Absent progesterone receptor expression in the lymph node metastases of ER-positive, HER2-negative breast cancer is associated with relapse on tamoxifen

Despite unprecedented amount of information now available in medical records, health data remain underexploited due to their heterogeneity and complexity. Simple charts and hypothesis-driven statistics can no longer apprehend the content of information-rich clinical data. There is, therefore, a clear need for powerful interactive visualization tools enabling medical practitioners to perceive the patterns and insights gained by state-of-the-art machine learning algorithms. Here, we report an interactive graphical interface for use as the front end of a machine learning causal inference server (MIIC), to facilitate the visualization and comprehension by clinicians of relationships between clinically relevant variables. The widespread use of such tools, facilitating the interactive exploration of datasets, is crucial both for data visualization and for the generation of research hypotheses. We demonstrate the utility of the MIIC interactive interface, by exploring the clinical network of a large cohort of breast cancer patients treated with neoadjuvant chemotherapy (NAC). This example highlights, in particular, the direct and indirect links between post-NAC clinical responses and patient survival. The MIIC interactive graphical interface has the potential to help clinicians identify actionable nodes and edges in clinical networks, thereby ultimately improving the patient care pathway.

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“…4d ) 21 , 22 , 37 , 38 . The link between has also been found between PR negativity and a higher risk of brain metastasis 39 – 43 (Fig. 4e ).…”

Section: Resultsmentioning

confidence: 59%

Interactive exploration of a global clinical network from a large breast cancer cohort

et al. 2022

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“…As IHC validated our previous mRNA analyses, we wondered whether SMARCD3 protein level could be used to predict patient outcome. To answer this query, we made use of a cohort recently published (18), which contains 229 ER+, HER2-breast cancer patients with axillary nodal metastatic disease, with median followup time of 4.9 years. Relapse was used as a surrogate for breast cancer survival and occurred in 46 patients (20.1%; see (18)) with a median relapse-free time of 7.7 years (SD 3.8 years).…”

Section: Immunohistochemistry (Ihc) Staining Of Patient Samples Reveamentioning

confidence: 99%

“…To answer this query, we made use of a cohort recently published (18), which contains 229 ER+, HER2-breast cancer patients with axillary nodal metastatic disease, with median followup time of 4.9 years. Relapse was used as a surrogate for breast cancer survival and occurred in 46 patients (20.1%; see (18)) with a median relapse-free time of 7.7 years (SD 3.8 years). SMARCD3 expression using IHC could be assessed in 207 tumor cores and SMARCD3 nuclear staining intensity ( Fig.…”

Section: Immunohistochemistry (Ihc) Staining Of Patient Samples Reveamentioning

confidence: 99%

“…Immunohistochemistry (IHC). Antigen retrieval was performed with the Ventana Discovery ULTRA Staining module, using Discovery CC1 for 32 min, on TMA from US Biomax (1921b) or Mater patient cohort (18). Primary immunostaining was performed using antibodies against SMARCD3 (Abcam ab1711075) and Ventana antibody dilution buffer for 36 min at 36°C.…”

Section: Real-time Quantitative Pcr (Rt-qpcr)mentioning

confidence: 99%

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The chromatin remodeler SMARCD3 regulates cell cycle progression and its expression predicts survival outcome in ER+ breast cancer

