Premenopausal women with breast cancer in the early post-partum period show molecular profiles of invasion and are associated with poor prognosis

Nimbalkar, Vidya P; Snijesh, V. P.; Rajarajan, Savitha; Alexander, A.; Kaluve, Rohini; Ramesh, Rakesh; Srinath, B S; Prabhu, Jyothi S

doi:10.1007/s10549-023-06956-6

Cited by 5 publications

(6 citation statements)

References 41 publications

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“…Evidence that these physiologic stromal changes durably alter PPBC is supported by the distinct molecular and cellular profiles observed in PPBC compared to stage and ER-subtype matched tumors diagnosed in nulliparous women 59,60 . Specifically, PPBC profiles strongly associate with normal breast involution profiles, including increased tumor collagen fibrosis, lymphovascular invasion, immune infiltrate, and gene expression profiles characterized by immunosuppression and tumor cell invasion 59,60 . Whether BRCA mutant PPBC tumors display a distinct molecular profile consistent with involution and disease progression, as predicted based on the poor outcomes observed in this UK cohort, remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

A Postpartum Breast Cancer Diagnosis Reduces Survival in GermlineBRCApathogenic variant Carriers

Zhang,

Ye,

Bernhardt

et al. 2023

Preprint

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IMPORTANCEIn young-onset breast cancer, a diagnosis within 5-10 years of childbirth associates with increased mortality. Women with germlineBRCA1/2pathogenic variants (PVs) are more likely to be diagnosed with breast cancer at younger ages, but the impact of childbirth on mortality is unknown.OBJECTIVEDetermine whether time between recent childbirth and breast cancer diagnosis impacts mortality among young-onset breast cancer patients with germlineBRCA1/2PVs.DESIGN, SETTING, AND PARTICIPANTSThis prospective cohort study includes 903 women with germlineBRCA1/2PVs diagnosed with stage I-III breast cancer at ≤45 years of age, between 1950-2021 in the UK.MAIN OUTCOMES AND MEASURESThe primary outcome is all-cause mortality, censored at 20 years post-diagnosis. The primary exposure is time between most recent childbirth and breast cancer diagnosis, with recent childbirth defined as >0-<10 years post childbirth (n=419)], further delineated to >0-<5 years (n=228) and 5-<10 years (n=191). Mortality of nulliparous cases (n=224) was compared to the recent postpartum groups and the ≥10 years postpartum (n=260) group. Cox proportional hazards regression analyses were adjusted for patient age, tumor stage, further stratified by tumor estrogen receptor (ER) andBRCAgene status.RESULTSFor allBRCAPV carriers, increased all-cause mortality was observed in women diagnosed >0-<10 years postpartum, compared to nulliparous and ≥10 years groups, demonstrating the transient duration of postpartum risk. Risk of mortality was greater for ER-positive cases in the >0-<5 group [HR=2.35 (95% CI, 1.02-5.42)] and ER-negative cases in the 5-<10 group [HR=3.12 (95% CI, 1.22-7.97)] compared to the nulliparous group. Delineated byBRCA1orBRCA2, mortality in the 5-<10 group was significantly increased, but only forBRCA1carriers [HR=2.03 (95% CI, 1.15-3.58)].CONCLUSIONS AND RELEVANCEYoung-onset breast cancer with germlineBRCAPVs confers increased risk for all-cause mortality if diagnosed within 10 years of childbirth, with risk highest for ER+ cases at >0-<5 years postpartum, and for ER-cases at 5-<10 years postpartum.BRCA1carriers are at highest risk for poor prognosis when diagnosed at 5-10 years postpartum. No such associations were observed forBRCA2carriers. These results should inform genetic counseling, prevention, and treatment strategies forBRCAPV carriers.Key PointsQuestionIs a postpartum diagnosis an independent risk factor for mortality among young-onset breast cancer patients with germlineBRCA1/2PVs?FindingsA diagnosis <10 years postpartum associates with higher risk of mortality compared to nulliparous and ≥10 years postpartum cases. Peak risk after childbirth varies for ER-positive (>0-<5 years) vs. ER-negative cases (5-<10 years).BRCA1carriers had peak risk of mortality 5-10 years postpartum, with no associations observed forBRCA2carriers.MeaningA breast cancer diagnosis within 10 years of childbirth independently associates with increased risk for mortality in patients with germlineBRCA1/2PVs, especially for carriers ofBRCA1PVs.

