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Hormonal and novel therapy
in metastatic breast cancer
Dr Ajeet Kr Gandhi
MD (AIIMS), DNB, UICCF (MSKCC,USA)
Assistant pro...
A constant evolution, several mutations in ESR1 have been
identified
Different sub-clones exist within the primary tumou...
Fulvetrant Anastrozole
TTP 23.4 13.1
OS 54.1 48.4
Mehta et al, NEJM,2012
Fulvestrant plus anastrozole or placebo versus exemestane alone after
progression on non-steroidal aromatase inhibitors in...
Result of SoFEA Trial
Result of SoFEA Trial
13
Aim: To eradicate or control resistant clones from the
beginning
14
Upfront use of
mTOR inhibitor
Failed to improve
survival
Response: LET only
:27%
compared to
BOLERO2 0.4%
15
Hormonal Management- At
recurrence ER/PR+/-, Her2neu3+
Trial Regimen n Median PFS (months)
HT alone HT+ Anti Her2
TAnDE...
Hormone Resistance
 Intrinsic—resistance occurs de novo at the initial exposure
to endocrine therapy
 Relapse while on t...
Resistance to hormonal drugs
17
18
Overcoming hormone resistance
Need of targeted Agents
 Survival has reached Plateau with Chemotherapy
 Possibility of reducing toxicity with selective...
Targeted signaling
 EGFR pathway
 Ras-Raf-MapK pathway
 PI3K-mTOR pathway
 Met mutation
 BRAF mutation
 Sonic hedgeh...
21
22
Study design- BoleroII
R
A
N
D
O
M
I
Z
A
T
I
O
N
•multicenter,
•open-label
•phase III study
•N=724
•Randomizatio
n2:1 r...
BOLERO-2 Met Primary Endpoint: Final PFS Analysis (18-mo)
Based on Local Assessment Demonstrated a 4.6-mo
Prolongation of ...
BOLERO-2 (39-mo): Final OS Analysis
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 4...
BOLERO-2 (39-mo):
Post-study Treatment Anticancer Therapies
Therapy Type
Everolimus + Exemestane
(n = 485), %
Placebo + Ex...
BOLERO-2 (39-mo): Longer Median Time From
Randomization to First Chemotherapy or Death (Everolimus
Plus Exemestane Arm)
Ti...
BOLERO-2 (39-mo): No New Safety Signals at Final OS
Analysis (Safety Set)
Everolimus +
Exemestane
(n = 482a), %
Placebo +
...
Overall Survival in Patients With HR+, HER2–
Advanced Breast Cancer—Clinical Evidence
 In patients previously treated wit...
mTOR Resistance
 The mTOR-activated kinase S6K1 phosphorylates and
destabilizes the insulin-receptor substrate 1 and 2 (I...
30
Cell cycle
checkpoints
are
dominated
by CDK
31
PALOMA-1 Trial Finds Palbociclib/Letrozole Doubles Progression-Free
Survival in Metastatic Breast Cancer
Palbociclib is...
32Turner et al, NEJM, 2015
33Turner et al, NEJM, 2015
34Turner et al, NEJM, 2015
PD-L1
36
Possible treatment Plan
37
Possible treatment Plan
38
Optimum outcome,
minimal morbidity
Goal of Treatment
Personalization
of Treatment
39
Hormonal Management- At
recurrence for ER/PR+, Her2neu-
Repeat hormonal profile from metastatic site
If Post menopausal...
Trastuzumab resistance was defined as recurrence during
or within 12 months of adjuvant treatment or progression
during or...
Progression-free survival
41
Forest plot
analysis of
locally
assessed
progressio
n-free
survival
42
mTOR Resistance
 The mTOR-activated kinase S6K1 phosphorylates
and destabilizes the insulin-receptor substrate 1 and 2
(I...
44
Cell cycle
checkpoints
are
dominated
by CDK
• Cleopatra Study -2013, 2015
• Pertuzumab
• Median FU-49.5 mth
• 808 pts
• metastatic breast cancer who had not received ...
 PFS was significantly improved after first-line therapy with pertuzumab,
trastuzumab, and docetaxel, as compared with pl...
Adjuvant therapeutic strategies
 HER 2 Blockade
 Angiogenesis inhibition
 PI3K – mTOR – AKT pathway inhibition
 CDK 4/...
