Postpartum Breast Cancer
URGENT NOTICE
Postpartum breast cancer has 3X risk… but there’s an emerging strategy
Postpartum breast cancer (PPBC), defined as breast cancer within 10 years of giving birth, has a threefold increased risk for metastasis and death. Most studies show that the poor prognosis is independent of maternal age, cancer subtype (hormone or HER2 status) , tumour size, lymph node status, or tumor grade (aggression level). In fact, women with early stage disease (stage 1) have a worse prognosis than women diagnosed with stage 3 disease. Thankfully, new research is revealing a strategy that may eliminate the 3X risk.
Research Suggests Ibuprofen
Take Ibuprofen. Early research from University of Oregon suggests 300 mg a day of ibuprofen taken for 3-6 months at the time of weaning may help prevent PPBC, and if breast cancer is present, may reduce tumor size.
Vigilance for a Lifetime.
Often metastasis won’t occur until 10-15 years later. Do not assume that after 5 years you are out of the woods.
Demand treatment based on a PPBC risk level.
Ask your doctor to address the increased risk level of PPBC; you should not be treated like a women who has not had children. If your doctor is not factoring in these risks, you may not be getting adequate care.
Demand better ongoing screening.
Hopefully ctDNA testing will be available soon but until then, insist on regular blood marker tests and imaging.
Research Highlights
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"We find that postpartum breast cancers are infiltrated with high levels of “bad” immune cells that block the ability of “good” immune cells to attack the cancer. We find that ibuprofen specifically blocks these “bad” immune cells and activates the “good” immune cells, permitting tumor destruction."
An article from the V Organization, highlighting Dr. Pepper Schedin’s postpartum breast cancer research, notes that half of all young women’s breast cancers (within 5 years of birth) are related to a recent pregnancy, equating to 180,000 women annually.
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“Our lab found that this population has a three-fold increase in metastasis and death, and we traced the increased death to the inflammatory effects of breast tissue “remodeling” following pregnancy –the time when breast tissue is removed to phase out of the job of lactation.“
“Results from this Kay Yow Cancer Fund grant confirm that the window of time following weaning is unique, characterized by tissue remodeling that is driven by the same protein that drugs like aspirin and ibuprofen inhibit. We anticipate that aspirin and ibuprofen, when combined with standard of care treatments for breast cancer, will reduce mortality in young women diagnosed with postpartum breast cancer. “
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A 2021 research paper also written by Dr. Schedin, provides ideas for possible therapeutic options.
Nonsteroidal anti-inflammatory drugs (ibuprofen/aspirin) for macrophage differentiation, T-cell recruitment, and tumor suppression
Immune checkpoint inhibitor drugs for PD-L1 to relieve immunosuppression in the tumor microenvironment
Reduce tumor-associated macrophage recruitment and activation (proven in pre-clinical work, no drug listed)
The article also suggests that work with macrophages to “fix” tumor suppression attributes may provide new drug targets.
STAGE 1, Cancer Alert
In this chart, we see women under the age of 45 who experience early, stage 1 postpartum breast cancer have the worst overall survival, yet no one is talking about it. My OB/GYN, who I think is pretty sharp, has never heard of this before. Share this information with your doctors, and MAKE SURE you treat stage 1 and DCIS cancers aggressively. Layer on the strategies and be vigilant.
Change starts with awareness of the problem. Sign up for my newsletter and you’ll be alerted when I publish my podcast on this topic.
Nulli/nulliparous=female, not given birth
Parous=female, has given birth
PPBC= Postpartum breast cancer (within 5 years)
Source: Overall survival is the lowest among young women with postpartum breast cancer, European Journal of Cancer, 2022.
Is your PPBC ER+ tumor acting more like an ER- tumor?
Here’s why…
PPBC has unique metabolic signatures that may confound your doctors. While the majority of PPBC cases are highly estrogen receptor positive (ER+), they may act like an estrogen receptor negative (ER-) cancer. This means they may be using signaling pathways usually seen in ER- cancer, so the ER+ drugs may not be as effective. Discuss this with your doctor because you may need to consider additional treatments or combinations of treatment.
