predominantly lytic bone lesion
• ECOG performance status ≤1
(N=572)
ALP 300 mg QD PO + FUL 500 mg IM*
n=169
PBO + FUL 500 mg IM*
n=172
PIK3CA-mutant cohort
(n=341)R
1:1, stratified by presence of liver/lung metastases and prior
CDK4/6 inhibitor treatment
Primary endpoint• PFS in PIK3CA-mutant cohort
(locally assessed)Secondary endpoints include:• OS (PIK3CA-mutant cohort)
• PFS (PIK3CA-non-mutant cohort)
• PFS (PIK3CA-mutation in ctDNA)
• OS (PIK3CA-non-mutant cohort)
• ORR/CBR• Safety
R
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ENDOCRINE THERAPY• Endocrine therapy (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 rapidly progressive disease needing a fast response
• The optimal sequence of endocrine-based therapy is uncertain. It depends on which agents were previously used (in the (neo)adjuvant or advanced settings), the burden of the disease, patients’ preference, costs and availability.
•Available options include AI, tamoxifen, fulvestrant, AI/fulvestrant + CDK4/6 inhibitor, AI/tamoxifen/fulvestrant + everolimus. In later lines, also megestrol acetate and estradiol, as well as repetition of previously used agents, may be used.(LoE/GoR : I/A) (95%)
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ER POSITIVE / HER-2 NEGATIVE ABCThe addition of a CDK4/6 inhibitor to an aromatase inhibitor, in patients naïve or pre-exposed to ET, provided a significant improvement in median PFS (~10 months), with an acceptable toxicity profile, and is therefore one of the preferred treatment options*. Patients relapsing < 12 months from the end of adjuvant AI were not included in the published studies and may not be suitable for this combination. OS results are still awaited. QoL was comparable to that with ET alone.(LoE/GoR : I/A) (90%)
ESMO-MCBS: 3
The addition of a CDK4/6 inhibitor to fulvestrant, in patients previously exposed to ET, provided significant improvement in median PFS (6 to 7 months), a non-statistically-significant improvement in OS (7 months) and an improvement in QoL, and is the preferred treatment option, if a CDK4/6 inhibitor was not previously used.
(LoE/GoR : I/A) (90%)ESMO-MCBS: 4ATTENTION: PROPOSED CHANGES. NOT YET VOTED NOR APPROVED!ESO-E
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ER POSITIVE / HER-2 NEGATIVE ABCThe addition of everolimus to an AI is a valid option for some patients previously exposed to endocrine therapy, since it significantly prolongs PFS, albeit without evidence of OS benefit. The decision to treat must take into account the toxicities associated with this combination, lack of statistical significant OS benefit, cost and availability. (LoE/GoR : I/B) (88%)Tamoxifen or fulvestrant can also be combined with everolimus. (LoE/GoR : II/B) (80%)Adequate prevention, close monitoring and proactive treatment of adverse events is needed, particularly in older patients treated with everolimus due to the increased incidence of toxic deaths reported in the Bolero-2 trial. (LoE/GoR : I/B) (97%) ESMO-MCBS: 2
Everolimus and CDK4/6 inhibitors should NOT be used after disease progression on that specific agent (i.e. beyond progression). (LoE/GoR : NA/E) (74%)