Postpartum breast cancer has a distinct molecular profile that predicts poor outcomes

Jindal, Sonali; Pennock, Nathan D.; Sun, Duanchen; Horton, Wesley; Ozaki, Miwako; Narasimhan, Jayasri; Bartlett, Alexandra; Weinmann, Sheila; Goss, Paul E.; Borges, Virginia F.; Xia, Zheng; Schedin, Pepper

doi:10.1038/s41467-021-26505-3

Cited by 24 publications

(24 citation statements)

References 114 publications

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“…30 Comparative RNA sequence expression analyses on treatment-naive breast cancer tissues from young patients revealed PPBC tumors had enrichment of gene signatures associated with the normal process of weaning-induced breast involution compared with breast cancers diagnosed in young nulliparous patients. 46,53 We also performed a first site of metastasis analysis and found that ER-positive disease was enriched in bone metastases and ER-negative disease was enriched in nervous system and brain metastases, consistent with previous reports. 58 Previous studies in YOBC have identified bone as the most common site of metastasis in both ER-positive and ER-negative disease, with approximately 2-fold higher rates of metastasis to bone compared with liver.…”

Section: Jama Network Open | Oncologysupporting

confidence: 88%

Young-Onset Breast Cancer Outcomes by Time Since Recent Childbirth in Utah

et al. 2022

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ImportanceBreast cancer diagnosed within 5 to 10 years after childbirth, called postpartum breast cancer (PPBC), is associated with increased risk for metastasis and death. Whether a postpartum diagnosis is an independent risk factor or a surrogate marker of cancer features associated with poor outcomes remains understudied.ObjectiveTo determine whether diagnostic temporal proximity to childbirth is associated with features of breast cancer associated with poor outcomes, including tumor stage, estrogen receptor (ER) status, and risk for distant metastasis and breast cancer–specific mortality, using a population database from the state of Utah.Design, Setting, and ParticipantsThis population-based cohort study using the Utah Population Database (UPDB) included individuals with stage I to III breast cancer diagnosed at age 45 years or younger between 1996 and 2017, followed-up until February 2020. Participant data were analyzed from November 2019 to August 2022.ExposureThe primary exposures were no prior childbirth or time between most recent childbirth and breast cancer diagnosis. Patients were grouped by diagnoses within less than 5 years, 5 to less than 10 years, or 10 years or more since recent childbirth.Main Outcomes and MeasuresThe 2 primary outcomes were distant metastasis–free survival and breast cancer–specific death. Cox proportional hazard models were used to investigate associations between exposures and outcomes adjusting for diagnosis year, patient age, tumor stage, and estrogen receptor (ER) status.ResultsOf 2970 individuals with breast cancer diagnosed at age 45 years or younger (mean [SD] age, 39.3 [5.0] years; 12 Black individuals [0.4%], 2679 White individuals [90.2%]), breast cancer diagnosis within 5 years of recent childbirth was independently associated with approximately 1.5-fold elevated risk for metastasis (hazard ratio [HR], 1.5; 95% CI, 1.2-2.0) and breast cancer–specific death (HR, 1.5; 95% CI, 1.1-2.1) compared with nulliparous individuals. For cancers classically considered to have tumor features associated with good outcomes (ie, stage I or II and ER-positive), a postpartum diagnosis was a dominant feature associated with increased risk for metastasis and death (eg, for individuals with ER-positive disease diagnosed within &lt;5 years of childbirth: age-adjusted metastasis HR, 1.5; 95% CI, 1.1-2.1; P = .01; age-adjusted death HR, 1.5; 95% CI, 1.0-2.1; P = .04) compared with nulliparous individuals. Furthermore, liver metastases were specifically increased in the group with diagnosis within 5 years postpartum and with positive ER expression (38 of 83 patients [45.8%]) compared with the nulliparous (28 of 77 patients [36.4%]), although the difference was not statistically significant. Overall, these data implicate parity-associated breast and liver biology in the observed poor outcomes of PPBC.Conclusions and RelevanceIn this cohort study of individuals with breast cancer diagnosed at age 45 years or younger, a postpartum breast cancer diagnosis was a risk factor associated with poor outcomes. Irrespective of ER status, clinical consideration of time between most recent childbirth and breast cancer diagnosis could increase accuracy of prognosis in patients with young-onset breast cancer.

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Section: Jama Network Open | Oncologysupporting

confidence: 88%

Young-Onset Breast Cancer Outcomes by Time Since Recent Childbirth in Utah

et al. 2022

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“…PABC was associated with increased tumor infiltrating lymphocyte (TIL) infiltration (2), and programmed cell death protein 1 (PD-L1) is highly expressed in TILs in PABC (51,52). In a recent study using RNA expression data from clinically matched estrogen receptor positive (ER+) cases (n = 16), postpartum breast cancer had pronounced T-cell presence and T-cell activation/exhaustion signatures, reduced TP53 activity, reduced ER signaling, and increased cell cycle gene signatures compared with breast cancer in nulliparous women (53).…”

Section: Discussionmentioning

confidence: 99%

The Risk Factors, Incidence and Prognosis of Postpartum Breast Cancer: A Nationwide Study by the SMARTSHIP Group

Park

Lee²,

Yoon³

et al. 2022

Front. Oncol.