“A dominant molecular distinction in our genomic cohort data was reduced ER signaling in PPBC cases as compared with NPBC. This observation was surprising given that immunohistochemical assessments revealed these tumors to be highly ER-positive. One simple interpretation of these data is that in the postpartum setting, ER-positive breast cancer is more analogous to ER-negative disease with respect to downstream ER signaling pathways. Consistent with our observations of reduced estrogen signaling in PPBC, in a study of postpartum normal and tumor breast tissue, the signatures of ER signaling (ESR1) were reduced in postpartum cases compared with their nulliparous counterparts. As with P53, it is possible that the downregulation of ER signaling in tumor cells is a specific adaptation to the involution microenvironment. Signal transducer and activator of transcription (Stat) 5a is a well-established positive regulator of lactation and its suppression is a requisite for the execution of epithelial cell death after weaning. Further, Stat5 expression is under estrogen control in the murine mammary gland. Thus, one untested possibility is that ER+ tumor cells maintain Stat5 survival signaling during involution by downregulating ER signaling. Consistent with this hypothesis, expression of a constitutively activated variant of Stat5 in the murine mammary gland prevented weaning-induced involution and was associated with ER+ adenocarinomas.”
Details & Additional Research
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Early research from University of Oregon suggests that 300 mg a day of ibuprofen taken for 3-6 months at the time of weaning may help prevent PPBC, and if breast cancer is present, may reduce tumor size.
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Overall survival is the lowest among young women with postpartum breast cancer (link), European Journal of Cancer, 2022.
Pooling data from the Colorado Young Women Breast Cancer cohort and the Breast Cancer Health Disparities Study (N = 2519 cases), researchers examined the association of parity, age, and clinical factors with overall survival (OS) of breast cancer over 15 years of follow-up.
Postpartum breast cancer (PPBC) is diagnosed within 5 years since childbirth.
In multivariate analysis, PPBC is an independent driver of poor prognosis — negative outcomes are not found in breast cancer diagnosed during pregnancy.
Young women with PPBC have the worst overall survival (OS) at 15 years of follow-up.
The association between young age at diagnosis and adverse outcomes is the strongest among women with luminal and early-stage disease
Negative effect of PPBC on OS is the greatest in patients diagnosed at ≤35 years.
Even in stage I disease, the negative effect of PPBC on OS is significant.
Incidence of metastatic breast cancer in young women is rising by 2% a year.
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Postpartum breast cancer has a distinct molecular profile that predicts poor outcomes (link). Nature Communications, 2021
1.6X increase in young women’s breast cancer between 2000-2015.
2-3X increased risk of death for PPBC (10 years).
Older age at first pregnancy negatively impacts survival and is more associated with PPBC mutations in P53 which is associated with T-cell exhaustion signature
Reduced ER signaling in PPBC even when tumors are revealed to be ER+, making ER+ BC more analogous to ER- with respect to ER signaling pathways.
PPBC shows upregulation of signatures for immune exhaustion, ER-negative, and proliferation.
PPBC shows gene instability; found mutations in TP53 but not KI67
PPBC patients hav a “hotter” immune response— usually a good thing— but they express PD-1 and TOX1 which are associated with T-Cell exhaustion signature
If PPBC patients have increased PD-1 expression, they may benefit from checkpoint blockaid inhibitors (COX2 suppression as well)
Upregulation of E2F1, E2F4 and downregulation of TP53 and ESR1
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Clinical Characteristics & Prognosis of PPBC (link), Breast Cancer Research & Treatment, 2023.
Researchers reviewed 208,780 patients with breast cancer from the Korean Breast Cancer Society registry database between 1/2000 and 12/2014. They included premenopausal women aged 20–50 years who underwent breast cancer surgery. Patients were classified by 5-year intervals from the first birth to the breast cancer diagnosis.