Dual inhibition
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
Hormonal and novel therapies in metastatic breast cancer
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Hormone receptor positive breast cancers and others novel developments in management and therapy

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Hormonal and novel therapies in metastatic breast cancer

  1. 1. Hormonal and novel therapy in metastatic breast cancer Dr Ajeet Kr Gandhi MD (AIIMS), DNB, UICCF (MSKCC,USA) Assistant professor, Radiation oncology Dr Ram Manohar Lohia Institute of Medical Sciences, Lucknow
  2. 2. A constant evolution, several mutations in ESR1 have been identified Different sub-clones exist within the primary tumour An increased level of heterogeneity From tumour evolution standpoint intuitive concept—prolonged endocrine therapy will exert selection pressure on the cancer Resistant Clones present from begining: This hypothesis is based on the newer insights into tumour heterogeneity and the so-called theory of ‘branched evolution Prevalence of the resistant populations Newer concepts: A continuous Evolution
  3. 3. Fulvetrant Anastrozole TTP 23.4 13.1 OS 54.1 48.4
  4. 4. Mehta et al, NEJM,2012
  5. 5. Fulvestrant plus anastrozole or placebo versus exemestane alone after progression on non-steroidal aromatase inhibitors in postmenopausal patients with hormone-receptor-positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicentre, phase 3 randomised trial Aim: assess a maximum double endocrine targeting approach with the steroidal anti- oestrogen fulvestrant in combination with continued oestrogen deprivation Post menopausal HR+ NSAI failure WHO 0-2 CBC/LFT/KFT R A N D O M I Z A T I O N Fulvestrant+Anastrozole (243) Fulvestrant+Placebo (231) Exemestane (249)
  6. 6. Result of SoFEA Trial
  7. 7. Result of SoFEA Trial
  8. 8. 13 Aim: To eradicate or control resistant clones from the beginning
  9. 9. 14 Upfront use of mTOR inhibitor Failed to improve survival Response: LET only :27% compared to BOLERO2 0.4%
  10. 10. 15 Hormonal Management- At recurrence ER/PR+/-, Her2neu3+ Trial Regimen n Median PFS (months) HT alone HT+ Anti Her2 TAnDEM (2009) ANA+/- Trastuzumab 208 2.4 4.8 EGF 30008 (2009) Let+/- Lapatinib 219 3.0 8.2 eLEcTRA Let+/-Trastuzumab 92 3.3 14.1
  11. 11. Hormone Resistance  Intrinsic—resistance occurs de novo at the initial exposure to endocrine therapy  Relapse while on the first 2 years of adjuvant  PD within 6 months of starting first-line endocrine therapy  Acquired—resistance manifests over time after an initial response to endocrine therapy  After the first 2 years,  Relapse within 12 months of completing such therapy  PD at ≥6 months after initiating endocrine therapy for MBC 16
  12. 12. Resistance to hormonal drugs 17
  13. 13. 18 Overcoming hormone resistance
  14. 14. Need of targeted Agents  Survival has reached Plateau with Chemotherapy  Possibility of reducing toxicity with selectively blocking cell signaling pathway  Possibility of modulating the tumor biology and improving the disease control Better understanding of biology 19
  15. 15. Targeted signaling  EGFR pathway  Ras-Raf-MapK pathway  PI3K-mTOR pathway  Met mutation  BRAF mutation  Sonic hedgehog pathway  Wnt pathway 20
  16. 16. 21
  17. 17. 22 Study design- BoleroII R A N D O M I Z A T I O N •multicenter, •open-label •phase III study •N=724 •Randomizatio n2:1 ratio Exemestane 25 mg OD +Placebo 20 mg/d Exemestane 25 mg OD + everolimus 10 mg/d. March 2008 and May 2009, • The primary end point PFS • Secondary end points: overall survival, overall response rate, clinical benefit rate, time to deterioration of ECOG performance status, safety, and quality of life • At least one measurable lesion or mainly lytic bone lesions in the absence of measurable disease • Exclusion criteria included a history of brain metastases and previous treatment with exemestane or mTOR inhibitors
  18. 18. BOLERO-2 Met Primary Endpoint: Final PFS Analysis (18-mo) Based on Local Assessment Demonstrated a 4.6-mo Prolongation of PFS 1.0 0.8 0.6 Probabilityof Progression-FreeSurvival 0.4 0.2 0 2826242220181614 Time, months 121086420 0 0 1 0 4 0 10 1 13 1 23 2 42 6 57 9 99 17 147 27 194 42 236 61 318 103 394 146 485 239 EVE+EXE PBO+EXE No. at risk HR = 0.45 (95% CI, 0.38-0.54) Log-rank P < .0001 Kaplan-Meier medians EVE+EXE: 7.8 months PBO+EXE: 3.2 months Censoring times EVE+EXE (n/N = 310/485) PBO+EXE (n/N = 200/239) Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival. Yardley DA, et al. Adv Ther. 2013;30(10):870-884.
