imageBy Monica J. Smith

Phoenix—Within the population of breast cancer patients, there is a group that is particularly discomfiting to surgeons: women under the age of 40 years, which includes, on rare occasion, women diagnosed with breast cancer while pregnant.

These challenging and poignant cases are few and far between, but “when it happens, it’s really important that people know what to do or know how to get information on what to do,” said Ann H. Partridge, MD, MPH, Dana-Farber Cancer Institute, Boston, who addressed the topic at the American Society of Breast Surgeons’ annual meeting.

Breast cancer in young women is difficult, partly because it is so uncommon, representing only a small proportion of the breast cancers that surgeons see. “It’s more unknown to us, and the stakes are high. Therefore, it becomes problematic in trying to care for them,” Dr. Partridge said.

Surgeons may not meet these patients often, but breast cancer strikes about 12,000 women under the age of 40 every year in the United States, and tens of thousands worldwide, and it is the leading cancer-related cause of death in young women. Things may have changed with the availability of trastuzumab (Herceptin, Genentech) but Surveillance, Epidemiology and End Results [SEER] data published seven years ago (plus recent information provided by the American Cancer Society) showed a significant difference in five-year survival rates between younger breast cancer patients and those aged 40 years or older, at 84% and 90%, respectively. “We all see this clinically, unfortunately,” Dr. Partridge said.

This is due largely to the fact that younger women present at a more advanced stage of the disease. Reliable screening is lacking for this group, as is awareness; diagnosis is difficult in young women who are pregnant; and younger patients are more likely than older patients to have access issues.

Younger women are more likely to have estrogen receptor negative (ER-) disease, lymphovascular invasion and possibly more HER2-positive disease, and 60% to 67% of young women with breast cancer present with high-grade disease, making it more difficult to achieve negative margins and increasing the risk for recurrence. Young black women in particular appear to be more likely to develop aggressive basal-like subtypes of breast cancer than older black women and non-black women in general (JAMA 2006;295:2492-2502).

At a Glance

Breast cancer strikes about 12,000 under the age of 40 every year in the United States, and tens of thousands worldwide, and it is the leading cancer-related cause of death in young women.

Data for lymphoma suggest that radiation can be used successfully to treat pregnant patients, without adverse outcomes for the baby.

Research shows that young age was not associated with a higher risk for mortality in women with estrogen receptor negative [ER-] disease and HER2-positive disease.

“All of these data beg the question: Is this a different disease in young women, or is it a different mix of tumor subtypes?” Dr. Partridge asked. So far, she said, there is no evidence that it is a different disease. “If it is, that’s something we could capitalize on. But it’s not clear at this point.”

Although on average, the prognosis is worse for young women, recent studies (that control for known prognostic and predictive variables in tumor subtypes) suggest young age alone does not explain the reason for this. Dr. Partridge’s research team examined data from the HERA trial of women with HER2-positive disease who were randomly selected to receive trastuzumab or no trastuzumab (N Engl J Med 2005;353:1659-1672) and found no statistically significant difference across age groups (Breast Cancer Res Treat 2010). “Age was neither a prognostic nor a predictive factor for early recurrence,” she said.

The researcher also examined the National Comprehensive Cancer Network data, and found that young age was not associated with a higher risk for mortality in women with ER- disease and HER2-positive disease (Partridge et al, SABCS 2011; poster 010805).

“There’s a lot more work to do in this area, but I think as we flesh things out we’ll be thinking a lot more about tumor subtype related to age and less age alone over time,” Dr. Partridge said.

One of the biggest questions cancer care teams face now in the care of young women with breast cancer is whether some patients can forgo chemotherapy. “Young women can and do get wimpy tumors, so we need to think about whom we can spare from some of the toxicity of additional therapies,” Dr. Partridge said.

“There are definitely studies that suggest that some young women can do quite well with hormonal therapy only,” she said, noting that doctors can use parameters, such as Oncotype DX, to identify these women. This raises the question of whether ovarian function suppression or oophorectomy is the optimal solution for these patients. A lot of the benefit of heavy chemotherapy for young women stemmed from the chemo-endocrine effect, Dr. Partridge explained. “Especially in older regimens like CMF [cyclophosphamide, methotrexate and 5-fluorouracil (5-FU)], ovaries were shot by the chemotherapy.”

Some research suggests ovarian suppression is beneficial in the metastatic setting (J Natl Cancer Inst 2000;92:903-911) and in the adjuvant setting (N Engl J Med 2010). Results of the Suppression of Ovarian Function trial [SOFT]—in which women were randomized to tamoxifen alone or tamoxifen plus ovarian suppression, or the aromatase inhibitor exemestane plus ovarian suppression—should answer the question, perhaps in the next year or two. “My personal hunch is that ovarian suppression will add to some degree, and we’ll spend the next decade or so figuring out for whom it adds and whether it’s worth it,” Dr. Partridge said.

SOFT is also collecting a lot of data on tolerability, quality of life and other issues that are important when deciding whether small benefits are worth it, she added, noting that the late and long-term effects of diagnosis and treatment are much different for younger women than for older ones. The ramifications of very premature menopause, the potential for second cancers, the ongoing pursuit of genetic issues—all lead to a heavy psychosocial burden at diagnosis and at follow-up.

