Patients in the Genomic Era Marc Lippman, MD The Sylvester - - PowerPoint PPT Presentation

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Patients in the Genomic Era Marc Lippman, MD The Sylvester - - PowerPoint PPT Presentation

Feb 12, 2023 125 likes •767 views

Selecting Therapy for Breast Cancer Patients in the Genomic Era Marc Lippman, MD The Sylvester Comprehensive Cancer Center at the University of Miami PERSONALIZED MEDICINE FOR BREAST CANCER PATIENTS A WORKING DEFINITION: SUFFICIENT

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Selecting Therapy for Breast Cancer Patients in the Genomic Era

Marc Lippman, MD The Sylvester Comprehensive Cancer Center at the University of Miami

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PERSONALIZED MEDICINE FOR BREAST CANCER PATIENTS

  • A WORKING DEFINITION: SUFFICIENT

KNOWLEDGE ABOUT THE MOLECULAR FEATURES OF THE TUMOR OR HOST TO MAKE SPECIFIC THERAPEUTIC CHOICES WHICH MAXIMIZE EFFECTIVENESS AND MINIMIZE TOXICITY.

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PERSONALIZED MEDICINE FOR BREAST CANCER PATIENTS

  • Perhaps not quite such new thing…
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PERSONALIZED MEDICINE FOR BREAST CANCER PATIENTS

  • Perhaps not quite such new thing…
  • A BRIEF HISTORICAL PERSPECTIVE – THE TUMOR

– THE ESTROGEN/PROGESTERONE RECEPTOR AXIS – HER2/neu/ERBB2 – CLONOGENIC AND OTHER IN VITRO SENSITIVITY ASSAYS – PDX MODELS FOR CUSTOMIZED TESTING

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PERSONALIZED MEDICINE FOR BREAST CANCER PATIENTS

  • A BRIEF HISTORICAL PERSPECTIVE – THE HOST

– CUSTOMIZED DRUG DOSING

  • MTX, PLATINUM,

– CUSTOMIZED ANALYSES OF PHARMACOGENOMICS

  • TAMOXIFEN
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THE END OF COUNTRY OF ORIGIN AS THE CRITICAL FACT DETERMINING CANCER TREATMENT ??

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Overall Survival, Median = 21.3 months Progression-Free Survival, median = 11.5 months 0.8 0.6 0.4 0.2 24 46 72 96 120 144 168 192 216 0.0 1.0 240

Months From the Start of Treatment Proportion Surviving

Overall and progression free survival of 1581 patients with metastatic breast carcinoma treated on 18 successive, doxorubicin-containing standard dose chemotherapy protocols from 1973 to 1982 at the M.D. Anderson Cancer Center.

SURVIVAL FOLLOWING THE DIAGNOSIS OF METASTATIC BREAST CANCER

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1,00E+00 1,00E+01 1,00E+02 1,00E+03

Log Mutation Rate per 10 Megabases

Background Mutation Rates Across Different Cancer Types

1 per Mbp 10 per Mbp

100 per Mbp Pediatric cancers De novo and secondary AMLs GBMs OVCs BRCs LUCs

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Significantly Mutated Genes (All 507 Cases) (FDR<0.15)

SMGs with FDR<0.15 by at least two tests (Fisher’s, LR, or Convolution)

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Tumour Phylogenetic Evolution (Renal Cell Cancer)

Normal

KDM5C (missense)

Gerlinger, M., et al.; N Engl J Med; 2012

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368:1199-209, 2013

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Dawson et al. N Engl J Med 368:1199-209, 2013

Circulating Plasma Cell Free Tumor DNA in Breast Cancer

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Mutation Tracking of ptDNA May Be More Prognostic than a Single Point in Time

Garcia-Murllias et al Science Translational Med 2015 Single time- point post Surgery

Multiple time-points for Mutational Tracking

N=7 N=13

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A PAIR OF INFORMATIVE EXAMPLES

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IMPLICATIONS

  • IT SEEMS TO ME WE ARE EITHER GOING TO

HAVE TO FIGURE OUT FEASIBLE STRATEGIES TO VALIDATE THESE THERAPIES EARLIER IN THE CLINICAL COURSE, OR,

  • WE MAY NEED TO RETHINK OUR PARADIGMS

AND FOCUS MORE ON THE HOST.