  19. 19. BOLERO-2 (39-mo): Final OS Analysis 0 20 40 60 80 100 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 50 ProbabilityofOverallSurvival Time, months EVE+EXE (n/N = 267/485) PBO+EXE (n/N = 143/239) 232 109 248 113 266 120 279 130 292 145 311 153 330 162 347 170 373 182 399 194 414 201 429 211 448 220 471 232 485 239 EVE+EXE PBO+EXE No. at risk HR = 0.89 (95% CI, 0.73-1.10) Log-rank P = .14 Kaplan-Meier medians EVE+EXE: 30.98 months PBO+EXE: 26.55 months Censoring times 11 5 23 8 39 18 58 28 91 41 118 56 154 77 196 98 216 102 0 0 1 1 • At 39 months’ median follow-up, 410 deaths had occurred (data cutoff date: 03 October 2013) – 55% deaths (n = 267) in the EVE+EXE arm vs 60% deaths (n = 143) in the PBO+EXE arm – 13 pts still on treatment
  20. 20. BOLERO-2 (39-mo): Post-study Treatment Anticancer Therapies Therapy Type Everolimus + Exemestane (n = 485), % Placebo + Exemestane (n = 239), % Any posttreatment therapy 84 90 Chemotherapy 53 63 Hormonal therapy 47 44 Targeted therapy 10 11 Radiation therapy 9 11 Surgery 1 1 Immunotherapy <1 0 Other 2 1 10% more patients in placebo arm received chemotherapy compared with the everolimus arm. Chemotherapy 53 63 Taxane 28 36 Capecitabine 24 28 Anthracyclines 13 15 Cyclophosphamide 9 9 Vinorelbine 7 13 Platinum-based regimens 4 2 Gemcitabine 4 5
  21. 21. BOLERO-2 (39-mo): Longer Median Time From Randomization to First Chemotherapy or Death (Everolimus Plus Exemestane Arm) Time From Randomization to First Chemotherapy or Death Everolimus + Exemestane (n = 485) Placebo + Exemestane (n = 239) Number of events, n (%) 366 (75.5) 192 (80.3) Chemotherapy 257 (53.0) 150 (62.8) Death 109 (22.5) 42 (17.6) Number censored, n (%) 119 (24.5) 47 (19.7) Discontinued from study 105 (21.6) 45 (18.8) Ongoing at data cutoffa 14 (2.9) 2 (0.8) Time from randomization to first chemotherapy or death, months 25th percentile (95% CI) 5.68 (5.03-6.57) 3.06 (2.53-3.48) Median (95% CI) 11.86 (10.45-13.08) 5.98 (5.09-7.39) 75th percentile (95% CI) 25.10 (22.97-28.06) 14.16 (10.74-18.50) a Ongoing without any chemotherapy by the cutoff date.
  22. 22. BOLERO-2 (39-mo): No New Safety Signals at Final OS Analysis (Safety Set) Everolimus + Exemestane (n = 482a), % Placebo + Exemestane (n = 238a), % All deaths 55 60 On-treatment deathsb 5 2 Disease progression as primary cause of death 3 1 AE as primary cause of death 2 <1 Serious AEs 33 16 Suspected to be drug-related 13 2 Grade 3/4 AEs 55 29 Suspected to be drug-related 41 8 AEs leading to discontinuation 29 5 Categories are not mutually exclusive. Patients with multiple events in the same category were counted only once in that category. Patients with events in more than 1 category were counted once in each of those categories. aSafety set. b Deaths occurring >28 days after end of treatment are not included. Abbreviations: AE, adverse events; OS, overall survival.
  23. 23. Overall Survival in Patients With HR+, HER2– Advanced Breast Cancer—Clinical Evidence  In patients previously treated with NSAI, the only reports of an OS benefit to date has been with a small phase 2 trial where OS was an exploratory endpoint • TAMRAD [N = 111; everolimus + tamoxifen vs tamoxifen alone] Trial Treatment Arms OS Durations Post-NSAI population EFECT (N = 693) FUL 250 mg vs EXE 24.3 mo vs 23.1 mo SoFEA (N = 723) FUL 250 mg vs EXE vs FUL+ANA 19.4 mo vs 21.6 mo vs 20.2 mo BOLERO-2 (N = 724) EVE+EXE vs PBO+EXE 31.0 mo vs 26.6 mo Prior AI therapy not required CONFIRM (N = 736; post-AI subset = 42.5% of total or 313 pts) FUL 500 mg vs FUL 250 mg 25.1 mo vs 22.8 mo at final PFS analysis; P = .091 26.4 mo vs 22.3 mo at final OS analysis; nominal P = .016 (not significant as α was fully spent) 28 ANA, anastrozole; EVE, everolimus; EXE, exemestane; FUL, fulvestrant, NSAI, nonsteroidal aromatase inhibitor; OS, overall survival; PBO, placebo; PFS, progression-free survival. Longest OS Observed 31 Months .. Clinically Significant or Statically Significant???
