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Giorgio Minotti
Dipartimento di Medicina
Università Campus Bio-Medico Roma
Mutazioni PI3KCA e mutazioni ER:
quale impatto sull’outcome delle pazienti con carcinoma mammario?
Roma, 25 maggio 2019
Activating mutations in PIK3CA gene are commonly associated with
endometrial cancer, breast cancer (>>ER+/HER2-), colon cancer, head and neck cancers.
Hot spot mutations clusterize in helical and kinase domains
Clin Cancer Res 2009 Mutations of the helical domain have
been associated with a more aggressive phenotype
Mutations of the kinase domain have been associated with older age and a
more favourable phenotype
PIK3CA mutations are significantly associated with a better IDFS, DDFS and OS at univariable analysis, but only 5
years benefit in IDFS persists after multivariable analysis
The overall genomic landscape reveals the frequent presence of multiple concomitant
oncogenic alterations in addition to PIK3CA.
Both PIK3CA mutation and loss of PTEN are required to drive tumor growth
PIK3CA mutations are spatiotemporally
heterogeneous
Fewer satellite
mutations
Baselga JCO 2018
PIK3CA mutations and clinical benefit rate in ER+/HER2- breast cancer
Alpelisib
Baselga JCO 2018 Fritsch MCT 2014
Intertreatment plasma [C] >IC
50correlates with tumor response
25.0% AE driven
treatment discontinuation
PIK3CA mutated
PIK3CA wt
4.2% AE driven
treatment discontinuation
inhibition=hyperglycemia
Sci Transl Med 2018
ESR1 mutations are most commonly missense mutations clusterize in the LBD and result in ligand-independent constitutive activation of the receptor
ESR1 mutations accumulate in multiply treated tumors and contribute to ER independent growth signalling
Nat Med 2014
ESR1 mutations accumulate in multiply treated tumors and contribute to ER independent growth signalling
Nat Med 2014 Ann Oncol 2018
ESR1 mutations worsen PFS and OS after progression on first-line of AI
Oncotarget 2016
ESR1 mutation, D53BG, reduces PFS benefit from adding everolimus to
exemestane
JAMA Oncol 2016
ESR1 mutations worsen PFS in placebo/fulvestrant of PALOMA 3
Nat Commun 2018
MUTATIONAL BURDEN?
SENSITIVITY TO PREVIOUS ET
NO SENSITIVITY TO PREVIOUS ET
FVT<AZD9496
FVT=AZD9496
Cancer Discov 2017
MUTATIONAL CROSS TALKS AND PATIENTS HETEROGENEITY
Nat Commun 2018
CONCLUSIONS
PI3KCA mutations show variable effects on disease course
On balance, PI3KCA inhibitors seem to offer an opportunity to improve patient’s outcome
ER mutations consistently worsen patient’s outcome
Much remains to be done for designing SERMS, SERDS or SERCS with activity on ER mutants
Much remains to be done for intercepting multiple ER mutations in a patient and for tailoring interventions in accordance
