“Pregnancy confers a dual effect” on breast cancer risk, “with an initial transient increased risk for breast cancer that is followed by long-term protection over time,” Luis Zabala Blanco, Jr, MD, noted in an update on the pathology of pregnancy-associated breast cancer, which was presented at the 2022 Lynn Sage Breast Cancer Symposium.1 Dr. Blanco is Associate Professor, Department of Pathology, and Director of the Breast Pathology Fellowship at Northwestern University Feinberg School of Medicine, Chicago. More than 550 physicians, nurses, and other health-care professionals attended the symposium, hosted by the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Underrecognized Link
The “influence of pregnancy on breast cancer” was noted as far back as the early 1900s. In an article in the Annals of Surgery in 1907, the authors wrote: “Cancer of the breast under the stimulus of pregnancy takes on a specially malignant character and runs a furiously rapid course.”2 Yet pregnancy-associated breast cancer is still “underrecognized,” Dr. Blanco said in an interview with The ASCO Post. “I want to help spread awareness about this,” he added, “because it does behave worse than nonpregnancy-associated breast cancer.”
“Pregnancy confers a dual effect on breast cancer risk, with an initial transient increased risk for breast cancer that is followed by long-term protection over time.”— Luis Zabala Blanco, Jr, MD
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Dr. Blanco continued: “Even in my field, in pathology, you will not find the words ‘pregnancy-associated breast cancer’ in the report. It is not a specific type of breast cancer. It happens to be breast cancer that occurs in women who have had a recent pregnancy and may be any subtype of breast cancer. Just like in nonpregnant patients, the majority are ductal. Up to 90% are invasive ductal carcinomas.”
Younger Women
Pregnancy-associated breast cancer currently refers to breast cancer diagnosed during gestation, lactation, and within 5 years postpartum. About 3,500 cases of pregnancy-associated breast cancer are diagnosed in the United States each year.
The great majority of pregnancy-associated breast cancers are diagnosed postpartum, and Dr. Blanco and others have proposed revised terminology to differentiate breast cancer occurring during pregnancy from that occurring in the postpartum period extending 5 to 10 years after birth. Separate investigations could “decipher the pathways underlying the differences in tumor biology and optimize therapeutic modalities,” he explained.
In a study by Genin et al, pregnancy-associated breast cancer occurred in significantly younger women, with a mean age of 34.9 years compared with 38.5 years in nonpregnant patients.3 “They also noted that in women younger than age 35, one-third of breast cancers were associated with pregnancy,” Dr. Blanco reported.
Advanced Disease
“The physiologic changes that occur during pregnancy and lactation—such as increased breast volume, palpable nodularity, firmness, and increased parenchymal density—make a physical exam and imaging challenging in these patients. Therefore, most cases of pregnancy-associated breast cancer present as advanced disease,” Dr. Blanco stated. The largest proportion of stage II to IV disease occurs in women diagnosed with breast cancer during pregnancy and within up to 2 years postpartum.
Breast tumors associated with pregnancy are usually larger, with an average of 3.5 cm vs 2.0 cm in those not associated with pregnancy. Women with pregnancy-associated breast cancer “also have increased risk of metastasis at diagnosis, 2.5 times more likely compared with nonpregnant patients,” Dr. Blanco reported. “And, they have higher rates of lymph node involvement, up to 89% compared with 54% in the nonpregnant group.”
Up to 70% of pregnancy-associated breast tumors are negative for both estrogen receptor and progesterone receptors. “They are also more frequently triple-negative,” Dr. Blanco said. “If they are not triple-negative, these tumors have more frequent overexpression of HER2 and have a very high proliferation rate.”
Initial Transient Increase in Risk
The initial transient increase in breast cancer risk following pregnancy “is most pronounced the later the first pregnancy occurs,” according to Dr. Blanco. “Overall, it has been reported that there is a 3.5% to 5.3% increase in lifetime relative risk of breast cancer with each year of increased maternal age at first birth.”
