Tag: Breast Cancer

Six Prognostic Factors That Predict Invasive Breast Cancer Recurrence after DCIS

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Carcinoma in situ of the breast also known as Ductal Carcinoma In Situ (DCIS) is defined as a malignant proliferation of ductal epithelial cells that are confined to the milk ducts without invasion of the basement membrane, and is a precursor lesion to invasive carcinoma. DCIS accounts for approximately 25% of all newly diagnosed breast cancers. Patients with small, screening-detected lesions, are often treated with breast-conserving surgery (to prevent the development of invasive breast cancer), followed by adjuvant radiation and hormonal therapy, although neither of the latter two interventions have been shown to improve survival outcomes. As such, a significant number of patients are overtreated. There remains a large unmet need, to distinguish relatively benign DCIS from DCIS that will develop into invasive breast cancer.Normal-Milk-Duct DCIS Invasive-Breast-Cancer

The authors in this study performed a systematic review from 1970 to 2018, with meta-analyses of 1,781 articles from the PubMed database, to summarize current knowledge on prognostic factors for invasive disease, after a diagnosis of DCIS. The number of patients in the included studies ranged from 52 to 37,692. Of all the articles reviewed, 40 articles met the inclusion criteria. Eligible studies assessed risk of invasive recurrence in women primarily diagnosed and treated for DCIS, and included at least 10 ipsilateral-invasive breast cancer events and 1 year of follow up. The mean follow up time ranged from 3.2 to 15.8 years. Quality in Prognosis Studies (QUIPS) tool was used for risk-of-bias assessment (A working group comprising epidemiologists, statisticians, and clinicians developed this tool based on previous research and this tool can inform judgements of risk-of-bias in prognostic research). Meta-analyses were performed to estimate the average effect size of the prognostic factors.

The researchers identified six prognostic factors in the meta-analyses that were statistically significant and were associated with a 36% to 84% increase in the relative risk of recurrence of invasive disease after a DCIS diagnosis. These six factors included- 

1) African American race (43% higher risk)

2) Premenopausal status (59% higher risk)

3) Detection by palpation (84% higher risk)

4) Positive margins (63% higher risk)

5) High histologic grade (36% higher risk)

6) High p16 expression (51% higher risk).

Further, the authors identified frequently occurring biases in studies on invasive recurrence after DCIS and the highest risk of bias was attributable to insufficient handling of confounders and poorly described study groups. They added that avoiding these common methodological pitfalls can improve future study designs.

It was concluded that this study results may help clinicians distinguish indolent from potentially aggressive DCIS and prevent overtreatment.

Predictors of an Invasive Breast Cancer Recurrence after DCIS: A Systematic Review and Meta-analyses. Visser LL, Groen EJ, van Leeuwen FE, et al. Cancer Epidemiol Biomarkers Prev. 2019;28:835-845

High Body Fat Level Increases Breast Cancer Risk in Postmenopausal Women with Normal BMI

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There is an approximately 30% increased risk of breast cancer recurrence or death in those who are obese, compared to those with ideal body weight. Obesity is associated with alterations in Insulin/glucose homeostasis, adipokines, and sex hormones, which may all play a role in breast cancer outcomes.
BMI (Body Mass Index) does not discriminate between adiposity and muscle, and individuals deemed healthy based on a normal BMI may still be prone to cardiometabolic disorders due to high levels of visceral fat. It has been reported that approximately 18% of women with normal BMI had excess fat, detected on DEXA scan.
In a recently published article in JAMA Oncology involving 3460 postmenopausal women with normal BMI, there was a 56% increase in the risk of developing ER-positive breast cancer per 5-kg increase in trunk fat, despite a normal BMI. This study concluded that a normal BMI may not be an adequate proxy for the risk of breast cancer in postmenopausal women but high body fat levels and altered levels of circulating metabolic and inflammatory factors may be associated with a higher risk of invasive breast cancer.

