AREAS OF CONFUSION IN ONCOLOGY
Breast Cancer in Women Under 40
By Jeffrey Peppercorn, MD, MPH1 |
May 14, 2009
1Assistant Professor of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina
Several choices confront the clinician considering chemotherapy regimens in this setting. First, one must consider whether to use a more or less intensive regimen in terms of duration of therapy and combination/ sequencing of chemotherapeutic agents, and second, there is the question of precisely which regimen to use. For patients at greatest risk of recurrence—for example, those with multiple positive lymph nodes or those with triple-negative breast cancer, for whom chemotherapy is the only effective systemic therapy— several third-generation regimens offer large reductions in risk of recurrence through the addition of a taxane to an anthracycline-based regimen. For patients at lower risk of recurrence, either anthracycline-based or taxane-based chemotherapy might be appropriate.
Select Chemotherapy Regimens for Consideration in Young Women With Breast Cancer
With regard to the more intensive regimens, common considerations include (1) dose-dense chemotherapy with AC (doxorubicin [Adriamycin] and cyclophosphomide) followed by paclitaxel(Drug information on paclitaxel) (AC-T), (2) FEC (5-FU, epirubicin(Drug information on epirubicin) [Ellence], and cyclophosphomide) followed by docetaxel(Drug information on docetaxel) (FEC-D), or (3) TAC (docetaxel [Taxotere], doxorubicin(Drug information on doxorubicin), and cyclophosphomide). All have proved superior to non–anthracycline- containing regimens in large phase III randomized trials, and have not been compared directly to each other, making any of the above an acceptable choice of therapy (see Table 2).
Both Cancer and Leukemia Group B (CALGB) 9344 and NSABP B-28 demonstrated improvements in disease-free survival of approximately 17% with four cycles of AC followed by four cycles of paclitaxel, compared to four cycles of AC alone, although a survival benefit was seen only in CALGB 9344.[43, 44] Further incremental improvement was indentified in CALGB 9741, in which AC-T on an every-2-week basis with granulocyte colony-stimulating factor (G-CSF, Neupogen) support proved superior to every-3-week therapy, with a 24% improvement in disease-free survival and a 31% improvement in overall survival.
Similarly, in the PACS 01 trial, FEC-100 (where 100 represents the dose in mg/m² of epirubicin) followed by three cycles of docetaxel yielded significant improvements in disease-free survival (increased by 17%) and overall survival (increased by 27%) compared to six cycles of FEC-100. While febrile neutropenia rates were higher for patients on FEC-D (11.2 vs 8.4%), nausea and vomiting was greater with six cycles of FEC (20.5% vs 11.2%). Overall, the rates of serious adverse events were comparable between regimens.
||Develop a risk-based strategy for treatment and discussion of options with young women with breast cancer.
||Consider the addition of ovarian suppression and adjuvant bisphosphonate therapy, particularly for young women receiving endocrine therapy alone.
||Discuss with patients the relevant data for reduction in risk of recurrence, short- and long-term toxicities from therapy (including fertility issues), and the limitation of available data, and allow patients to make informed collaborative decisions regarding therapy.
Finally, in the Breast Cancer International Research Group (BCIRG) 001 trial, patients with positive lymph nodes were randomized to six cycles of TAC vs six cycles of FAC. TAC provided a 28% disease-free survival improvement (75% vs 68% at 5 years), and a 30% improvement in overall survival. TAC caused markedly greater hematologic toxicity, with approximately 25% of patients developing febrile neutropenia compared to 2.5% with FAC. In addition, the researchers reported greater asthenia with TAC (11.2% vs 5.6%), but TAC was less emetogenic than FAC.
The relative efficacy of concurrent anthracycline and taxane vs sequential anthracycline followed by taxane remains unknown, and any of the above, as well as several similar regimens (such as AC followed by docetaxel or weekly paclitaxel), are acceptable. Recent data from NSABP B-30 suggest that the sequential strategy may be superior, but both approaches appeared equivalent in BCIRG 005, and longer follow-up is required to address this question.[48, 49]
For patients at lower risk of recurrence, AC alone remains a standard chemotherapy option. However, in a large randomized trial, Jones et al compared four cycles of AC to four cycles of TC (docetaxel plus cyclophosphomide). TC proved superior in terms of both disease-free survival and overall survival, and is an acceptable alternative to AC for patients with 0 to 3 involved lymph nodes. As a nonanthracyline regimen, TC has the advantage of posing a lower risk of life-threatening cardiomyopathy and leukemia, but is also associated with a higher risk of febrile neutropenia. The ongoing CALGB 40101 trial, which is comparing AC vs paclitaxel alone, will help further address the issue of taxane- vs anthracycline-based regimens for patients at lower risk of recurrence.
For patients with HER2-positive breast cancer, the use of adjuvant trastuzumab(Drug information on trastuzumab) (Herceptin) has dramatically altered expected outcomes of standard therapy. The primary questions now facing clinicians are which trastuzumab-based regimen to select, and how small a tumor to consider for systemic therapy.
With regard to chemotherapy, the major decision is whether to administer an anthracycline-containing regimen. This is also a concern in older patients, who are at higher risk of cardiac toxicity. In the young patient, we not only wish to avoid a potentially life-threatening toxicity, but we face conflicting impulses of another sort: While we would like to pursue maximal therapy with a class of drugs long considered the most effective for breast cancer, we must be careful to avoid any factor that might prevent the patient from seeing the full benefit of trastuzumab. We are currently without data to determine the best approach.