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ENDOCRINE THERAPY

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THE EXACT SAME THERAPY WHICH CAN PREVENT BREAST CANCER GIVEN BEFORE DIAGNOSIS AND CURE SOME PATIENTS IN THE ADJUVANT SETTING CURES NO ONE IN THE METASTATIC SETTING. WHY WILL ANY OTHER KIND OF THERAPY BE DIFFERENT ?

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ESR1 MUTATIONS

  • Hypothesis

– Prior Endocrine therapy selects for ESR1 variants – These variants:

  • Are still estrogen sensitive
  • But also estrogen independent
  • AIs no longer effective

– Patients with ESR1 variants may respond to high doses of SERMs or SERDs.

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Identification of Mutations in ESR1 in Patients with ER+ Metastatic Breast Cancer (and Endometrial Cancers)

Robinson et al, Nature Genetics 2013

  • First identified in 1997 Fuqua in a single patient with metastatic breast cancer

treated with diethylstibesterol (but since then thought to be rare)

  • 6 out of 11 ER+ metastatic breast cancer (all are post- aromatase Rx)
  • Not in ER- breast cancers
  • Not in ER+ tamoxifen only treated patients
  • 4 of 373 endometrial cancers (from TCGA)
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ESR1 Mutant Signaling Is Estrogen Independent

HEK-293T human embryonic kidney cells transfected with ESR (WT or Mutant)

Robinson, et al., Nat Genet 2013

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ESR1 activating mutations are not present in primary tumors

  • 134 ER+ samples
  • 58 primary BCs
  • 76 metastatic samples
  • 115 ER- samples
  • 9/76 (12%) samples contained a somatic

mutation in codon 537 or 538

  • None of the primary tumors, treatment

naïve ER+ cancers or ER- tumors harbored the mutation

  • 13 ER+ samples
  • 5/13 patients contained the D538G

mutation in liver mets

  • The mutation was not detected in

the primary tumors prior to endocrine treatment

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ESR1 MUTATIONS

  • Conclusions

–Uncommon in Primary Cancers –Appear to be selected by ET

–Focused in Ligand Binding Domain

  • AA 536-538

– Confer Ligand–independent Signaling – Remain dependent on ER signaling pathway

–Resistance:

  • ?Absolute to E2 depletion (AI)
  • Relative to SERM/SERD
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Hazard Ratio (95% CI): 0.80 (0.68, 0.94) p-value: 0.006

3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Proportion of patients progression free

Time (Months)

Fulvestrant 250mg Fulvestrant 500mg

CONFIRM Study: PFS

Di Leo, et al., J Clin Oncol 28:4594-600, 2010

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Conclusions

Somatic variants in ESR1 are common (~20%) in advanced metastatic BC. Tumors with these mutation are signaling through the ER pathway Tumors are resistant to endocrine therapies

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A FEW CONCLUDING COMMENTS

  • UNQUESTIONABLY THE NOTION THAT THERE

IS ENORMOUS CANCER DIVERSITY IMPLIES THAT THERE MUST BE DIVERSE TREATMENTS.

  • AND IT ALSO IMPLIES THAT IF WE COULD

ONLY MIX AND MATCH THESE CORRECTLY TO OUR PATIENTS WE WOULD ACHIEVE GREAT THINGS.

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A FEW CONCLUDING COMMENTS

  • UNQUESTIONABLY THE NOTION THAT THERE IS

ENORMOUS CANCER DIVERSITY IMPLIES THAT THERE MUST BE DIVERSE TREATMENTS.

  • HOWEVER, GIVEN THE REMARKABLE NUMBER OF

POTENTIALLY CONTRIBUTORY MUTATIONS AND THE [RELATIVELY] INFREQUENT NUMBER OF AGENTS TO TARGET THESE MUTATIONS AND GIVEN THE LACK OF DURABLE SUCCESS WHEN THOSE AVAILABLE AGENTS ARE USED [AT LEAST IN THE ADVANCED DISEASE SETTING] WE OBVIOUSLY HAVE A VERY LONG WAY TO GO BEFORE ‘’PERSONALIZED MEDICINE’’ IS THE REALITY WE WOULD ALL HOPE IT TO BE…..

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A FEW CONCLUDING COMMENTS

  • IT SEEMS TO ME WE ARE EITHER GOING TO

HAVE TO FIGURE OUT FEASIBLE STRATEGIES TO VALIDATE THESE THERAPIES EARLIER IN THE CLINICAL COURSE, OR,

  • WE MAY NEED TO RETHINK OUR PARADIGMS

AND FOCUS MORE ON THE HOST.

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