“It’s the stress of having a higher-risk disease, the tendency to receive more aggressive chemotherapy, and [being at] a time in their lives where their role at home or at work may be less replaceable,” Dr. Partridge said. “They are worried more than older women in general about beauty and attractiveness, sexual functioning, fertility, family planning—these things are of paramount importance to the younger set.”

This stress is compounded by the fact that there is less information and less support for younger women. “They’re the youngest woman in the room in breast-only clinics. In support groups, the other women are worried about seeing their grandchildren grow up while young women are worried about even getting a date with no breast,” Dr. Partridge said. “The good news is that a lot of groups now are focusing on the unique needs of young women.”

Breast cancer in pregnant women is exceptionally rare, estimated to occur in about one in 3,000 women per year in the United States. Over the course of a career, a surgeon might encounter only a few of these patients for whom the cancer poses “an ethical dilemma; an existential threat to two human beings—the patient with the cancer and her unborn child,” said Richard Theriault, MD, professor, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston. “The psychosocial dynamics around that make it a particularly poignant and difficult clinical management process, and it is a process.”

At his institution, management of these patients involves a multidisciplinary team of maternal–fetal medicine specialists, surgeons, medical oncologists and often a geneticist, who work together to evaluate the patient’s pregnancy and the state of her disease before deciding on a course of action.

Patients who have been advised to terminate the pregnancy need to be assured that it may not be necessary; available data do not suggest it improves patient outcomes.

“The decision to terminate must be made by the woman who has been informed of the risks, harms, burdens and potential benefits of treatments for herself, and potential fetal risks, with cancer treatment or no treatment,” Dr. Theriault said. “It’s an ethical, moral, religious, philosophical decision and it’s not the doctor’s to make. The major indications for considering termination would be fetal malformation and mother’s choice.”

If the patient decides to maintain the pregnancy, evaluation of the patient and the extent of her disease does not differ much from that of a nonpregnant patient. “We conduct an evaluation with mammography and ultrasound of the breast and nodal basins; a chest radiograph; and an ultrasound of the liver, which can be done concomitantly with ultrasound of the fetus,” Dr. Theriault said. If the medical team suspects bone abnormalities that might affect the pregnancy, they will look at a screening noncontrast magnetic resonance imaging of the spine.

Biopsy can and should be done as soon as possible, as these patients are likely to have had a lump for months and to have been told that it’s just a plugged milk duct or a cyst. “If it’s been there more than two or three weeks, it needs to be evaluated; we can easily do core biopsies or fine-needle aspirations,” Dr. Theriault said, noting that the latter may be more problematic for the pathologist to interpret due to pregnancy’s effect on the breast, whereas core biopsy provides more information.

Treatment is guided by the extent of the disease. The options are similar to those for any breast cancer patient: surgery, radiation and systemic therapy, although radiation is best suspended until after the birth of the child. Surgery can be performed at any point during the pregnancy. Mastectomy is not associated with an increased risk for fetal abnormality, “but if you’re going to do surgery after week 25 of gestation, I would recommend you have obstetricians available in case there is a precipitous delivery,” Dr. Theriault said.

Breast-conserving surgery is technically feasible, but does require radiation, which Dr. Theriault prefers to avoid until the patient is postpartum, although it is not clear whether radiation is contraindicated in pregnancy: Data for lymphoma suggest that radiation can be used successfully during pregnancy without adverse outcomes for the baby. “You can ask your medical physicists to calculate the fetal dosimetry and give a risk assessment if you feel that it’s absolutely necessary to do radiation,” Dr. Theriault said.

For localization in sentinel lymph node biopsy, Dr. Theriault uses technetium-99m, and one of his colleagues assessed the fetal radiation dose to be less than the 5 cGy exposure that is problematic to the National Council on Radiation Protection and Measurements.

Dr. Theriault’s team does not use isosulfan blue dye because, similar to chemotherapy, it is teratogenic, but some regimens are less toxic than others. When the proper agent is restricted to the second and third trimesters, the risk for fetal malformation is about 1.3%, similar to that seen in the general population.

“Most of the case series look at anthracycline-based therapies, and supporting experiences with chemotherapy regimens including AC [adriamycin and cyclophosphamide], FAC [5-FU, doxorubicin and cyclophosphamide] and FEC [5-FU, epirubicin and cyclophosphamide] during the second and third trimesters. There are limited data on dose-dense anthracycline safety and tolerance, but theoretically it is just as safe as the others,” Dr. Theriault said. Dosage is based on the patient’s weight and body surface area. “The practical aspect of that is, as the pregnancy progresses, most women gain weight, and the dose of chemotherapy goes up. Some people get a little bit frightened by that.”

Endocrine therapy is reserved for postdelivery. “We don’t want to interfere with the hormonal milieu of the pregnancy by fiddling around with estrogen receptors,” Dr. Theriault said.

Monitoring the pregnancy throughout treatment is crucial. At MD Anderson, pregnant patients consult with a maternal–fetal medicine specialist the day before each cycle of chemotherapy. “If everything looks normal, we proceed with our next cycle of chemotherapy; we don’t want to give chemotherapy if the baby appears to be in extremis,” Dr. Theriault said. If there is evidence of oligohydramnios or intrauterine growth retardation, suspending systemic treatment until after the delivery can be arranged.