Reasons for the initial transient increase in risk include pregnancy-related hormones, such as estrogen, progesterone, and insulin-like growth factor 1, “which are known to promote previously initiated cells. In addition, the immune-suppressive effects of pregnancy, as well as postpartum involution that mimics aspects of wound healing and immunosuppression, have contributed to the increased risk of breast cancer,” he explained.
Crossover Effect
“Eventually, this risk crosses over to protection over time, with the greatest protection the earlier the first pregnancy occurs,” Dr. Blanco said.
“A study showed that uniparous women younger than age 25 have a 36% lifetime risk reduction, with a 7% decrease in lifetime risk for each additional birth,”4 Dr. Blanco reported. High parity, defined as at least five, and age up to 20 at first birth were “associated with the greatest ultimate reduction in risk,” and “age 35 appears to be associated with a permanent increase in breast cancer risk,” he added. “In older first-time mothers, there is a greater chance for premalignant lesions to develop, and they can then by promoted either by pregnancy or an event associated with pregnancy,” such as postpartum involution.
“Increasing parity reduces lifetime menstrual cycling, leading to reduced exposure to cycling hormones,” Dr. Blanco noted. Another reason pregnancy may offer protection against breast cancer is that “full-term pregnancy induces terminal differentiation and renders the gland less susceptible to tumorigenesis.” Although younger cells are susceptible to becoming cancerous, the terminally differentiated cells are not affected by external factors to become cancer. “If pregnancy pushes young cells to become differentiated, it is less likely there is a population of cells that can start to gain mutations and could potentially become cancerous,” he added.
Effects of Lactation
“Lactation also has a protective effect against breast cancer, with “up to a 64% reduction in relative risk for premenopausal breast cancer and a 4.3% decrease in relative risk for every 12 months of lactation,” Dr. Blanco noted. “However, this effect seems to be lost after 10 years postpartum,” he noted.
The reasons for the protective effect of lactation are like those for pregnancy—promotion of terminal differentiation of cells and decreased exposure to cycling hormones. “If, however, a patient is diagnosed with breast cancer, the recommendation is to stop lactation. And, if the patient hasn’t started, not to start lactation,” indicated Dr. Blanco.
Treatment During Pregnancy
Pathologic features of pregnancy-associated breast cancer, such as larger tumor size, higher grade and stage, increased risk of metastasis at presentation, and higher rates of lymph node involvement, are also major factors of a poorer prognosis. For this reason, treatment for those diagnosed during pregnancy is recommended as soon as possible postpartum.
Although most women who are diagnosed with breast cancer during pregnancy wait to start treatment postpartum, it can be started during pregnancy. However, the disclaimer is that a pathologist deals “more with diagnostics than treatment,” Dr. Blanco admitted. And, according to the literature, he commented: “If a person is diagnosed with breast cancer during pregnancy, she can undergo surgery in the second trimester. And, data have shown that if she waits until the second trimester, the outcomes are actually very good.”
Chemotherapy is not generally recommended during the first trimester. However, anthracyclines seem to be safe in the second and third trimesters. So, that approach may be a consideration for a woman in need of chemotherapy, Dr. Blanco said. However, hormone therapy, he added, “would be highly teratogenic and so should be avoided throughout pregnancy.”
DISCLOSURE: Dr. Blanco reported no conflicts of interest.
REFERENCES
1. Blanco L Jr: Updates in the pathology of pregnancy associated breast cancer. 2022 Lynn Sage Breast Cancer Symposium. Session 2. Presented September 22, 2022.
2. Cheesman WS: Influence of pregnancy on cancer of the breast. Ann Surg 46:487-488, 1907.
3. Genin AS, Lesieur B, Gligorov J, et al: Pregnancy-associated breast cancers: Do they differ from other breast cancers in young women? Breast 21:550-555, 2012.
4. Lyons TR, Schedin PJ, Borges VF: Pregnancy and breast cancer: When they collide. J Mammary Gland Biol Neoplasia 14:87-98, 2009.