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Section: Discussionmentioning

confidence: 99%

A Postpartum Breast Cancer Diagnosis Reduces Survival in GermlineBRCApathogenic variant Carriers

Zhang,

Ye,

Bernhardt

et al. 2023

Preprint

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“…These protumor stromal changes include the presence of activated fibroblasts, protumor collagen deposition, lymphangiogenesis, and immune infiltrate of immune suppressive and regulatory cells . Evidence that these physiologic stromal changes durably alter PPBC is supported by the distinct molecular and cellular profiles observed in PPBC compared with stage- and ER-subtype–matched tumors diagnosed in nulliparous women . Specifically, PPBC profiles are strongly associated with normal breast involution profiles, including increased tumor collagen fibrosis, lymphovascular invasion, immune infiltrate, and gene expression profiles characterized by immunosuppression and tumor cell invasion .…”

Section: Discussionmentioning

confidence: 99%

“… 54 , 55 , 56 , 57 , 58 Evidence that these physiologic stromal changes durably alter PPBC is supported by the distinct molecular and cellular profiles observed in PPBC compared with stage- and ER-subtype–matched tumors diagnosed in nulliparous women. 59 , 60 Specifically, PPBC profiles are strongly associated with normal breast involution profiles, including increased tumor collagen fibrosis, lymphovascular invasion, immune infiltrate, and gene expression profiles characterized by immunosuppression and tumor cell invasion. 59 , 60 Whether BRCA variant PPBC tumors display a distinct molecular profile consistent with involution and disease progression, as expected based on the poor outcomes observed in this UK cohort, remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Postpartum Breast Cancer and Survival in Women With Germline BRCA Pathogenic Variants

Zhang,

Ye,

Bernhardt

et al. 2024

JAMA Netw Open

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ImportanceIn young-onset breast cancer (YOBC), a diagnosis within 5 to 10 years of childbirth is associated with increased mortality. Women with germline BRCA1/2 pathogenic variants (PVs) are more likely to be diagnosed with BC at younger ages, but the impact of childbirth on mortality is unknown.ObjectiveTo determine whether time between most recent childbirth and BC diagnosis is associated with mortality among patients with YOBC and germline BRCA1/2 PVs.Design, Setting, and ParticipantsThis prospective cohort study included women with germline BRCA1/2 PVs diagnosed with stage I to III BC at age 45 years or younger between 1950 and 2021 in the United Kingdom, who were followed up until November 2021. Data were analyzed from December 3, 2021, to November 29, 2023.ExposureTime between most recent childbirth and subsequent BC diagnosis, with recent childbirth defined as 0 to less than 10 years, further delineated to 0 to less than 5 years and 5 to less than 10 years.Main Outcomes and MeasuresThe primary outcome was all-cause mortality, censored at 20 years after YOBC diagnosis. Mortality of nulliparous women was compared with the recent post partum groups and the 10 or more years post partum group. Cox proportional hazards regression analyses were adjusted for age, tumor stage, and further stratified by tumor estrogen receptor (ER) and BRCA gene status.ResultsAmong 903 women with BRCA PVs (mean [SD] age at diagnosis, 34.7 [6.1] years; mean [SD] follow-up, 10.8 [9.8] years), 419 received a BC diagnosis 0 to less than 10 years after childbirth, including 228 women diagnosed less than 5 years after childbirth and 191 women diagnosed 5 to less than 10 years after childbirth. Increased all-cause mortality was observed in women diagnosed within 5 to less than 10 years post partum (hazard ratio [HR], 1.56 [95% CI, 1.05-2.30]) compared with nulliparous women and women diagnosed 10 or more years after childbirth, suggesting a transient duration of postpartum risk. Risk of mortality was greater for women with ER-positive BC in the less than 5 years post partum group (HR, 2.35 [95% CI, 1.02-5.42]) and ER-negative BC in the 5 to less than 10 years post partum group (HR, 3.12 [95% CI, 1.22-7.97]) compared with the nulliparous group. Delineated by BRCA1 or BRCA2, mortality in the 5 to less than 10 years post partum group was significantly increased, but only for BRCA1 carriers (HR, 2.03 [95% CI, 1.15-3.58]).Conclusions and RelevanceThese findings suggest that YOBC with germline BRCA PVs was associated with increased risk for all-cause mortality if diagnosed within 10 years after last childbirth, with risk highest for ER-positive BC diagnosed less than 5 years post partum, and for ER-negative BC diagnosed 5 to less than 10 years post partum. BRCA1 carriers were at highest risk for poor prognosis when diagnosed at 5 to less than 10 years post partum. No such associations were observed for BRCA2 carriers. These results should inform genetic counseling, prevention, and treatment strategies for BRCA PV carriers.

