CME
Current Research on New Treatments for Patients With Difficult-to-Treat Advanced Breast Cancer:
An Interactive Discussion of Challenges, Opportunities, and Practical Considerations
Hope S. Rugo, MD
University of California,
San Francisco
Helen Diller Family Comprehensive Cancer Center
San Francisco, California
The Course Director, Dr. Hope S. Rugo, provides her answers below.
triple-negative breast cancers, in both node-negative and node-positive patients? What do you think about the idea of IV bisphosphonates
as adjuvant therapy after chemotherapy, especially for patients with
triple-negative tumors? Also, is there a trial using PARP inhibitors as adjuvant therapy for patients with these tumors?
Triple-negative cancers are highly proliferative tumors; recent subset data have suggested that these cancers benefit from more aggressive adjuvant chemotherapy regimens, including the addition of paclitaxel to an anthracycline/cyclophosphamide combination, and a dose-dense or combination treatment approach, as opposed to standard every-3-week or sequential dosing (Amir E et al. Nat Rev Clin Oncol. 2010;7(2):79-80). In addition, a subset of triple-negative tumors has a relatively high rate of pathologic complete remission to neoadjuvant chemotherapy, ranging from 30% to 40%; these patients have an excellent long-term outcome (Leon JP et al. 45th Annual Meeting of the American Society of Clinical Oncology [ASCO 2009]. Abstract 625). Based on these data, the most appropriate chemotherapy regimens for patients with triple-negative breast cancer today would include an anthracycline and taxane. A shorter course of treatment, such as docetaxel and cyclophosphamide, could be considered for small, node-negative disease. Ongoing clinical trials are testing the benefit of adding bevacizumab or carboplatin to paclitaxel or a PARP inhibitor to gemcitabine and carboplatin in the neoadjuvant setting. Based on the data from these trials, clinical studies in the adjuvant setting will be available in the next year or two.
Data from the ABCSG-12 trial suggested that 3 years of every-6-month zoledronic acid in premenopausal women with early-stage, hormone receptor–positive breast cancer reduced the risk of breast cancer recurrence (Gnant M et al. N Engl J Med. 2009;360:679-691). Follow-up is still short at 4 years. Other studies have demonstrated a trend toward decreased recurrence, but these trials were all done in women with hormone receptor–positive disease. Two trials should help to answer the question of whether potent bisphosphonates reduce recurrence in patients with triple-negative breast cancer: the AZURE trial (zoledronic acid) and NSABP B-33 (clodronate). Both trials have completed accrual, and first results are expected next year. SWOG 0307 just completed accrual; this trial also randomized women with any type of early-stage breast cancer to receive one of three bisphosphonates with the primary endpoint of disease-free survival. At the present time, there is not enough data to use zoledronic acid as standard adjuvant therapy. I would use this bisphosphonate for bone loss using standard indications.
In general, recurrent disease should be biopsied if at all possible. First, it is important to confirm that the metastatic tumors are indeed of breast origin. Second, and most importantly, there is known and significant discordance between primary and metastatic tumors including ER, PR, and HER2. In addition, discordance within the primary tumor has been reported, so repeating markers is beneficial in a number of ways. Understanding the markers of the active malignancy can have important implications for treatment. In the future, hopefully these biopsies will be used to individualize specific therapy to the biology of the tumor.
The only situation where a biopsy might be delayed is when the biopsy itself is associated with greater risk than the potential benefit of obtaining pathology. Fine-needle aspirations can be performed on lung lesions relatively safely, but core biopsies should be avoided. Bone biopsies can often be performed, but decalcification can potentially reduce the ability to detect ER and PR.
PARP1 is an important DNA repair enzyme that repairs single-strand DNA breaks. Patients with BRCA mutations have a defect in another DNA repair pathway, homologous recombination. In patients with BRCA mutations, monotherapy with the oral PARP inhibitor AZD2281 has led to durable tumor responses in the setting of heavily pretreated metastatic disease. This concept is referred to as “synthetic lethality,” as blocking these two important DNA repair pathways would be expected to lead to cell death (Tutt A et al. ASCO 2009. Abstract CRA501). Interestingly, responses have been seen in patients with BRCA1 and BRCA2 mutations, even though the tumors in patients with BRCA2 mutations are usually hormone receptor–positive, unlike the triple-negative cancers commonly seen in women with BRCA1 mutations. Indeed, resistance to PARP in BRCA-associated cancer has been linked with recovery of BRCA function.
In contrast, triple-negative breast cancer may or may not have intact BRCA gene function, and represents a biologically heterogeneous disease. Unpublished data have demonstrated upregulation of PARP expression in these tumors, perhaps representing a unique mechanism of chemotherapy resistance. Preclinical data have also shown synergy between DNA-damaging agents such as gemcitabine, carboplatin, cyclophosphamide, and temozolomide. A recently reported randomized phase 2 trial demonstrated a significant improvement in response, progression-free, and overall survival when the intravenous PARP inhibitor BSI-201 was added to weekly gemcitabine and carboplatin (O'Shaughnessy J et al. J Clin Oncol. 2009;27[Suppl]:18s [Abstr 3]). A phase 3 trial testing this combination has recently completed accrual and results are expected within a year. This combination is also being tested in an ongoing neoadjuvant study. Early-phase trials are testing oral parp inhibitors in combination with several of the agents listed above.
Therefore, the rationality of monotherapy or combination therapy with PARP inhibitors is based on the process that drives tumor growth and chemotherapy resistance. Understanding the heterogeneity of tumor biology within these cancers is critical to identifying which triple-negative tumors are most likely to benefit from this novel therapy.