  24. 24. mTOR Resistance  The mTOR-activated kinase S6K1 phosphorylates and destabilizes the insulin-receptor substrate 1 and 2 (IRS1 and IRS2) proteins in insulin-like growth factor (IGF)- responsive cells  mTOR inhibition can block the negative feedback on IGF- 1R signaling interfering on AkT/PI3K signaling.  The result is an increase in Akt phosphorylation, protein kinase activity, and downstream signaling, which could potentially counteract the inhibition of mTOR 29
  25. 25. 30 Cell cycle checkpoints are dominated by CDK
  26. 26. 31 PALOMA-1 Trial Finds Palbociclib/Letrozole Doubles Progression-Free Survival in Metastatic Breast Cancer Palbociclib is a first-in-class cyclin-dependent kinase (CDK) 4/6 inhibitor that inhibits cell proliferation and cellular DNA synthesis by preventing cell- cycle progression. Progression-free survival was 26.1 months for the combination of palbociclib plus letrozole vs 5.7 months for letrozole alone (P < .0001) ASCO,2014
  27. 27. 32Turner et al, NEJM, 2015
  28. 28. 33Turner et al, NEJM, 2015
  29. 29. 34Turner et al, NEJM, 2015
  30. 30. PD-L1
  31. 31. 36 Possible treatment Plan
  32. 32. 37 Possible treatment Plan
  33. 33. 38 Optimum outcome, minimal morbidity Goal of Treatment Personalization of Treatment
  34. 34. 39 Hormonal Management- At recurrence for ER/PR+, Her2neu- Repeat hormonal profile from metastatic site If Post menopausal- Tamoxifen pretreated- AI If progressed in 2nd line HT 3rd /4th line HT- Exemestane/Fulvestrant (EFFECT/CONFIRM trial) Progression after 4th line Exemestane +Everolimus (BLOERO II) Hormone therapy remains choice of treatment, if not in visceral crisis Visceral crisis: Brain metastasis, lymph-angitis, Multiple liver metastasis, marrow metastasis
  35. 35. Trastuzumab resistance was defined as recurrence during or within 12 months of adjuvant treatment or progression during or within 4 weeks of treatment for advanced disease SD after treated CNS metastases were eligible treatment completed 8 weeks before Exclusion criteria >3 previous lines of CT, previous treatment with vinca alkaloids or mTOR inhibitors, concomitant immunosuppressive agents or chronic corticosteroids RT to >25% bone marrow Everolimus +Trastuzumab+Vinorelbin e Placebo +Trastuzumab+Vinorelbin e R A N D O M I Z A T I O N 40
  36. 36. Progression-free survival 41
  37. 37. Forest plot analysis of locally assessed progressio n-free survival 42
  38. 38. mTOR Resistance  The mTOR-activated kinase S6K1 phosphorylates and destabilizes the insulin-receptor substrate 1 and 2 (IRS1 and IRS2) proteins in insulin-like growth factor (IGF)-responsive cells  mTOR inhibition can block the negative feedback on IGF-1R signaling interfering on AkT/PI3K signaling.  The result is an increase in Akt phosphorylation, protein kinase activity, and downstream signaling, which could potentially counteract the inhibition of mTOR 43
  39. 39. 44 Cell cycle checkpoints are dominated by CDK
  40. 40. • Cleopatra Study -2013, 2015 • Pertuzumab • Median FU-49.5 mth • 808 pts • metastatic breast cancer who had not received previous chemotherapy or anti-HER2 therapy for their metastatic disease to receive the pertuzumab combination or the placebo combination
  41. 41.  PFS was significantly improved after first-line therapy with pertuzumab, trastuzumab, and docetaxel, as compared with placebo, trastuzumab, and docetaxel.  Overall survival was significantly improved with pertuzumab to 56.5 mth  First-line therapy with pertuzumab, trastuzumab, and docetaxel significantly improved overall survival among patients with HER2-positive metastatic breast cancer
  42. 42. Adjuvant therapeutic strategies  HER 2 Blockade  Angiogenesis inhibition  PI3K – mTOR – AKT pathway inhibition  CDK 4/6 Inhibition  PARP Inhibition
  43. 43. Dual inhibition

Hormone receptor positive breast cancers and others novel developments in management and therapy

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