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“…Breast cancer (BC) represents the prevailing malignancy globally, with an annual incidence of approximately 2.3 million cases 1,2 . Despite notable improvement in early diagnosis and treatment, around 30% of cases experience recurrence or metastasis within the initial 5 years 3 .…”

Section: Introductionmentioning

confidence: 99%

Differential role of glucocorticoid receptor based on its cell type specific expression on tumor cells and infiltrating lymphocytes

Nimbalkar,

Patil

et al. 2024

Preprint

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Background: The glucocorticoid receptor (GR) is frequently expressed in breast cancer (BC), and its prognostic implications are contingent on estrogen receptor (ER) status. To address conflicting reports and explore therapeutic potential, a GR signature (GRsig) independent of ER status was developed. We also investigated cell type-specific GR protein expression in BC tumor epithelial cells and infiltrating lymphocytes. Methods: GRsig was derived from Dexamethasone-treated cell lines through a bioinformatic pipeline. Immunohistochemistry assessed GR protein expression. Associations between GRsig and tumor phenotypes (proliferation, cytolytic activity (CYT), immune cell distribution, and epithelial-to-mesenchymal transition(EMT)) were explored in public datasets. Single-cell RNA sequencing data evaluated context-dependent GR roles, and a cell type-specific prognostic role was assessed in an independent BC cohort. Results: High GRsig levels were associated with a favorable prognosis across BC subtypes. Tumor-specific high GRsig correlated with lower proliferation, increased CYT, and anti-tumorigenic immune cells. Single-cell data analysis revealed higher GRsig expression in immune cells, negatively correlating with EMT while a positive correlation was observed with EMT primarily in tumor and stromal cells. Univariate and multivariate analyses demonstrated the robust and independent predictive capability of GRsig for favorable prognosis. GR protein expression on immune cells in triple-negative tumors indicated a favorable prognosis. Conclusion: This study underscores the cell type-specific role of GR, where its expression on tumor cells is associated with aggressive features like EMT, while in infiltrating lymphocytes, it predicts a better prognosis, particularly within TNBC tumors. The GRsig emerges as a promising independent prognostic indicator across diverse BC subtypes.

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Premenopausal women with breast cancer in the early post-partum period show molecular profiles of invasion and are associated with poor prognosis

Cited by 5 publications

References 41 publications

A Postpartum Breast Cancer Diagnosis Reduces Survival in GermlineBRCApathogenic variant Carriers

A Postpartum Breast Cancer Diagnosis Reduces Survival in GermlineBRCApathogenic variant Carriers

Postpartum Breast Cancer and Survival in Women With Germline BRCA Pathogenic Variants

Differential role of glucocorticoid receptor based on its cell type specific expression on tumor cells and infiltrating lymphocytes

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