Reference Detail

Ref Type

Journal Article

PMID

(29236940)

Authors

Condorelli R, Spring L, O'Shaughnessy J, Lacroix L, Bailleux C, Scott V, Dubois J, Nagy RJ, Lanman RB, Iafrate AJ, Andre F, Bardia A

Title

Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Annals of oncology : official journal of the European Society for Medical Oncology	29	3	2018 Mar 01	640-645	Ann Oncol

URL

Abstract Text

While deregulation of the cyclin D1-CDK4/6-retinoblastoma pathway is common in hormone receptor positive (HR+) breast cancer, Rb is usually intact in HR+ breast cancer, and targeted CDK 4/6 inhibitors that act upstream of Rb, are routinely being utilized in clinical practice. However, factors that can lead to clinical resistance to CDK 4/6 inhibitors are not known.We identified patients who had pre- and post-genotyping in tissue and peripheral blood samples after receiving CDK 4/6 inhibitors. Genotyping was carried out in tumor tissue or blood collected before start of CDK 4/6 inhibitor and after disease progression on CDK 4/6 inhibitor, covering more than 90% of the coding region in RB1.We identified detectable acquired RB1 mutations in circulating tumor DNA (ctDNA) after exposure to CDK4/6 inhibitor (palbociclib, palbociclib, ribociclib) for 5, 8, and 13 months, respectively, in three patients. The RB1 mutations included substitution in donor splicing site of exon 8 of the RB1 gene in patient #1; substitution in donor splicing site of exon 22 of RB1 gene, exon 19 deletion, exon 3 insertion in patient #2; and RB1 exon 16 H483Y mutation in patient #3. None of these RB1 mutations were present in the pre-CDK 4/6 specimen highlighting these molecular alterations, which lead to functional loss of Rb1, likely emerged under selective pressure from the CDK4/6 inhibitor potentially confering therapeutic resistance.This is the first clinical report to describe the emergence of somatic RB1 mutations after exposure to palbociclib or ribociclib, in patients with metastatic breast cancer. Further research is needed to validate these findings, identify how these mutations temporally emerge under selective pressure of CDK 4/6 inhibitor, and develop rational therapeutic strategies.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
RB1	H483Y	missense	unknown	RB1 H483Y lies within domain A of the Rb1 protein (UniProt.org). H483Y has been identified in the scientific literature (PMID: 29236940, PMID: 33539671), but has not been biochemically characterized and therefore, its effect on Rb1 protein function is unknown (PubMed, Oct 2023).
RB1	T738_R775del	deletion	unknown	RB1 T738_R775del results in the deletion of 38 amino acids in domain B of the Rb1 protein from amino acids 738 to 775 (UniProt.org). T738_R775del has been identified in the scientific literature (PMID: 29236940), but has not been biochemically characterized and therefore, its effect on Rb1 protein function is unknown (PubMed, Nov 2023).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RB1 I101fs RB1 E268* RB1 V654fs RB1 T738_R775del	Her2-receptor negative breast cancer	predicted - resistant	Fulvestrant + Palbociclib	Case Reports/Case Series	Actionable	In a clinical case study, RB1 mutations including E268*, I101fs, T738_R775del, and V654fs were identified in the circulating tumor DNA of a patient with estrogen receptor positive, progesterone receptor positive, and Erbb2 (Her2)-negative, invasive ductal carcinoma at the time of disease progression after 8 months of Ibrance (palbociclib) and Faslodex (fulvestrant) combination treatment (PMID: 29236940).	29236940
RB1 H483Y	Her2-receptor negative breast cancer	predicted - resistant	Letrozole + Ribociclib	Case Reports/Case Series	Actionable	In a clinical case study, RB1 H483Y was identified in the circulating tumor DNA of a patient with estrogen receptor (ESR1)-positive, progesterone receptor (PGR)-positive, and Erbb2 (Her2)-negative, invasive ductal carcinoma at the time of disease progression after 13 months of Kisqali (ribociclib) and Femara (letrozole) combination treatment (PMID: 29236940).	29236940
RB1 K240Sfs*22 TP53 R248W	Her2-receptor negative breast cancer	predicted - resistant	Fulvestrant + Palbociclib	Case Reports/Case Series	Actionable	In a clinical case study, RB1 K240Sfs*22 and TP53 R248W were identified in the circulating tumor DNA of a patient with estrogen receptor positive, progesterone receptor positive, and Erbb2 (Her2)-negative, invasive ductal carcinoma at the time of disease progression after 5 months of Ibrance (palbociclib) and Faslodex (fulvestrant) combination treatment (PMID: 29236940).	29236940