PPBC patients (<5 years) were younger, had a more advanced stage, had lower estrogen receptor (ER) and progesterone receptor (PR) expression, and had a higher human epidermal growth factor receptor 2 (HER2) positive rate.
PPBC < 5 years group had a worse survival rate than the nulliparous and other groups (5-year cumulative survival: PPBC < 5 years group, 89%; nulliparous group, 97.3%; 5 ≤ PPBC < 10 years group, 93%). In the multivariate analysis, the PPBC < 5 years group was associated with a worse survival rate (hazard ratio 1.55, 95% confidence interval [CI] 1.148–2.094, p 0.004) after adjustment for age at diagnosis, breast cancer stage, ER and HER2 status, Ki-67 level, and chemotherapy.
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Postpartum breast cancer progression is driven by semaphorin 7a mediated invasion and survival description (link), Oncogene, 2020.
The postpartum involution (weaning) cellular environment is similar to tumor-promotional microenvironments.
SEMA7A protein is expressed in DCIS.
SEMA7A expressing cells exhibit enhanced metastatic capabilities.
SEMA7A is associated in breast tumor cell growth, motility, invasion, and tumor associated-lymphangiogenesis, all of which are also increased in pre-clinical models of PPBC.
Results show silencing of SEMA7A decreases tumor growth in PPBC while overexpression increases growth in nulliparous hosts.
SEMA7A promotes multiple drivers of PPBC progression including tumor associated COX-2 expression and fibroblast-mediated collagen deposition in the tumor microenvironment.
SEMA7A expressing cells deposit fibronectin to promote tumor cell survival.
SEMA7A supports tumor cell invasion by stably altering cells to a more mesenchymal phenotype, which promotes cell survival in anchorage-independent conditions to allow for colonization of distant organs.
SEMA7A may promote metastasis by conferring resistance to current therapies.
Co-expression of SEMA7A/COX-2/FN predicts for poor prognosis in breast cancer patient cohorts.
SEMA7A as a key mediator of BC progression and targeting SEMA7A may lead to novel therapeutic strategies
Who might benefit?
Women diagnosed with breast cancer within 10 years of giving birth (PPBC) , and especially those diagnosed within 5 years of giving birth.
Characteristics that amplify the already heightened risk level for PPBC:
Younger in age
Shorter time between diagnosis and birth (the closer the diagnosis is to the time to birth, the worse prognosis)
Early stage (stages 1-2)
Diagnosed after breastfeeding was completed
Did not breastfeed or breastfed shorter than 3 months
This news is challenging to hear. It sucks. There’s no way around it, so face it, and take action now.
Investigate the use of ibuprofen and look for other strategies to help you outperform these crummy outcome statistics.
You can do better. Take charge.
I didn’t understand my long-term risks, and for 13-years after my initial diagnosis, not ONE of the 7 different oncologists, cancer surgeons, OB/GYN, or primary care doctors I saw during that time ever mentioned it.
At the time of this photo, breast cancer was the furthest thing from my mind. Yet, a few months later, I was diagnosed with highly aggressive (grade 5) stage-0 breast cancer at age 39. I had bilateral mastectomy after an earlier lumpectomy didn’t get clean margins, and a micro-invasion area indicated it was probably HER2+ (an aggressive subtype), although they didn’t have enough cells to complete a definitive FISH test.
What we know today is that PPBC is 3X more likely to metastasize and limit survival. Add a grade 5 aggression level which also indicates likelihood to metastasize, and the fact that I was never given radiation, or tamoxifen, or any other treatment, and it’s not surprising that 13 years later I was diagnosed as metastatic. I encourage you to take control of your healthcare today. Do your research and stay current with the latest discoveries. There are things you can do to stave off this disease.
Stay tuned.
We are working to secure a leading researcher with expertise in this area.
As with all our strategies, the lead researcher will be featured in a podcast on this topic. Sign up for my newsletter and I’ll let you know when new information is uploaded.