[Paper-level Aggregated] PMCID: PMC6368247

Evidence Type(s): Functional

Summary: Mutation: Q75E | Summary: The Q75E mutation in ESR1 is mentioned in relation to changes in dominant mutations and sub-clonal selection, suggesting it may have functional implications, although it is not recognized as a cause of resistance.

Evidence Type: Functional Mutation: Q257X | Summary: The Q257X mutation is likely to result in abrogated Rb function due to the introduction of a stop codon, affecting the molecular function of the RB1 protein.

Gene→Variant (gene-first): ESR1(2099):Q75E RB1(5925):Q257X

Genes: ESR1(2099) RB1(5925)

Variants: Q75E Q257X

[Paper-level Aggregated] PMCID: PMC6368247

Evidence Type(s): Oncogenic

Summary: Mutation: Y537S | Summary: The Y537S mutation in ESR1 is associated with the emergence of new driver mutations during treatment and contributes to tumor development or progression, as it is positively selected during treatment.

Evidence Type: Oncogenic Mutation: p.Q257X | Summary: The p.Q257X mutation in RB1 is associated with resistance to treatment and the development of resistance to palbociclib and fulvestrant, indicating its role in tumor progression.

Evidence Type: Oncogenic Mutation: p.N519fs | Summary: The p.N519fs mutation in RB1 is linked to the emergence of a resistant subclone, suggesting its contribution to tumor development or progression.

Evidence Type: Oncogenic Mutation: p.K569E | Summary: The p.K569E mutation in FGFR2 is described as an activating mutation that contributes to tumor development, particularly in the context of resistance to treatment with palbociclib plus fulvestrant.

Evidence Type: Oncogenic Mutation: D538G | Summary: The D538G mutation in ESR1 was negatively selected during treatment, indicating its role in tumor progression and response to therapy, thus supporting its oncogenic potential.

Evidence Type: Oncogenic Mutation: E542K | Summary: The E542K mutation shows limited evidence for positive selection, indicating its potential role in tumor development or progression.

Evidence Type: Oncogenic Mutation: E545K | Summary: The E545K mutation is one of the most common acquired variants, suggesting its contribution to tumor development or progression.

Evidence Type: Oncogenic Mutation: H1047L | Summary: The H1047L mutation is validated as an acquired variant, indicating its potential role in tumor development or progression.

Evidence Type: Oncogenic Mutation: H1047R | Summary: The H1047R mutation is validated as an acquired variant, indicating its potential role in tumor development or progression.

Gene→Variant (gene-first): PTEN(5728):Y537S RB1(5925):p.Q257X RB1(5925):p.N519fs FGFR2(2263):p.K569E FGFR2(2263):D538G PIK3CA(5290):E542K PIK3CA(5290):E545K PIK3CA(5290):H1047L PIK3CA(5290):H1047R

Genes: PTEN(5728) RB1(5925) FGFR2(2263) PIK3CA(5290)

Variants: Y537S p.Q257X p.N519fs p.K569E D538G E542K E545K H1047L H1047R

[Paper-level Aggregated] PMCID: PMC6368247

Evidence Type(s): Prognostic

Summary: Mutation: Y537S | Summary: The presence of the Y537S mutation correlates with progression-free survival outcomes, suggesting its prognostic significance.

Gene→Variant (gene-first): PTEN(5728):Y537S

Genes: PTEN(5728)

Variants: Y537S

[Paper-level Aggregated] PMCID: PMC6368247

Evidence Type(s): Predictive

Summary: Mutation: Y537S | Summary: The Y537S mutation is associated with resistance to CDK4/6 inhibitors and fulvestrant treatment, indicating its predictive value in therapy response and correlation with treatment selection in patients with advanced estrogen receptor positive breast cancer.

Gene→Variant (gene-first): PTEN(5728):Y537S

Genes: PTEN(5728)

Variants: Y537S

[Paragraph-level] PMCID: PMC6368247 Section: RESULTS PassageIndex: 17

Evidence Type(s): Predictive, Oncogenic, Prognostic

Summary: Evidence Type: Predictive | Mutation: Y537S | Summary: The Y537S mutation is associated with resistance to fulvestrant treatment, indicating its predictive value in therapy response. Evidence Type: Oncogenic | Mutation: Y537S | Summary: The Y537S mutation contributes to tumor development or progression, as it is positively selected during treatment. Evidence Type: Prognostic | Mutation: Y537S | Summary: The presence of the Y537S mutation correlates with progression-free survival outcomes, suggesting its prognostic significance.

Gene→Variant (gene-first): 5728:Y537S

Genes: 5728

Variants: Y537S

[Paragraph-level] PMCID: PMC6368247 Section: RESULTS PassageIndex: 15

Evidence Type(s): Predictive

Summary: Evidence Type: Predictive | Mutation: Y537S | Summary: The variant Y537S is associated with treatment selection, indicating a correlation with response or resistance to specific therapies.