High Body Fat Level Increases Breast Cancer Risk in Postmenopausal Women with Normal BMI

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Obesity is an important contributing factor to postmenopausal breast cancer incidence and mortality. Based on recently published meta-analysis, in women diagnosed with breast cancer, there is an approximately 30% increased risk of disease recurrence or death in those who are obese, compared to those with ideal body weight. Increasing physical activity may lower the risk of breast cancer recurrence. According to the consensus from the St Gallen Consensus Conference in 2015, obesity has been associated with poor breast cancer outcomes. Obesity is associated with alterations in Insulin/glucose homeostasis, adipokines, and sex hormones, which may all play a role in breast cancer outcomes. Weight loss can lead to reductions in C-reactive protein, Insulin, glucose, and Leptin. These mediators have all been implicated to have prognostic significance in breast cancer.

Body Mass Index (BMI) measures body size and is calculated based on height and weight. It is used as a measure of obesity. BMI however does not discriminate between adiposity and muscle and individuals deemed healthy based on a normal BMI may still be prone to cardiometabolic disorders due to high levels of visceral fat. Dual-energy X-ray absorptiometry (DXA or DEXA) is often utilized to measure bone mineral density and is the most accurate method presently available for the diagnosis of osteoporosis and to estimate fracture risk. DEXA scan can also be used to measure total body composition and fat content including the amount of visceral fat, with a high degree of accuracy by its ability to break down fat, bone and muscle tissue. It has been reported that approximately 18% of women with normal BMI had excess fat, detected on DEXA scan.

There are two types of adipose tissue in the human body, White Adipose Tissue (WAT) and Brown Adipose Tissue (BAT) which have antagonistic functions. White Adipose Tissue or white fat cells represent the body’s main type of fat tissue and each fat cell has a single lipid droplet. They are distributed in the subcutaneous tissue, around a person's waist and thighs and around internal organs (visceral fat). WAT stores excess energy as triglycerides and serves as an energy reservoir. Brown Adipose tissue (BAT) which is abundant in small mammals and in newborns generates heat by burning calories and helps them to survive cold temperatures. Brown adipocytes contain several small lipid droplets, and a high number of iron-containing mitochondria which gives brown fat its dark tan color. Most BAT is distributed in the lower neck and interscapular area of an adult, and above the collarbone. Higher quantities of BAT are associated with lower body weight and BAT decreases and body weight increases with increasing age.

Leptin is a hormone produced primarily by adipose tissue and circulating Leptin levels correlate with the body fat stores, with increased circulating Leptin levels noted in individuals with excess adiposity. Leptin can induce Aromatase which synthesizes estrogen, can directly stimulate cancer cell proliferation and survival, and activate Estrogen Receptor α via ligand-independent mechanism.Obesity-and-Breast-Cancer

The increased risk of postmenopausal breast cancer in women with normal BMI is poorly understood. Recent studies have shown that in these women with normal BMI, excess body fat is associated with adipocyte hypertrophy which correlates with WAT inflammation, increased circulating Leptin levels, elevated levels of Aromatase and elevated Insulin levels. Dysregulation of Insulin signaling can activate the PI3K/Akt/mTOR and Ras/Raf/MAPK pathways which in turn can enhance cell proliferation and increase the risk of breast cancer. Further, Insulin also induces insulin like growth factor-1 (IGF-1), which can activate ERα. Insulin resistance leads to reduced levels of sex hormone–binding globulin, resulting in elevated levels of free estradiol. It has been suggested that all of these changes collectively may play a role in the pathogenesis of obesity-related breast cancer. The present study was conducted to investigate the association between body fat and breast cancer risk in women with normal BMI.

The authors in this long-term prospective study examined the association between body fat mass, measured by DEXA scan, and the risk of breast cancer, in a secondary analysis of 3460 postmenopausal women with normal BMI (18.5-24.9), enrolled in the Women’s Health Initiative (WHI) clinical trials or observational study. The goal of this study was to understand whether excess adipose tissue is associated with an increased breast cancer risk in women with normal BMI. Participants 50-79 years old with a mean age of 64 years underwent body fat measurement (the percentage of whole-body fat, trunk fat, and fat mass in both legs) with DEXA scan at 3 US designated centers at the time of study entry into the WHI clinical trials, and years 1, 3, 6, and 9. Levels of Insulin, glucose, C-reactive protein, interleukin-6, triglycerides, HDL cholesterol, estradiol, sex hormone-binding globulin, adiponectin, and Leptin were measured in 3-13% of participants using baseline fasting blood specimens.

