Ph. D. Project
Title:
Using genomic and transcriptomic signatures to differentiate response profiles to first-line endocrine therapy +/- CDK4/6
inhibitors in patients with advanced ER+ HER2- breast cancer
Dates:
2025/10/01 - 2028/09/30
Supervisor(s):
Description:
Endocrine therapy (ET) has long been the cornerstone of treatment for estrogen receptor-positive, HER2-negative (ER+
HER2-) advanced breast cancer (ABC). Its origins date back to the pioneering observations of Scottish surgeon George
Beatson in the late 19th century, who demonstrated that oophorectomy could induce tumor regression in patients with
advanced breast cancer⬔a discovery that decisively established hormone dependence as a therapeutic vulnerability.
The pharmacological era began several decades later with the development of selective estrogen receptor modulators
(SERMs), notably tamoxifen, followed by aromatase inhibitors (AIs), two classes that profoundly shaped the standard of
care and prolonged the survival of many patients, both in early stages and in metastatic settings. Subsequently, the
introduction of selective estrogen receptor degraders (SERDs)⬔first fulvestrant, then several oral agents still in clinical
development⬔added an additional dimension to endocrine therapy, enabling direct receptor degradation and circumventing
certain resistance mechanisms, notably ESR1 mutations that confer ligand-independent activation of the estrogen receptor
and lead to resistance to AIs and SERMs.
A major therapeutic advance has been made with the introduction of CDK4/6 inhibitors, which, when combined with
endocrine therapy, have significantly improved progression-free survival and overall survival in multiple clinical settings.
Nevertheless, clinical heterogeneity persists: patients exhibit distinct response profiles to ET and CDK4/6i, which are
increasingly recognized as critical predictors of benefit from subsequent lines of endocrine therapy ± targeted therapies.
Building on these advances, therapeutic escalation and de-escalation strategies are being developed to more precisely align
treatments with tumor biology, adapting to both the reactivity and aggressiveness of different forms of the disease.
Among the new targeted approaches, the selective PI3K? inhibitor inavolisib has recently shown promising results. By
circumventing resistance mechanisms in tumors harboring PIK3CA mutations⬔historically associated with a poor
prognosis⬔inavolisib further expands the scope of precision endocrine therapy and underscores the importance of tailoring
treatment strategies to molecularly defined subgroups. More recently, the phase III SERENA-6 trial⬔presented at ASCO
2025⬔showed that an early switch to camizestrant, an oral SERD, while continuing the same CDK4/6i, upon detection of
ESR1 mutations, halved the risk of progression or death and significantly delayed the deterioration in quality of life.
We previously conducted the CICLADES study, which aimed to evaluate the prognostic value and temporal dynamics of
ESR1, PIK3CA, and TP53 mutations, as well as progression signals detected by circulating tumor DNA (ctDNA). A
prospective cohort of 146 patients with ER+ HER2- ABC treated in the first-line setting with ET ± CDK4/6i was included.
Plasma ctDNA was analyzed by a 35-gene NGS panel at baseline, at follow-up visits, and at investigator-assessed
progression or at study end (after 36 months). Associations between mutation status and progression-free survival (PFS)
were investigated for ESR1, PIK3CA, and TP53.
Additional analyses explored mutation emergence, polyclonality, and molecular progression, defined as a ?50% increase in
allele frequency (VAF). Transient variants not detected at baseline or progression were evaluated as potential markers of
subclone dynamics. These results will be presented by the end of 2025.
Formalin-fixed, paraffin-embedded (FFPE) tissue samples were collected for ancillary biological studies from patients who
provided informed consent. We thus have tissue samples from 124 patients (TBV) who received the ET + CDK4/6i
combination and from 22 patients (TBV) who received ET alone.
In this new project, we will determine tumor genomic and transcriptomic signatures likely to distinguish different
therapeutic response profiles by analyzing nucleic acids (DNA and RNA) extracted from FFPE samples from patients in the
CICLADES study.
Patients were classified into four categories based on investigator-assessed PFS duration on CDK4/6i-based therapy:
Primary resistance or non-responders (<6 months)
Early progression (6 to 12 months)
Intermediate response (12 to 24 months)
Durable response (?24 months)
These thresholds were chosen based on data from prospective trials (e.g., EMERALD, long-term follow-up of PARSIFAL)
and real-world series, which highlight the prognostic relevance of early progression and favorable outcomes associated with
longer treatment durations. They provide clinically meaningful thresholds to differentiate response profiles and assess their
predictive value for subsequent lines of therapy.
Objective: To determine whether genomic or transcriptomic signatures exist to discriminate treatment response profiles.
Particular attention will be paid to signatures associated with primary resistance or sustained response, which could inform
the design of therapeutic escalation and de-escalation strategies.
If such signatures are identified, a validation phase will be conducted on an independent cohort of patients treated at our
center. Within this cohort, we will also assess the predictive value of the signatures with respect to the expected benefit of
subsequent lines of hormone therapy.