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The term ‘pregnancy-associated breast cancer’ is no longer used as it has been consistently reported that breast cancer during pregnancy and breast cancer after delivery (postpartum breast cancer) have different characteristics and prognosis. The purpose of this study is to define postpartum breast cancer by analyzing the incidence rate, related factors, and prognosis according to the timing of breast cancer. Data from the Korean National Health Insurance Service were used to analyze 1,292,727 women aged 20-49 years who birthed their first child between 2007 and 2012. The annual incidence rate of breast cancer after delivery increased every year (7.7 per 10,000 person-years after 5 years, 19.36 per 10,000 person-years after 10 years). The risk of breast cancer was significantly higher (hazard ratio 1.15, 95% CI 1.05-1.27, P=0.0037) in women diagnosed with gestational diabetes, but that was not associated with overall survival (OS). Patients diagnosed with breast cancer within 5 years of delivery had a poorer prognosis than those diagnosed later (5-year OS, <5 years: 91.1% vs. 5-10 years: 96.0%). In multivariate analysis of OS, the hazard ratio of patients diagnosed within 5 years after delivery was twice as high as of patients diagnosed between 5 and 10 years. Women diagnosed with gestational diabetes had an increased risk of breast cancer. Breast cancer patients diagnosed within 5 years of delivery had a poorer prognosis than those diagnosed later. In this regard, careful screening for early diagnosis of high-risk patients and intensive research on new treatment strategies are needed.

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“…In female rodents, where the process of involution has been extensively studied, more than 80% of lactating mammary epithelial cells die during developmentally regulated tissue remodeling ( 45 ). Jindal et al ( 46 ) found that ER+ PPBC was a molecular specific subtype with a poor prognosis, with a high p53 gene mutation, and was insensitive to chemotherapy drugs. They also believed that cell-cycle inhibitors, such as CDK4/6 inhibitors, may have better efficacy in treating PPBC than conventional treatment.…”

Section: Discussionmentioning

confidence: 99%

A rapid reduction in tumor size by cyclin-dependent kinase inhibition in hormone receptor-positive postpartum breast cancer: a case report of two patients and a review of the literature

Han¹,

Wang²,

Li³

et al. 2022

Ann Transl Med

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Background: Postpartum breast cancer (PPBC) as an independent entity different from PABC. PPBC is defined as breast cancer (BC) diagnosed within 5 years after delivery in many relevant literatures and is associated with a poor prognosis and a decrease in overall survival. PPBC patients commonly present with inflammatory breast cancer (IBC) phenotype, multifocal lesions, and lymph node metastasis. Hormone receptor-positive (HR+) PPBC is an under-investigated subtype. In PPBC, the risk of death of HR+ subtype significantly increased two-fold, while that was only modestly increased for triple-negative breast cancer (TNBC) subtype, and was not significant in human epidermal growth factor receptor 2-positive (HER2+) subtype. HR+ PPBC is a subtype associating with enhanced signatures of cell cycle control, T-cell activation and exhaustion, decreased HR signaling, and altered P53 signaling. The recommended treatment for HR+ PPBC patients is still lacking. Cyclin-dependent kinase (CDK) 4/6 inhibitors are used as a novel treatment standard not only in pretreated patients but also in the first-line setting of HR+ metastatic breast cancer (MBC). However, there is no clinical case report on the application and efficacy of CDK4/6 inhibitors in HR+ PPBC patients.Case Description: This article describes the clinical cases of two patients with advanced HR+ PPBC who were rapidly relieved after receiving leuprorelin combined with letrozole combined with dalpiciclib. We reviewed the related literature of PPBC, and found that HR+ PPBC has not been clinically classified as a BC subtype, and only some basic studies suggested that HR+ PPBC may be sensitive to CDK4/6 inhibitors.The purpose of this study is to provide the basis for the related research on the therapeutic effect of CDK4/6 inhibitors in HR+ PPBC through the report of clinical cases.Conclusions: This article reports for the first time the good therapeutic effects of CDK4/6 inhibitors on HR+ PPBC patients. Based on our findings, we suggest that dalpiciclib combined with endocrine therapy can be considered as the first-line treatment for patients with advanced HR+ PPBC. Our case report provides new clinical evidence for the related research on the role of CDK4/6 inhibitors in HR+ PPBC therapy.

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Postpartum breast cancer has a distinct molecular profile that predicts poor outcomes

Cited by 24 publications

References 114 publications

Young-Onset Breast Cancer Outcomes by Time Since Recent Childbirth in Utah

Young-Onset Breast Cancer Outcomes by Time Since Recent Childbirth in Utah

The Risk Factors, Incidence and Prognosis of Postpartum Breast Cancer: A Nationwide Study by the SMARTSHIP Group

A rapid reduction in tumor size by cyclin-dependent kinase inhibition in hormone receptor-positive postpartum breast cancer: a case report of two patients and a review of the literature

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