At a median follow up of 16 years, 182 incident breast cancers were confirmed, and 146 (80%) were ER positive. It was noted that among postmenopausal women with normal BMI, relatively high body fat levels were associated with an elevated risk of invasive breast cancer. The authors specifically, found a 56% increase in the risk of developing ER-positive breast cancer per 5-kg increase in trunk fat, despite a normal BMI. Elevated trunk fat levels were also associated with metabolic dysregulation and inflammation characterized by increased circulating levels of Insulin, Leptin, C-reactive protein, Interleukin 6 and triglycerides, whereas levels of HDL cholesterol and sex hormone–binding globulin were lower.

It was concluded from this large prospective study that normal BMI may not be an adequate proxy for the risk of breast cancer in postmenopausal women. High body fat levels and altered levels of circulating metabolic and inflammatory factors may be associated with a higher risk of invasive breast cancer. Association of Body Fat and Risk of Breast Cancer in Postmenopausal Women with Normal Body Mass Index. A Secondary Analysis of a Randomized Clinical Trial and Observational Study. Iyengar NM, Arthur R, Manson JE, et al. JAMA Oncol. 2019;5:155-163

FDA Approves TECENTRIQ® and ABRAXANE® Combination for Advanced Triple Negative Breast Cancer

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Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. Those with metastatic disease have one of the worst prognosis of all cancers with a median Overall Survival of 13 months.

TECENTRIQ® (Atezolizumab) an anti PD-L1 monoclonal antibody given along with ABRAXANE® (Nanoparticle Albumin-Bound – nab Paclitaxel) improved the Progression Free Survival (PFS) by 20%, when compared with ABRAXANE® alone. This benefit was even more significant among patients with PD-L1–positive tumors with PFS improvement of 38%. The combination of TECENTRIQ® plus ABRAXANE® could potentially change how we manage patients with Triple Negative Breast Cancer.

FDA Approves TECENTRIQ® and ABRAXANE® Combination for Advanced Triple Negative Breast Cancer

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SUMMARY: The FDA on March 8, 2019 granted accelerated approval to TECENTRIQ® (Atezolizumab) in combination with ABRAXANE® (Paclitaxel protein-bound) for adult patients with unresectable locally advanced or metastatic Triple Negative Breast Cancer (TNBC) whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering 1% or more of the tumor area), as determined by an FDA-approved test. The FDA also approved the VENTANA PD-L1 (SP142) Assay as a companion diagnostic device for selecting TNBC patients for TECENTRIQ®. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease.

Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers. The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Nonetheless, patients with TNBC often receive chemotherapy in the neoadjuvant, adjuvant or metastatic settings and approximately 30-40% of patients achieve a pathological Complete Response (pCR) in the neoadjuvant setting. Those who do not achieve a pathological Complete Response tend to have a poor prognosis. It therefore appears that there are subsets of patients with TNBC who may be inherently insensitive to cytotoxic chemotherapy. Three treatment approaches appear to be promising and they include immune therapies, PARP inhibition and inhibition of PI3K pathway. Previously published studies have shown that tumor-infiltrating lymphocytes were associated with clinical benefit, when treated with chemotherapy and immunotherapy, in patients with TNBC, and improved clinical benefit was observed in patients with immune-enriched molecular subtypes of metastatic TNBC.