HER2-) advanced breast cancer (ABC). Its origins date back to the pioneering observations of Scottish surgeon George
Beatson in the late 19th century, who demonstrated that oophorectomy could induce tumor regression in patients with
advanced breast cancer⬔a discovery that decisively established hormone dependence as a therapeutic vulnerability.
The pharmacological era began several decades later with the development of selective estrogen receptor modulators
(SERMs), notably tamoxifen, followed by aromatase inhibitors (AIs), two classes that profoundly shaped the standard of
care and prolonged the survival of many patients, both in early stages and in metastatic settings. Subsequently, the
introduction of selective estrogen receptor degraders (SERDs)⬔first fulvestrant, then several oral agents still in clinical
development⬔added an additional dimension to endocrine therapy, enabling direct receptor degradation and circumventing
certain resistance mechanisms, notably ESR1 mutations that confer ligand-independent activation of the estrogen receptor
and lead to resistance to AIs and SERMs.
A major therapeutic advance has been made with the introduction of CDK4/6 inhibitors, which, when combined with
endocrine therapy, have significantly improved progression-free survival and overall survival in multiple clinical settings.
Nevertheless, clinical heterogeneity persists: patients exhibit distinct response profiles to ET and CDK4/6i, which are
increasingly recognized as critical predictors of benefit from subsequent lines of endocrine therapy ± targeted therapies.
Building on these advances, therapeutic escalation and de-escalation strategies are being developed to more precisely align
treatments with tumor biology, adapting to both the reactivity and aggressiveness of different forms of the disease.
Among the new targeted approaches, the selective PI3K? inhibitor inavolisib has recently shown promising results. By
circumventing resistance mechanisms in tumors harboring PIK3CA mutations⬔historically associated with a poor
prognosis⬔inavolisib further expands the scope of precision endocrine therapy and underscores the importance of tailoring
treatment strategies to molecularly defined subgroups. More recently, the phase III SERENA-6 trial⬔presented at ASCO
2025⬔showed that an early switch to camizestrant, an oral SERD, while continuing the same CDK4/6i, upon detection of
ESR1 mutations, halved the risk of progression or death and significantly delayed the deterioration in quality of life.
We previously conducted the CICLADES study, which aimed to evaluate the prognostic value and temporal dynamics of
ESR1, PIK3CA, and TP53 mutations, as well as progression signals detected by circulating tumor DNA (ctDNA). A
prospective cohort of 146 patients with ER+ HER2- ABC treated in the first-line setting with ET ± CDK4/6i was included.
Plasma ctDNA was analyzed by a 35-gene NGS panel at baseline, at follow-up visits, and at investigator-assessed
progression or at study end (after 36 months). Associations between mutation status and progression-free survival (PFS)
were investigated for ESR1, PIK3CA, and TP53.
Additional analyses explored mutation emergence, polyclonality, and molecular progression, defined as a ?50% increase in
allele frequency (VAF). Transient variants not detected at baseline or progression were evaluated as potential markers of
subclone dynamics. These results will be presented by the end of 2025.
Formalin-fixed, paraffin-embedded (FFPE) tissue samples were collected for ancillary biological studies from patients who
provided informed consent. We thus have tissue samples from 124 patients (TBV) who received the ET + CDK4/6i
combination and from 22 patients (TBV) who received ET alone.
In this new project, we will determine tumor genomic and transcriptomic signatures likely to distinguish different
therapeutic response profiles by analyzing nucleic acids (DNA and RNA) extracted from FFPE samples from patients in the
CICLADES study.
Patients were classified into four categories based on investigator-assessed PFS duration on CDK4/6i-based therapy:
Primary resistance or non-responders (<6 months)
Early progression (6 to 12 months)
Intermediate response (12 to 24 months)
Durable response (?24 months)
These thresholds were chosen based on data from prospective trials (e.g., EMERALD, long-term follow-up of PARSIFAL)
and real-world series, which highlight the prognostic relevance of early progression and favorable outcomes associated with
longer treatment durations. They provide clinically meaningful thresholds to differentiate response profiles and assess their
predictive value for subsequent lines of therapy.
Objective: To determine whether genomic or transcriptomic signatures exist to discriminate treatment response profiles.
Particular attention will be paid to signatures associated with primary resistance or sustained response, which could inform
the design of therapeutic escalation and de-escalation strategies.
If such signatures are identified, a validation phase will be conducted on an independent cohort of patients treated at our
center. Within this cohort, we will also assess the predictive value of the signatures with respect to the expected benefit of
subsequent lines of hormone therapy.
Keywords:
hormone sensitivity, ER+ HER2- breast cancer, molecular signature, anti-CDK4/6 targeted therapy
Conditions:
Diploma in medical oncology specializing in senology, employment on the CRAN site of the Lorraine Cancer Institute
Department(s):
| Biology, Signals and Systems in Cancer and Neuroscience |
Funds:
Private (ICL)
Publications: