Edited excerpts from the discussion:

DR ZELKOWITZ: This 64-year-old woman was very healthy until she presented to her primary care doctor with a cough and shortness of breath. She was given the typical Z-pack, but didn’t get better.

An x-ray showed a very large left-sided effusion. The doctor sent her for a CAT scan, which confirmed the presence of a large loculated effusion, mediastinal adenopathy, multiple bilateral small pulmonary nodules and probably a lesion in her left breast or on her chest wall. I may add that she had recently had a mammogram, which was reported to be normal.

She was referred to a pulmonologist for a thoracentesis, which revealed a poorly differentiated adenocarcinoma. She was referred to one of my partners with the diagnosis of lung cancer versus unknown primary. He commented that the lesion was likely to be in her breast.

She underwent a biopsy of the breast lesion, which revealed a poorly differentiated, triple-negative infiltrating ductal carcinoma.

DR LOVE: What was her medical condition at that point?

DR ZELKOWITZ: Prior to that, she was very healthy and enjoyed a wonderful quality of life. By the time she saw my partner, she was sick. She was very short of breath.

DR LOVE: How short of breath was she?

DR ZELKOWITZ: From the time of her diagnostic thoracentesis until seeing the oncologist, which was a week, she went back and had a second thoracentesis.

DR LOVE: Is it possible to differentiate how much of the shortness of breath is from the fluid, as opposed to the parenchymal disease?

DR ZELKOWITZ: I think part of it was from the fluid, but even after thoracentesis, she was short of breath.

DR LOVE: Would you talk more about her lifestyle?

DR ZELKOWITZ: Her husband was retired.They were well set financially and spent most of their time traveling.

DR LOVE: Did she fit the picture of metastatic or visceral crisis in your mind?

DR ZELKOWITZ: She certainly did.

DR LOVE: Vicente, how would you think this case through?

DR VALERO: My approach for chemotherapy-naïve patients with newly diagnosed metastatic breast cancer, especially for those with triple-negative disease, is to use a combination regimen. I know that some people use sequential therapy, but in this particular setting our group would be more in favor of combination therapy. A reasonable approach would be to administer FAC or TAC since the patient is quite symptomatic and has several organs involved.

DR LOVE: If you had to guess, which combination would it most likely be?

DR VALERO: I would consider TAC chemotherapy.

DR LOVE: What about bevacizumab?

DR VALERO: In the first-line setting, that would also be a great option to use in combination. Since the safety of TAC and bevacizumab is not very well established, giving her paclitaxel/bevacizumab would be very reasonable in this patient with triple-negative breast cancer.

DR CHLEBOWSKI: Our choices of first-line therapy have changed, and I must admit, for me, San Antonio changed another thing, too, because we had the paclitaxel/bevacizumab data before (Miller 2005b). We weren’t using much of it because we didn’t come back to a taxane after an adjuvant taxane. It doesn’t apply to this case, but we have used almost none for that reason.

Then the subgroup analysis demonstrated that the benefit, surprisingly, was even greater in the 20 percent of patients who had received an adjuvant taxane previously (Miller 2005b). That moved it to a competitive first-line therapy. For patients who had prior paclitaxel and anthracycline, the data were as good as anything, because we’d only had Phase II data for weekly nanoparticle paclitaxel or capecitabine. So that would be a competitive therapy.

Before San Antonio, we would probably have treated this patient with carboplatin and docetaxel. Interestingly, the data suggesting that platinums might be better for the “triple negatives” are all preclinical. We’ve treated many patients who presented with locally advanced tumors with neoadjuvant therapy, and we were spectacularly unimpressed with AC or taxanes in these triple negatives; everybody receives three or four cycles and then goes to surgery with not much change.

I think I’d use carboplatin and docetaxel versus paclitaxel and bevacizumab. We couldn’t give carboplatin/paclitaxel and bevacizumab; our chemotherapy pharmacy wouldn’t let us do that because we couldn’t show them Phase II or toxicity data on that combination.