TECENTRIQ® (Atezolizumab) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors, and thus enabling the activation of T cells. Single-agent TECENTRIQ® is presently approved for the treatment of metastatic Urothelial carcinoma and Non Small Cell Lung Cancer (NSCLC). TECENTRIQ® has also been shown to have clinical activity with acceptable safety profile in patients with other solid tumors including Triple Negative Breast Cancer. The premise for combining chemotherapy with immune checkpoint inhibitors is that chemotherapy may enhance release of tumor antigens and antitumor responses to immune checkpoint inhibition. Taxanes in particular may additionally activate toll-like receptor activity and promote dendritic-cell activity. ABRAXANE® (Nanoparticle Albumin-Bound – nab Paclitaxel) was selected as a chemotherapy partner in the present study because at the time that this trial was designed, the glucocorticoid premedication that is required with solvent-based Paclitaxel (TAXOL®), had been hypothesized to affect immunotherapy activity.

IMpassion130 is an international, randomized, double-blind, placebo-controlled phase III trial in which first-line treatment with TECENTRIQ® plus ABRAXANE®, was compared with placebo plus ABRAXANE®, in patients with locally advanced or metastatic Triple Negative Breast Cancer. Patients with untreated metastatic Triple Negative Breast Cancer (N=902) were randomly assigned in a 1:1 ratio and received TECENTRIQ® 840 mg IV or placebo on days 1 and 15 and ABRAXANE® 100 mg/m2 IV on days 1, 8, and 15 of every 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity. Stratification factors included presence or absence of liver metastases, use or non-use of neoadjuvant or adjuvant taxane treatment, and PD-L1 expression on tumor-infiltrating immune cells as a percentage of tumor area (less than 1% was considered PD-L1 negative versus1% or more considered PD-L1 positive) according to ImmunoHistochemical testing (IHC). Both treatment groups were well balanced. Approximately 40% of the patients were PD-L1 positive. The two Primary end points were Progression Free Survival (PFS) and Overall Survival (OS).

At a median follow up of 12.9 months, the median PFS in the intent-to-treat population was 7.2 months with TECENTRIQ® plus ABRAXANE®, as compared with 5.5 months with placebo plus ABRAXANE® (HR=0.80; P=0.002). This suggested a 20% improvement in PFS with the TECENTRIQ® combination. At the time of the first interim analysis, the median overall survival was 21.3 months in the TECENTRIQ® plus ABRAXANE® group and 17.6 months in the placebo plus ABRAXANE® group (HR for death=0.84; P=0.08). The Objective Response Rate (ORR) in the intent-to-treat population was 56% in the TECENTRIQ® and ABRAXANE® group versus 45.9% in the placebo plus ABRAXANE® group.

Among patients with PD-L1–positive tumors, the benefit was even more significant. The addition of TECENTRIQ® improved PFS by 38% (HR=0.62; P<0.001) and similar benefit was noted in the OS, with a median OS of 25 months with the TECENTRIQ® combination and 15.5 months with placebo plus ABRAXANE® (HR=0.62). Grade 3 or 4 adverse events were 48.7% in the TECENTRIQ® and ABRAXANE® and 42.2% in the placebo plus ABRAXANE® group.

It was concluded that TECENTRIQ® plus ABRAXANE® significantly prolonged Progression Free Survival among patients with metastatic Triple Negative Breast Cancer in both the intent-to-treat population and the PD-L1 positive subgroup, and could potentially change how we manage patients with Triple Negative Breast Cancer. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. Schmid P, Adams S, Rugo HS, et al. N Engl J Med 2018; 379:2108-2121

TECENTRIQ® (Atezolizumab)

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The FDA on March 8, 2019 granted accelerated approval to TECENTRIQ® in combination with Paclitaxel protein-bound for adult patients with unresectable locally advanced or metastatic Triple Negative Breast Cancer (TNBC) whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering 1% or more of the tumor area), as determined by an FDA-approved test. The FDA also approved the VENTANA PD-L1 (SP142) Assay as a companion diagnostic device for selecting TNBC patients for TECENTRIQ®. TECENTRIQ® is a product of Genentech Inc.