Tropée

Avalos

Gough

et al. 2019

Preprint

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Chromatin remodeling plays an essential role in regulating transcriptional networks and timing of gene expression. Chromatin remodelers such as SWItch/Sucrose Non-Fermentable (SWI/SNF) harbor many protein components, with the catalytic subunit providing ATPase activity to displace histones along or from the DNA molecules, and associated subunits ensuring tissue specificity and transcriptional or cotranscriptional activities. Mutations in several of the SWI/SNF subunits have been linked to cancer. Here, we describe how SMARCD3/Baf60c expression is associated with hormone positive (ER+) breast cancer. The level SMARCD3, as detected by immunohistochemistry in breast cancer patient samples, is correlated with differential long-term disease-free survival. In contrast, the expression level of SMARCD1/Baf60a and SMARCD2/Baf60b, which are mutually exclusive within the SWI/SNF complex and have a partially redundant function, lacks predictive value in breast cancer patient samples. Lower proliferation rates are observed in SMARCD3 depleted cells, which reflects a failure to fully progress through G2/M, and an increase in endoreplication. In the absence of SMARCD3, p21 accumulates in cells but does not halt the cell cycle, and DNA damage accumulates and remains unrepaired. Taken together, our data begin to explain why ER+ breast cancer patients with low SMARCD3 expressing tumors exhibit reduced survival rates compared to patients expressing normal or higher levels of SMARCD3. SMARCD3 might act as a tumor suppressor role through regulation of cell cycle checkpoints and could be a reliable and specific breast cancer prognostic biomarker. SignificanceMutations in chromatin remodelers are a leading cause of cancer. Estrogen Receptor positive (ER+) breast cancers represent approximately 80% of all cases diagnosed. Although these tumors can be treated with hormone therapy, most breast cancer fatalities occur in ER+ breast cancer patients, due to metastasis. Low expression of SMARCD3 in ER+ cancer is associated with diminished survival rates. As such, SMARCD3 could be used as a predictive biomarker for survival. In addition, we have identified a role for SMARCD3 in the cell cycle, which could at least partially explain its protective role in breast cancer. While catalytic subunits are often viewed as the major components in chromatin remodeling function, we show here new evidence that mutations or silencing of SMARCD3 may also contribute to genomic instability and thus development of breast cancer.

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“…3 Antibodies used to detect PR for clinical and investigative purposes largely detect both PR isoforms and using these, PR has been established as a biomarker of good prognosis in breast cancer. 4 Higher levels of PR expression are associated with a good response to tamoxifen, 4,5 which until the development of aromatase inhibitors (AIs) was the major first-line adjuvant endocrine therapy for all cases of ER-positive (ER+) breast cancer. Currently, tamoxifen is mainly prescribed to pre-menopausal women and AIs to postmenopausal women, with some exceptions.…”

Section: Introductionmentioning

confidence: 99%

Improved relapse-free survival on aromatase inhibitors in breast cancer is associated with interaction between oestrogen receptor-α and progesterone receptor-b

et al. 2018

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BackgroundRecent pre-clinical studies indicate that activated progesterone receptor (PR) (particularly the PR-B isoform) binds to oestrogen receptor-α (ER) and reprogrammes transcription toward better breast cancer outcomes. We investigated whether ER and PR-B interactions were present in breast tumours and associated with clinical parameters including response to aromatase inhibitors.MethodsWe developed a proximity ligation assay to detect ER and PR-B (ER:PR-B) interactions in formalin-fixed paraffin-embedded tissues. The assay was validated in a cell line and patient-derived breast cancer explants and applied to a cohort of 229 patients with ER-positive and HER2-negative breast cancer with axillary nodal disease.ResultsHigher frequency of ER:PR-B interaction correlated with increasing patient age, lower tumour grade and mitotic index. A low frequency of ER:PR-B interaction was associated with higher risk of relapse. In multivariate analysis, ER:PR-B interaction frequency was an independent predictive factor for relapse, whereas PR expression was not. In subset analysis, low frequency of ER:PR-B interaction was predictive of relapse on adjuvant aromatase inhibitor (HR 4.831, p = 0.001), but not on tamoxifen (HR 1.043, p = 0.939).ConclusionsThis study demonstrates that ER:PR-B interactions have utility in predicting patient response to adjuvant AI therapy.

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Absent progesterone receptor expression in the lymph node metastases of ER-positive, HER2-negative breast cancer is associated with relapse on tamoxifen

Abstract: Evaluation of PR expression in ALN metastasis may enable prediction of patients who are less likely to benefit from adjuvant tamoxifen. This study should be replicated in other cohorts.

Cited by 9 publications

References 26 publications

Interactive exploration of a global clinical network from a large breast cancer cohort

Interactive exploration of a global clinical network from a large breast cancer cohort

The chromatin remodeler SMARCD3 regulates cell cycle progression and its expression predicts survival outcome in ER+ breast cancer

Improved relapse-free survival on aromatase inhibitors in breast cancer is associated with interaction between oestrogen receptor-α and progesterone receptor-b

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