BREAST CANCER IN YOUNG WOMEN

Breast cancer in young women tends to be more aggressive. However, a German meta-analysis presented at the 2012 San Antonio Breast Cancer Symposium by Sibylle Loibl, MD, PhD, of the German Breast Group, indicates that biological differences in tumors of the very young may render them more chemoresponsive. Lidia Schapira, MD, Assistant Professor of Medicine at Harvard Medical School and Assistant Physician at Massachusetts General Hospital, spoke to Dr. Loibl about neoadjuvant chemotherapy in breast cancer patients 35 years of age or younger and the unique management challenges that exist in this patient population.

Neoadjuvant Chemo Benefits Young Patients

Dr. Schapira: Could you tell us about the study you presented here?

Dr. Loibl: We presented data^[1] from our neoadjuvant meta-analysis consisting of almost 9000 patients. We recruited more than 700 women aged 35 or younger, and we combined this very young age group with patients aged 36-50 and those older than 50 years. We found that the tumor was more often node-negative in these young women, but in contrast they had more grade 3 tumors.

The youngest group (aged 35 or younger) included more triple-negative and hormone receptor-positive HER2-negative patients. The triple-negative and the so-called "luminal-like" tumors -- hormone receptor-positive and HER2-negative -- each accounted for about one third of patients in that group. With increasing age the proportions changed: More patients had luminal-like tumors, and the rate of triple-negative disease declined. This was one of our findings, but the most important finding was that the pathologic complete response (pCR) is independently influenced by age. The pCR rate was approximately 23% for the very young women, decreasing to 13.5% in women older than 50 years. This was especially true for triple-negative patients, in which there was a huge difference between the age groups, but it was also apparent in the luminal-like tumors.

Disease-free and local recurrence-free survival rates are significantly influenced by age. Very young women have inferior disease-free and local recurrence-free survival. The age curves split even more when looking at the survival results according to whether patients did or did not achieve pCR. The young women who did not achieve a pCR had inferior survival in all those groups. Overall survival almost reached significance, but there was no difference in the patients who achieved a pCR.

Dr. Schapira: Do you have any idea why young age affects outcome?

Dr. Loibl: This can only be hypothesized. Some data indicate that very young women have a different gene profile. My belief is that age is just a phenotype for more aggressive tumor behavior that we have been unable to measure. Young women have more aggressive tumors, but on top of that, age is an independent risk factor, especially for women with triple-negative and hormone receptor-positive HER2-negative disease. Younger women have an excellent rate of survival if they have a pCR but inferior survival if they do not have a pCR. This suggests that young women are more chemosensitive, and even if they have a hormone receptor-positive HER2-negative tumor, they might benefit from adding neoadjuvant chemotherapy to their endocrine treatment.

Dr. Schapira: Do you have any plans to study new chemotherapy combinations for the younger women? Is there a need for that?

Dr. Loibl: Currently we are running a phase 2 clinical trial investigating the addition of carboplatin to the regimen for HER2-positive as well as triple-negative disease, but we are not looking at the luminal-like tumors. I don't believe that younger women will benefit from carboplatin. We know that amenorrhea is a factor. The duration of therapy and the amount of cyclophosphamide affect amenorrhea. Women with amenorrhea have a better survival, but this doesn't mean that we need to treat them exclusively with a high-dose regimen, because the meta-analysis of the dose-intensified studies did not suggest that age plays an important role.^[2] Many of these women were younger than 50 years.

Ovarian Suppression: How Long?

Dr. Schapira: That brings us to another complicated problem, which is that for these very young women with hormonally sensitive tumors, the type and duration of endocrine therapy remains controversial. What is your recommendation, and what kind of studies do you think will help us answer those questions?

Dr. Loibl: This is a very good question. We can argue about what is the right endocrine treatment. Given the data that we saw from the Swedish group last year,^[3] tamoxifen is an excellent treatment for these women. We are not totally convinced that they need to be treated with a luteinizing hormone-releasing hormone (LHRH) analog, especially given the side effects of this treatment. The ABCSG-12 data from the Austrian group^[4] showed no difference between the tamoxifen and aromatase inhibitor-treated patients who received an LHRH analog. Tamoxifen is a very good option. Women younger than 40 years might derive benefit from adding an LHRH analog.

Dr. Schapira: For how many years do you recommend ovarian suppression?

Dr. Loibl: We say 2-5 years, because a lot of data are available for 2 years, but the ABCSG data are for 5 years. I am not quite sure that we need 5 years, considering the side effects experienced by these women. It's not nice to be menopausal.

