DR LOVE: This patient has received three endocrine therapies. Can you discuss the sequence of those agents?
DR DE FUSCO: Initially she received adjuvant tamoxifen. After the MA17 data were released in 2003, we discussed the results and she began letrozole (Goss 2003; [1.8]). However, she experienced insomnia, so we switched to anastrozole and she had no further problems. She has been receiving essentially continuous hormonal therapy.
DR LOVE: Kathy, would you try another endocrine therapy or switch to chemotherapy at this point?
DR MILLER: I see nothing that suggests her disease is refractory to hormones. The disease-free interval was long, and while she has some local symptoms, the disease bulk is limited. I would try another hormonal therapy, probably fulvestrant with a loading dose. Switching to a steroidal aromatase inhibitor would be equally beneficial and reasonable (Chia 2008).
I wouldnít use chemotherapy until the disease progressed with the next one or two hormones, or if we encountered difficulty controlling her symptoms.
DR PEREZ: Certainly hormonal therapy is much better tolerated than chemotherapy, but these agents are not as effective after tumor progression on a nonsteroidal aromatase inhibitor. Kathy alluded to the EFECT data, which showed a similar benefit when comparing fulvestrant to exemestane for postmenopausal women with hormone receptor-positive breast cancer progressing on a nonsteroidal aromatase inhibitor (1.9). However, the median time to progression was notably short for both agents, so they were equivalently poor in terms of disease management.
DR LOVE: If you felt her disease was hormone insensitive, what chemotherapy regimen would you use?
DR MILLER: In my mind, we have two alternatives. The first is single-agent capecitabine, which is oral and doesnít cause alopecia or myelosuppression. Given her history, I would be slightly concerned about her bone marrow reserves and her ability to tolerate myelosuppressive chemotherapy.
The other option is weekly paclitaxel with bevacizumab, as used in the ECOG-E2100 trial (Miller 2007). This was well tolerated and it also does not cause serious myelosuppression. In addition, it may help her pleural effusion because of bevacizumabís effect on vascular permeability.
DR LOVE: How does that relate to why bevacizumab appears to have a positive impact on ascites in the treatment of ovarian cancer?
DR MILLER: The old name for VEGF was vascular permeability factor because one of the first effects identified of that particular protein was an increase in the leakiness of blood vessels. Inhibiting VEGF tends to have the opposite function, so it increases the strength of tight junctions and decreases leakage of lymphatic fluids into the surrounding tissues.
In ovarian cancer, itís been difficult to determine whether bevacizumab is directly affecting the cancer cells, or whether this major clinical improvement occurs because ascites and pleural effusions are major components of that disease.
DR LOVE: Edith, how would you treat this patient considering you felt her disease was hormone resistant?
DR PEREZ: I would look for a clinical trial because we donít have a single best choice for first-line management of metastatic breast cancer. In the absence of an applicable clinical trial, I would go through the menu of options, and Kathyís approach sounds appropriate.
DR LOVE: Eric, what would be your approach?
DR WINER: I agree with Kathy 100 percent both in terms of using a hormone now and in terms of the chemotherapy options. Iím not terribly confident that bevacizumab adds a great deal to capecitabine in metastatic breast cancer. I may be wrong, but at the moment I believe the data suggest that it doesnít. The point of using capecitabine would be the benefit of an oral regimen.
I also agree that paclitaxel/bevacizumab would be a reasonable alternative.
DR LOVE: Kathy, can you comment on the results of the AVADO trial, evaluating docetaxel with or without bevacizumab, and how it compared to the E2100 data?
DR MILLER: Differences between the patient populations of these two studies were minimal. The eligibility criteria were virtually identical. The AVADO trial demonstrated improvements in progression-free survival and response rate by adding bevacizumab to every three-week docetaxel, and the hazard ratios were favorable (Miles 2008).
However, the absolute improvement and the absolute progression-free survival results in the AVADO trial were quite modest compared to the E2100 data (1.10). In addition, the safety profiles were substantially different because of the toxicities associated with every three-week docetaxel.
DR LOVE: Eric, would you tell us about the CALGB-40502 trial?
DR WINER: This study is being led jointly by CALGB and NCCTG. It randomly assigns patients with locally recurrent or metastatic breast cancer to paclitaxel/bevacizumab versus nanoparticle albumin-bound (nab) paclitaxel/bevacizumab versus ixabepilone/bevacizumab (1.11).
The design is simple ó an antimicrotubule agent in combination with bevacizumab. We are asking a host of correlative questions to determine which tumors respond preferentially to one agent versus another.
DR LOVE: Kathy, would you comment on the association between VEGF genetic polymorphisms and outcome after treatment with paclitaxel/bevacizumab for metastatic breast cancer?
DR MILLER: Brian Schneider from our group examined whether host factors, particularly inherited polymorphisms of either the VEGF gene itself or the VEGF receptor 2 gene, might influence benefit or potential toxicities from bevacizumab. Hypertension was the toxicity selected because other side effects are so infrequent that the numbers simply donít exist to conduct this type of analysis.
He found two VEGF-A polymorphisms that clearly predicted improved overall survival for patients treated with paclitaxel and bevacizumab (Schneider 2008). It was fascinating that those two polymorphisms didnít predict an improvement in response rate or progression-free survival, only overall survival. In addition, these polymorphisms had no effect on overall survival for patients treated with paclitaxel alone.
He also found that two VEGF-A single nucleotide polymorphisms (SNPs) seemed to protect patients from developing Grade III or IV hypertension. With only one of those SNPs, only about three to four percent of the patients developed Grade III or IV hypertension.
Perhaps the most interesting finding was that no one who inherited one of the SNPs that portended a better overall survival inherited an SNP that protected them from hypertension. That prompted Brian to investigate whether an association existed between Grade III or IV hypertension and overall survival for the patients who received bevacizumab in the ECOG-E2100 trial, and indeed such an association was apparent.
DR LOVE: Dr De Fusco, would you bring us up to date on this patient?
DR DE FUSCO: After a long discussion with the patient, we decided on chemotherapy, and I prescribed nab paclitaxel and bevacizumab.
She began treatment in February and I administered six months of chemotherapy. By October, no disease was evident on PET or CAT scans. I continued her on bevacizumab, but when we restaged her disease last week, the liver lesions had reappeared. The pleural effusion has not reaccumulated and she is asymptomatic, but her disease-free interval was fairly short. Iím considering fulvestrant as our next step.
DR LOVE: Edith, this patient received almost one year of maintenance bevacizumab. Would you continue it?
DR PEREZ: I usually continue the chemotherapy along with the bevacizumab. I do not automatically discontinue chemotherapy at a set number of cycles because the interaction of those two mechanisms of action may be important for added tumor control ó unless, of course, the patient is experiencing significant toxicity from the chemotherapy.
When a patient does develop disease progression on bevacizumab, I stop it because we donít have any data suggesting that continuing it is a good approach.
DR LOVE: Edith, if after a year of endocrine therapy her disease progressed, would you consider using bevacizumab with chemotherapy again and, if so, with which agent?
DR PEREZ: Yes I would, and I believe ixabepilone would potentially be a good drug for this patient. We donít have any large trial data on this combination, but the preclinical data with bevacizumab and ixabepilone are excellent. I have used it for patients.
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