Adjuvant KADCYLA® Superior to HERCEPTIN® in High Risk HER2-Positive Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2, and adjuvant and neoadjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage as well as advanced metastatic breast cancer. Since the approval of HERCEPTIN®, several other HER2-targeted therapies have become available. The duration of adjuvant HERCEPTIN® therapy has been 12 months and this length of treatment was empirically adopted from the pivotal registration trials.

KADCYLA® (Ado-Trastuzumab Emtansine, T-DM1) is an Antibody-Drug Conjugate (ADC) comprised of the antibody HERCEPTIN® and the chemotherapy agent Emtansine, linked together. Upon binding to the HER2 receptor, it not only inhibits the HER2 signaling pathways but also delivers a chemotherapy agent Emtansine, a microtubule inhibitor, directly inside the tumor cells. This agent is internalized by lysosomes and destroys the HER2-positive tumor cells upon intracellular release. In the EMILIA trial, KADCYLA® was associated with significant increase in Overall Survival when compared with TYKERB® (Lapatinib) plus XELODA® (Capecitabine), in HER2-positive metastatic breast cancer patients, who had previously received HERCEPTIN® and a Taxane.Mechanism-of-Action-KADCYLA

It is well established that patients with HER2-positive early breast cancer following HERCEPTIN® based neoadjuvant therapies have a pathological Complete Response rate of 40-60%. Those without a pathological Complete Response tend to have significantly less favorable outcomes. These patients irrespective of pathological response status complete their standard adjuvant therapy which includes 12 months of HER2-targeted therapy. KATHERINE trial was conducted to evaluate the benefit of switching from standard HER2-directed therapy to single-agent KADCYLA®, after neoadjuvant chemotherapy along with either single or dual HER2 targeted therapy, in patients with residual invasive cancer at surgery. This study was conducted to address the unmet need of patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus HER2-targeted therapy.

The KATHERINE trial is an open-label, phase III global study, which compared KADCYLA® with HERCEPTIN®, as an adjuvant treatment for patients with HER2-positive early breast cancer, who had residual invasive disease following neoadjuvant chemotherapy and HERCEPTIN®. This study included 1,486 patients with HER2-positive early stage breast cancer, who were found to have residual invasive disease in the breast or axillary lymph nodes at surgery, following at least six cycles (16 weeks) of neoadjuvant chemotherapy with a Taxane (with or without Anthracycline) and HERCEPTIN®. Within 12 weeks of surgery, patients (N=1486) were randomly assigned in a 1:1 ratio to KADCYLA® 3.6 mg/kg IV every 3 weeks or HERCEPTIN® 6 mg/kg IV every 3 weeks, for 14 cycles (743 patients in each group). Both treatment groups were well balanced and hormone receptor positive disease was present in 72% of the patients. The majority of the patients (77%) had received an Anthracycline-containing neoadjuvant chemotherapy regimen, and in 19% of the patients, another HER2-targeted agent in addition to HERCEPTIN® (dual HER2 blockade) had been administered as a component of neoadjuvant therapy. The Primary end point was invasive Disease Free Survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause). The median duration of follow up was 41.4 months in the KADCYLA® group and 40.9 months in the HERCEPTIN® group.

At the prespecified interim analysis, invasive disease occurred in 12.2% of patients who received KADCYLA® and 22.2% of patients who received HERCEPTIN®. The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the KADCYLA® group and 77.0% in the HERCEPTIN® group. Invasive Disease Free Survival, which was the Primary end point of the study, was significantly higher in the KADCYLA® group than in the HERCEPTIN® group (HR=0.50; P<0.001).This suggested that KADCYLA® reduced the risk of developing an invasive breast cancer recurrence or death by 50%. Distant recurrence as the first invasive disease event occurred in 10.5% of patients in the KADCYLA® group and in 15.9% of the HERCEPTIN® group. A consistent benefit was seen across all prespecified subgroups. Adverse events were consistent with the known safety profile of KADCYLA®, with more toxicities associated with KADCYLA® than with HERCEPTIN®. Additional follow-up will be necessary to determine the Overall Survival benefit with adjuvant KADCYLA®.

