Breast Cancer Update 6

You are here: Home: BCU 6 | 2008: Erica L Mayer, MD, MPH

Erica L Mayer, MD, MPH

Tracks 1-16

Track 1	Multicenter study of adjuvant chemotherapy/bevacizumab in patients with residual disease after neoadjuvant anthracycline-containing chemotherapy
Track 2	Ongoing and proposed trials for patients with residual disease after neoadjuvant chemotherapy
Track 3	Clinical data and ongoing investigations of the multikinase inhibitor sunitinib in BC
Track 4	Proposed mechanisms of action of bevacizumab
Track 5	Continuation of bevacizumab on metastatic disease progression
Track 6	Grade III/IV hypertension and improved outcomes with bevacizumab-based therapy
Track 7	Safety of dose-dense ACpaclitaxel with trastuzumab in HER2-positive BC
Track 8	Nonprotocol chemotherapy for HER2-positive or HER2-negative, node-positive BC

Track 9	Weekly paclitaxel/trastuzumab for node-negative, HER2-positive BC
Track 10	Role of nab paclitaxel as an alternative to conventional taxanes
Track 11	Safety and tolerability of adjuvant dose-dense ACpaclitaxel/ trastuzumab with lapatinib
Track 12	Use of capecitabine/lapatinib for HER2-positive, trastuzumab-refractory mBC
Track 13	Combination therapy with capecitabine in the treatment of mBC
Track 14	Clinical experience with ixabepilone
Track 15	Prospective study of short-term intra-articular and tenosynovial changes in the aromatase inhibitor-associated arthralgia syndrome
Track 16	Investigations of novel therapies in triple-negative BC

Select Excerpts from the Interview

Track 1

DR LOVE: Based on a recent Patterns of Care study we conducted, oncologists and investigators find the issue of significant residual tumor at the time of surgery after neoadjuvant chemotherapy very problematic. What are your thoughts on this issue?

DR MAYER: Within this population of women, it has been observed that approximately 20 percent achieve a pathologic complete response by the time of surgery after neoadjuvant therapy. Over time this group fares well, as was evidenced in NSABP-B-18 and NSABP-B-27 (Rastogi 2008).

However, the women who achieve a lesser response have a worse prognosis and experience a higher rate of disease recurrence, possibly as a result of chemotherapy resistance, especially if a viable tumor is present after a neoadjuvant chemotherapy regimen is administered involving taxanes and anthracyclines.

With this scenario in mind, Hal Burstein and I developed a postoperative trial to study women who are considered to be at high risk and who may benefit from an alternative approach. Eventually, this study evolved into a multicenter collaboration and consists of four sequential cohorts (4.1).

The first consisted of one year of adjuvant bevacizumab, the second involved the use of bevacizumab in addition to metronomic chemotherapy (continuous low-dose oral chemotherapy with daily cyclophosphamide and weekly methotrexate) and the last two cohorts were capecitabine based: bevacizumab with a standard capecitabine dose and the Memorial Sloan-Kettering capecitabine schedule of seven days on, seven days off (Mayer 2008).

Safety data for cohorts B and C were presented at the 2008 ASCO meeting, with interesting toxicity differences (Mayer 2008). Patients on the metronomic chemotherapy/bevacizumab arm experienced a higher incidence of hypertension, proteinuria and headache, whereas patients enrolled on the capecitabine-containing arm experienced more hand-foot syndrome, rash and diarrhea. Considering these results, I am curious about the underlying biologic mechanisms of each of these regimens.

4.1

Another observation we noted is the high incidence of recurrence. The three-year disease-free survival rate was approximately 60 to 70 percent for the entire group. If you evaluate the subgroups, the three-year disease-free survival rate was 50 percent for patients with triple-negative disease compared to 80 percent for patients with ER-positive disease.

Track 3

DR LOVE: What do we know about the activity of sunitinib in breast cancer, and what do you think about the NSABP postoperative study with sunitinib monotherapy?