The benefit of adjuvant trastuzumab was first demonstrated in the combined analysis of NSABP B-31 and North Central Cancer Treatment Group (NCCTG) N9831, in which AC-T was compared to AC-T plus concurrent trastuzumab (AC-TH), given initially in combination with paclitaxel for 12 weeks, and then continued for a total of 1 year of trastuzumab therapy. Compared to AC-T alone, AC-TH resulted in a 52% improvement in disease-free survival and 33% improvement in overall survival. The primary problem with AC-TH was a 2.9% to 4.1% incidence of severe cardiac toxicity or cardiac death. Furthermore, because treatment started with an anthracycline, 6% of patients experienced a decline in ejection fraction and were unable to receive any trastuzumab therapy, and roughly 20% were unable to complete 1 year of therapy as planned due to cardiac toxicity.
The HERceptin Adjuvant (HERA) trial demonstrated that 1 year of trastuzumab following completion of anthracycline-based chemotherapy yielded comparable reductions in risk of recurrence (46%) and lower levels of cardiac toxicity. Patients with cardiac problems after chemotherapy were excluded from the study results.
Recently, the BCIRG 006 trial included a non–anthracycline-containing regimen, TCH (docetaxel, carboplatin(Drug information on carboplatin), trastuzumab). Although this regimen appeared comparably effective to AC followed by docetaxel plus trastuzumab (AC-DH), the relative reduction in risk from TCH compared to AC-DH was approximately 33%, raising the question of whether this cross-trial difference (vs 52% with AC-TH compared to AC-T in N9831/B-31) is due to a superior standard chemotherapy backbone, a less effective trastuzumab combination, or mere statistical chance. For lymph node–negative patients, who were essentially not represented in B-31/N9831, this author typically uses TCH, but for young women with multinode-positive disease, I continue to use an N9831-style regimen. Other approaches are clearly acceptable, pending further data.
The lower limits of tumor size that benefit from trastuzumab are unclear, with most studies requiring tumors of 1 cm or greater for enrollment, and comparable reductions in relative risk of recurrence seen across all tumor sizes. Given that biology appears to trump size with regard to both recurrence risk and benefit from therapy, there is controversy over whether to treat tumors less than 0.5 cm (T1a) with adjuvant systemic therapy. For HER2-positive patients, we would like to have data on trastuzumab alone, in combination with endocrine therapy, and with minimal chemotherapy. Clinical trials are underway to address each of these strategies.
The discussion above has focused on adjuvant systemic therapy. Many young women with breast cancer will be candidates for neoadjuvant therapy, ie, systemic therapy preceding surgery. Overall, the large randomized clinical trials comparing adjuvant to neoadjuvant chemotherapy demonstrated no difference in disease outcomes. However, these investigations did show an increased likelihood that patients with locally advanced breast cancer undergoing neoadjuvant therapy would have the option of breast-conserving surgery, compared to those undergoing adjuvant chemotherapy.
In addition to the increased chance for breast conservation, neoadjuvant therapy offers an opportunity to determine in a therapy is effective during treatment and a change to alternatives when indicated. This setting also offers an excellent opportunity for patients to consider clinical trials that can efficiently test new strategies and evaluate correlates of response and resistance to therapy. For patients who fail to achieve a pathologic complete response to neoadjuvant chemotherapy, clinical trials are underway to determine if additional chemotherapy combined with targeted strategies can reduce the risk of recurrence.
Concerns over fertility and desire for future pregnancy should be assessed in every patient under 40 considered for systemic therapy for breast cancer. Both endocrine therapy and chemotherapy have implications for the timing of any future pregnancy and fertility. Partridge et al have demonstrated that this is a major concern for young women with breast cancer, but the issue is not consistently addressed by oncologists. Evidence suggests that most women under 40 will retain or recover their fertility after systemic chemotherapy, but longterm data on modern regimens are lacking.
To date, studies with LHRH agonists to preserve fertility through ovarian suppression during chemotherapy have proven disappointing.[ 59] Women can choose to undergo oocyte or embryo cryopreservation using AI-based protocols that appear safer than traditional in vitro fertizilation techniques. However, data on successful pregnancies and long-term safety in this area are scant. Consideration of these issues requires referral to a reproductive specialist with experience in caring for young women with breast cancer. Fortunately, pregnancy following completion of breast cancer therapy appears to be safe.
The care of young women with breast cancer requires an understanding of the relatively higher risk for recurrence faced by this patient population and the range of options and issues that must be considered. While systemic therapy will still be guided primarily by breast cancer subtype as defined by endocrine receptor status and HER2, within each subcategory of disease multiple choices need to be considered, and for many questions data are emerging or nonexistent. In this context, it is important to at minimum deliver standard quality care with adjuvant tamoxifen for endocrine receptor–positive patients, chemotherapy for triple-negative patients, and a trastuzumab-based chemotherapy regimen for HER2- positive patients (with or without tamoxifen, depending on endocrine receptor status).
Financial Disclosure: Dr. Peppercorn has received honoraria for speaking (Genentech).
Acknowledgment: Dr. Peppercorn is supported by the American Society of Clinical Oncology and the Breast Cancer Research Foundation.
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