It was concluded that among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, substituting KADCYLA® for adjuvant HERCEPTIN® reduced the risk of recurrence of invasive breast cancer or death by 50%, with the benefit seen across all patient subgroups. The authors added that even though KATHERINE trial focused on higher-risk patients with residual invasive breast cancer after completion of neoadjuvant chemotherapy, CNS recurrence remains a persistent problem. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. von Minckwitz G, Huang C-S, Mano MS, et al. for the KATHERINE Investigators. (published online December 5, 2018). N Engl J Med 2019;380:617-628

Increased Risk of Breast Cancer after Recent Childbirth

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In a large International Premenopausal Breast Cancer study which included close to 900,000 women, compared with nulliparous women, parous women had an increased risk for breast cancer that peaked about 5 years after childbirth and then gradually decreased about 24 years after childbirth.The increase in breast cancer risk after childbirth may be due to proliferation of breast cells during pregnancy which could promote accelerated development of latent initiated tumor cells. Childbirth also brings about maternal changes beyond breast tissue including altered immune function and microbiota, increased stress, and accelerated aging processes. Health Care Professionals should take these factors into account when considering individual risk profiles for breast cancer in premenopausal women.

Increased Risk of Breast Cancer after Recent Childbirth

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Breast cancer is the most common cancer type in reproductive-aged women. Women with biological children (parous women) are at a lower risk for developing breast cancer compared to nulliparous women. However, parity as a protective factor largely applies to breast cancer developing after age 60 years and may not apply for younger premenopausal women. Evidence from national registry linkage studies in Scandinavian countries suggested that recent childbirth confers a short-term increase in breast cancer risk which may last for 10 years or more, and this risk may be further increased in women who are older at first childbirth. Studies published thus far have not shown consistent findings and have had limited ability to account for factors influencing breast cancer risk such as breastfeeding and family history of breast cancer.

One biological explanation for an increase in breast cancer risk after childbirth may be due to proliferation of breast cells during pregnancy which could promote accelerated development of latent initiated tumor cells. This may also explain the higher breast cancer risk, conferred by older age at first childbirth, as a result of higher proportion of latent initiated tumor cells at older ages. Further, the postpartum breast microenvironment, characterized by lactational involution may also facilitate cancer cell migration and metastasis. Childbirth also brings about maternal changes beyond breast tissue including altered immune function and microbiota, increased stress, and accelerated aging processes.

The authors in this study used data from the International Premenopausal Breast Cancer Collaborative Group and conducted a pooled analysis of individual-level data from 15 prospective cohort studies. In this analysis, the researchers included women younger than 55 years and evaluated the risk of breast cancer in relation to recent childbirth, while taking into account other factors that relate to breast cancer risk such as breastfeeding, numbers of pregnancies and births and family history of breast cancer. It is felt that understanding these risk patterns may have implications for identifying risk-reducing strategies among vulnerable subgroups. A total of 889, 944 women, were available for analysis after excluding women who reported a first birth before age 13 years, women who were 50 years or older at study entry and at most recent birth, or reached parity greater than 10 births before enrollment. All these events were considered to have greater potential for data errors. The mean age at study entry was 42 years.

The researchers noted that compared with nulliparous women, parous women had an increased risk for breast cancer that peaked about 5 years after childbirth and then gradually decreased about 24 years after childbirth. These findings however were not noted among women who had only 1 child, or had their first child before age 25 years. The risk was highest in women who were older at the time of first childbirth, multiparous women and those who had a family history of breast cancer. Among those women with a family history of breast cancer, the risk was the greatest for Estrogen Receptor negative breast cancer. Breast feeding did not influence breast cancer risk patterns.

It was concluded that compared with nulliparous women, parous women have an increased risk for breast cancer after childbirth that is highest the first 5 years but decreases over the following 20 years. Health Care Professionals should take these factors into account when considering individual risk profiles for breast cancer in premenopausal women. Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies. Nichols HB, Schoemaker MJ, Cai J, et al. Ann Intern Med. 2019;170:22-30