DR MAYER: Sunitinib is the most developed of the tyrosine kinase inhibitors against VEGF, but it also demonstrates activity against other receptors, including PDGFR and C-KIT, giving it the reputation of a “dirty” receptor tyrosine kinase inhibitor. Recently, Hal Burstein and Kathy Miller published Phase II data on sunitinib monotherapy in breast cancer, demonstrating a low response rate within a refractory population (Burstein 2008; [4.2]).

Subsequently, other studies have evaluated sunitinib in breast cancer. Luca Gianni presented a small Phase I study on sunitinib with docetaxel (Mariani 2008), and Mark Kozloff presented data on sunitinib with paclitaxel (Kozloff 2007). Both data sets demonstrated relatively high response rates and are moving into further-phase studies.

4.2

Studies in the first-line refractory metastatic setting include large ongoing Phase III studies, with one comparing paclitaxel and sunitinib to the standard ECOG-E2100 paclitaxel/bevacizumab regimen. Although we have not seen a complete blockbuster data set yet, a robust program exists to develop sunitinib in breast cancer, and we are all awaiting the NSABP-B-45 study of adjuvant sunitinib monotherapy in women with residual disease after neoadjuvant chemotherapy (4.3).

4.3

Track 4

DR LOVE: A lot of controversy has arisen with regard to the mechanism(s) of action of bevacizumab and whether it will work well in the adjuvant, postadjuvant or postneoadjuvant setting. What is your take on this controversy?

DR MAYER: The simplistic view of anti-angiogenics, cutting off the blood supply and starving the tumor, is the description I use with my patients. However, the actual mechanism is more sophisticated. Dr Rakesh Jain has proposed mechanisms of disordered tumoral blood flow coupled with increased permeability of fluids across blood barriers, making it difficult for chemotherapy to penetrate the tumor.

His theory suggests that with the addition of bevacizumab, blood flow to the tumor is normalized and the penetration of chemotherapy inside the tumor improves, decreasing the intratumoral hypertension (Jain 2008).

Although Jain’s is a respected theory, another theory depicts VEGF receptors present on both the tumor and endothelial cells resulting in dual VEGF expression with the possibility of direct antitumor activity from both the tumor and the endothelial cells.

Another proposed theory suggests that endothelial cell precursors, derived from bone marrow, appear to leave the marrow in response to endothelial cell toxicity.

With the addition of chemotherapy, the combination could be highly irritating to vasculature, thus stimulating a release of endothelial precursors. When an anti-angiogenic agent is combined with chemotherapy, the agent works to “mop up” these precursors, helping to repair the vasculature.

Tracks 5-6

DR LOVE: Would you continue bevacizumab beyond disease progression if a patient who received chemotherapy and bevacizumab followed by maintenance bevacizumab responded well but then experienced slow disease progression?

DR MAYER: The RIBBON studies — RIBBON 1, RIBBON 2 and a proposal for RIBBON 3, which would specifically evaluate the idea of continuing bevacizumab — are currently addressing this question.

At present, we have no data sets to guide this decision. However, on occasion I have prescribed a continuation of bevacizumab in clinical practice.

If a patient responded well to chemotherapy with bevacizumab but had to discontinue the chemotherapy because of neuropathy, the patient could still benefit from bevacizumab. In general, however, I avoid bevacizumab in the second-and third-line settings because Phase III data indicate a lack of benefit.

DR LOVE: Recently, data have emerged suggesting that side effects such as hypertension can serve as predictors of response to bevacizumab. Do you believe a correlation exists?

DR MAYER: I am glad you asked because I have been following this story with interest. Drs George Sledge and Bryan Schneider recently reported data demonstrating a subset of individuals from the ECOG-E2100 trial who developed Grade III or greater hypertension and who seemed to have improved outcomes and improved overall survival (Schneider 2008; [4.4]).

Similar observations have been made in other tumor types. Perhaps hypertension represents a sort of pharmacodynamic marker that could be used in identifying individuals with sensitivity to angiogenesis inhibitor therapy.

4.4