Gene→Variant (gene-first): 5728:Y537S

Genes: 5728

Variants: Y537S

[Paragraph-level] PMCID: PMC6368247 Section: RESULTS PassageIndex: 14

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: E542K | Summary: The E542K mutation shows limited evidence for positive selection, indicating its potential role in tumor development or progression. Evidence Type: Oncogenic | Mutation: E545K | Summary: The E545K mutation is one of the most common acquired variants, suggesting its contribution to tumor development or progression. Evidence Type: Oncogenic | Mutation: H1047L | Summary: The H1047L mutation is validated as an acquired variant, indicating its potential role in tumor development or progression. Evidence Type: Oncogenic | Mutation: H1047R | Summary: The H1047R mutation is validated as an acquired variant, indicating its potential role in tumor development or progression.

Gene→Variant (gene-first): 5290:E542K 5290:E545K 5290:H1047L 5290:H1047R

Genes: 5290

Variants: E542K E545K H1047L H1047R

[Paragraph-level] PMCID: PMC6368247 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: Q257X | Summary: The Q257X mutation in the RB1 gene is associated with the development of resistance to palbociclib and fulvestrant treatment, indicating its role in tumor progression. Evidence Type: Functional | Mutation: Q257X | Summary: The Q257X mutation is likely to result in abrogated Rb function due to the introduction of a stop codon, affecting the molecular function of the RB1 protein.

Gene→Variant (gene-first): 5925:Q257X

Genes: 5925

Variants: Q257X

[Paragraph-level] PMCID: PMC6368247 Section: RESULTS PassageIndex: 6

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: p.K569E | Summary: The p.K569E mutation in FGFR2 is described as an activating mutation that contributes to tumor development, particularly in the context of resistance to treatment with palbociclib plus fulvestrant. Evidence Type: Functional | Mutation: Q75E | Summary: The Q75E mutation in ESR1 is mentioned in relation to changes in dominant mutations and sub-clonal selection, suggesting it may have functional implications, although it is not recognized as a cause of resistance. Evidence Type: Oncogenic | Mutation: D538G | Summary: The D538G mutation in ESR1 was negatively selected during treatment, indicating its role in tumor progression and response to therapy, thus supporting its oncogenic potential.

Gene→Variant (gene-first): 2263:D538G 2099:Q75E 2263:p.K569E

Genes: 2263 2099

Variants: D538G Q75E p.K569E

[Paragraph-level] PMCID: PMC6368247 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: p.Q257X | Summary: The p.Q257X mutation in RB1 is associated with resistance to treatment, indicating its role in tumor development or progression. Evidence Type: Oncogenic | Mutation: p.N519fs | Summary: The p.N519fs mutation in RB1 is linked to the emergence of a resistant subclone, suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 5925:p.N519fs 5925:p.Q257X

Genes: 5925

Variants: p.N519fs p.Q257X

[Paragraph-level] PMCID: PMC6368247 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Predictive

Summary: Evidence Type: Oncogenic | Mutation: Y537S | Summary: The Y537S mutation in ESR1 is associated with the emergence of new driver mutations during treatment, indicating its role in tumor development and progression in breast cancer. Evidence Type: Predictive | Mutation: Y537S | Summary: The presence of the Y537S mutation may correlate with resistance to CDK4/6 inhibitors, suggesting its potential impact on treatment response in patients with advanced estrogen receptor positive breast cancer.

Gene→Variant (gene-first): 5728:Y537S

Genes: 5728

Variants: Y537S

[Paper-level Aggregated] PMCID: PMC6368247

Evidence Type(s): Oncogenic, Functional, Predictive, Prognostic

Justification: Oncogenic: The emergence of mutations such as ESR1 Y537S and PIK3CA mutations (E542K, E545K, H1047L, H1047R) during treatment suggests they play a role in driving resistance to therapy, indicating their oncogenic potential. Functional: The study discusses the functional consequences of mutations, particularly the selection of ESR1 Y537S and PIK3CA mutations, which are associated with treatment resistance, indicating their functional impact on tumor behavior. Predictive: The identification of specific mutations like ESR1 Y537S and PIK3CA variants that correlate with treatment resistance suggests they may serve as predictive biomarkers for response to endocrine therapy. Prognostic: The analysis of progression-free survival in relation to the acquisition of ESR1 Y537S mutations indicates that these mutations may have prognostic implications for patient outcomes following treatment.