Dr. Schapira: Many oncologists struggle with this issue, especially because the American Society of Clinical Oncology guidelines recommendagainst giving ovarian suppression to younger women. Another difficult topic is to decide on the duration of endocrine therapy for young women. What is your view about extended hormonal therapy for women who remain premenopausal after completing their adjuvant therapy?

Dr. Loibl: We have the data from the MA17 trial that an aromatase inhibitor beyond 5 years might be of benefit for post-menopausal and hormone receptor-positive women with nodal involvement.^[5] The ATLAS data, which were presented here at this conference and published in The Lancet,^[6] indicate that a longer treatment might also be of benefit for premenopausal women. However, we need to look into these data in more detail before we generally recommend extending tamoxifen treatment beyond 5 years for all premenopausal women.

Green Light for Pregnancy

Dr. Schapira: What advice do you give a young woman who remains premenopausal after breast cancer treatment of a hormonally sensitive tumor who now wants to become pregnant? Do you give these patients a green light?

Dr. Loibl: Yes, I do, certainly. A lot of my colleagues, especially my male colleagues, are very cautious about recommending pregnancy for these women, but there are new data from a meta-analysis^[7]supporting what has been shown previously: that in hormone receptor-positive disease, there is no indication that these women should avoid becoming pregnant. I wouldn't go so far as to recommend that these women become pregnant, but if it is part of a woman's social and emotional well-being to have a child, she should go ahead.

Dr. Schapira: Breast cancer complicates an estimated 1% of pregnancies. Is that number accurate?

Dr. Loibl: Approximately, yes. In Germany we don't have a cancer registry. We have some data from the Norwegian cancer registry showing that it is 1%-2%.

Dr. Schapira: Your work and that of others show that it is possible to treat breast cancer in pregnancy. While we cannot give radiation during pregnancy, it's possible to give chemotherapy safely in the second and third trimesters. Can you summarize the data on safety of specific chemotherapeutic drugs and recommend a safe regimen for use during pregnancy?

Dr. Loibl: Looking at our data from almost 500 pregnant women diagnosed with breast cancer during pregnancy, about 50% received chemotherapy during pregnancy.^[8] We have the largest amount of data for anthracycline- and cyclophosphamide-based regimens, and a minority received taxanes during pregnancy. Looking at data from other colleagues who investigated the taxanes, it's perfectly safe to give a taxane during pregnancy.^[9] Baboon data show that the amount of taxane that is detected in the fetus is negligible.^[10] This is different from the anthracyclines, however. A much higher rate of anthracycline is detected in the fetus. It seems that there are some binding proteins in the placenta, and these binding proteins seem to hold the taxane and bind it, so it's almost neutralized.

Dr. Schapira: Looking at data on babies born to women who received chemotherapy during pregnancy, the babies seem to be fine.^[11]

Dr. Loibl: They are not bald or ill or fatigued.

Dr. Schapira: What about giving growth factors during pregnancy? You did not mention that in your paper.

Dr. Loibl: We didn't capture those data. You could argue that chemotherapy doesn't work as well as in nonpregnant women, but our data do not support this.^[12] I would avoid a dose-dense regimen. I prefer a sequential regimen for the taxane and an anthracycline-phosphamide combination.

Dr. Schapira: What about HER2-directed therapy? Do we have any safety data, or should we postpone HER2-targeted therapy until after delivery?

Dr. Loibl: We have some data that show that it is not safe to give HER2-directed therapy during pregnancy.^[13] In most of the patients, the fetuses developed oligo- or anhydramnios. This is probably caused by an antiangiogenic effect of trastuzumab during pregnancy. Also, there are some data from the HERA trial of patients who became pregnant within 3 months after stopping the treatment.^[14] There was no effect on the children compared with those of women who became pregnant beyond 3 months of stopping trastuzumab. There was a higher rate of abortions in the group who became pregnant within 3 months of stopping trastuzumab, but it isn't known whether these were spontaneous or induced abortions. It might be a time or duration effect. It's not recommended to give trastuzumab during pregnancy, but you can use the HERA model^[14] and give it after completion of chemotherapy.

Dr. Schapira: Finally, are there other special considerations in the treatment of very young breast cancer patients?

Dr. Loibl: Maybe they need to be treated with neoadjuvant chemotherapy. I have no data to support that, but the NSABP^[15] showed that premenopausal women benefit from neoadjuvant therapy compared with the adjuvant therapy, and some data from the IBCSG^[16] showed that in the premenopausal patients, it's important that you start the chemotherapy as early as possible. We need to investigate whether they benefit from neoadjuvant compared with adjuvant therapy.