Gene→Variant (gene-first): FGFR2(2263):D538G ESR1(2099):Q75E FGFR2(2263):p.K569E PIK3CA(5290):E542K PIK3CA(5290):E545K PIK3CA(5290):H1047L PIK3CA(5290):H1047R RB1(5925):Q257X PTEN(5728):Y537S RB1(5925):p.N519fs RB1(5925):p.Q257X

Genes: FGFR2(2263) ESR1(2099) PIK3CA(5290) RB1(5925) PTEN(5728)

Variants: D538G Q75E p.K569E E542K E545K H1047L H1047R Q257X Y537S p.N519fs p.Q257X

[Paragraph-level] PMCID: PMC6368247 Section: RESULTS PassageIndex: 17

Evidence Type(s): Predictive, Prognostic, Oncogenic

Justification: Predictive: The passage discusses the positive selection of the ESR1 Y537S mutation through treatment and its association with resistance to fulvestrant, indicating a correlation with treatment response. Prognostic: The exploratory analysis of progression-free survival comparing patients with a Y537S mutation at day 1 to those who acquired it by the end of treatment suggests a correlation with disease outcome, independent of therapy. Oncogenic: The evidence presented indicates that the ESR1 Y537S mutation contributes to tumor development or progression, particularly in the context of promoting resistance to treatment.

Gene→Variant (gene-first): 5728:Y537S

Genes: 5728

Variants: Y537S

[Paragraph-level] PMCID: PMC6368247 Section: RESULTS PassageIndex: 15

Evidence Type(s): Predictive

Justification: Predictive: The mention of "Selection of ESR1 Y537S on treatment" suggests that the variant is associated with treatment response or resistance, indicating its predictive nature regarding therapy outcomes.

Gene→Variant (gene-first): 5728:Y537S

Genes: 5728

Variants: Y537S

[Paragraph-level] PMCID: PMC6368247 Section: RESULTS PassageIndex: 14

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the acquisition of PIK3CA mutations, including E542K, E545K, H1047L, and H1047R, in patients during treatment, indicating that these somatic variants contribute to tumor development or progression. Functional: The validation of acquired PIK3CA mutations using ddPCR and the mention of their allele fraction estimation suggest that these variants alter molecular or biochemical function, supporting their functional impact in the context of cancer.

Gene→Variant (gene-first): 5290:E542K 5290:E545K 5290:H1047L 5290:H1047R

Genes: 5290

Variants: E542K E545K H1047L H1047R

[Paragraph-level] PMCID: PMC6368247 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The Q257X mutation is described as part of RB1 aberrations that are likely to result in abrogated Rb function, indicating its contribution to tumor development or progression in the context of resistance to therapy. Predictive: The emergence of RB1 aberrations, including the Q257X mutation, is discussed in relation to the treatment with palbociclib plus fulvestrant, suggesting a correlation with resistance to this specific therapy.

Gene→Variant (gene-first): 5925:Q257X

Genes: 5925

Variants: Q257X

[Paragraph-level] PMCID: PMC6368247 Section: RESULTS PassageIndex: 6

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the selection of a subclone featuring the FGFR2 p.K569E mutation during treatment with palbociclib plus fulvestrant, indicating a correlation with resistance to therapy. Oncogenic: The FGFR2 p.K569E mutation is described as an activating mutation that contributes to the development of a resistant subclone, suggesting its role in tumor progression.

Gene→Variant (gene-first): 2263:D538G 2099:Q75E 2263:p.K569E

Genes: 2263 2099

Variants: D538G Q75E p.K569E

[Paragraph-level] PMCID: PMC6368247 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the presence of RB1 mutations, including p.Q257X and p.N519fs, in a resistant subclone during treatment with palbociclib plus fulvestrant, indicating a correlation with treatment resistance. Oncogenic: The RB1 mutations are described as contributing to the development of a resistant subclone, suggesting their role in tumor progression and resistance to therapy.

Gene→Variant (gene-first): 5925:p.N519fs 5925:p.Q257X

Genes: 5925

Variants: p.N519fs p.Q257X

[Paragraph-level] PMCID: PMC6368247 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the emergence of the ESR1 Y537S mutation in the context of resistance to CDK4/6 inhibitors, indicating a correlation with treatment response and resistance. Oncogenic: The mention of the ESR1 Y537S mutation as a new driver mutation suggests that it contributes to tumor development or progression, particularly in the context of breast cancer.

Gene→Variant (gene-first): 5728:Y537S

Genes: 5728

Variants: Y537S

[Paragraph-level] PMCID: PMC6368247 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the emergence of the ESR1 Y537S mutation in the context of resistance to CDK4/6 inhibitors, indicating a correlation with treatment response and resistance. Oncogenic: The mention of the ESR1 Y537S mutation as a new driver mutation suggests that it contributes to tumor development or progression, particularly in the context of breast cancer.

Gene→Variant (gene-first): 5728:Y537S

Genes: 5728

Variants: Y537S