DR LOVE: It’s been interesting, Vicente, looking at the evolution of bevacizumab, first in colon cancer, where it got picked up right away, and then we have some data in lung cancer, and we’re waiting for regulatory bodies to bless that. From talking to lung cancer researchers, I know they’re ready to use it with carboplatin/paclitaxel. In breast cancer, the response has been a little bit more mixed.

DR VALERO: I think that Rowan is right on target. One of the reasons bevacizumab hasn’t been used as much is that 20 percent of patients are basically being moved to use trastuzumab-based therapy, so we have fewer patients in the box. Additionally, we have patients who are hormone receptor-positive. This is more for the triple-negative breast cancer, like this patient. In our institution, we have been using taxanes for 10 years, so the majority of the patients we see have been exposed to taxanes.

In this trial, a small number of patients received taxanes, and they had to have more than a one-year disease-free interval. So the patients that we’re seeing have been taxane exposed and anthracycline exposed, and that’s the reason I don’t think it has taken into full blow the use of bevacizumab.

In triple-negative disease, like this case, the use of paclitaxel and bevacizumab with or without another drug would be my preference.

DR LOVE: Rowan, can you comment on this issue of the added benefit, clinically, particularly in the face of a relatively nontoxic treatment?

DR CHLEBOWSKI: These data were impressive, and the more I think about it, it becomes a spectacular result. The idea that this regimen of paclitaxel/bevacizumab had this big effect — 11 versus six months time to progression — in patients who were almost exclusively not HER2 overexpressers makes this one of the cleanest observations of that population that we have.

It took me a while to think through the issue. The taxanes in the no-subgroup interaction produced a tremendous result, suggesting that bevacizumab really is making the taxane therapy more effective. I think we’re going to see a lot more use of that as it evolves.

The other part of this consideration is the toxicity issue. People talk about proteinuria and blood pressure, and that’s okay; these can be managed. Very little bleeding was apparent, because there’s nothing to bleed, especially in early-stage patients.

Another aspect is desperation. The lung cancer population had nothing. They’re desperate because patients might have 12 months median survival. In breast cancer, you have so many therapies, you would need a more compelling reason to adopt this as your first choice.

DR LOVE: Putting aside the economic issue, if I’m the patient and I can take a relatively nontoxic therapy and double my time to progression, that sounds pretty good to me.

DR CHLEBOWSKI: Yes, that’s right.

DR LOVE: Alan?

DR ASTROW: Cliff Hudis suggested that for the first line, he’s basically administering bevacizumab with any number of chemotherapy drugs. I’m wondering what our speakers think of combining bevacizumab with other drugs for which we have no published data?

DR VALERO: Many regimens have been used with bevacizumab in other diseases (D’Adamo 2005; Hainsworth 2005; Herbst 2005; Hurwitz 2004, 2005; Johnson 2004; Kabbinavar 2005a, 2005b; Miller 2005a, 2005b; Kindler 2005). I wouldn’t have a problem using paclitaxel/carboplatin with bevacizumab for this triple-negative breast cancer patient. It has been used in other settings, so safety data exist on it, but you could stick with the specific data and use weekly paclitaxel with bevacizumab.

It was very well tolerated. The response rate is substantial in symptomatic patients such as this one, and this is the largest gain in time to progression that we have seen in clinical trials using chemotherapy that I’m aware of. I don’t think the data with the paclitaxel/carboplatin versus paclitaxel were as substantial as the data for the bevacizumab/paclitaxel versus paclitaxel alone.

DR LOVE: When you started treating this patient, were the bevacizumab data out yet?

DR ZELKOWITZ: She presented shortly after the ASCO meeting. We were sort of in a void between the bevacizumab data coming out at ASCO and getting the information to the insurance companies. We did discuss bevacizumab and attempted to get approval for it. In the interim, she was started on docetaxel and capecitabine.

DR LOVE: How did she tolerate the capecitabine and docetaxel?

DR ZELKOWITZ: She got better and felt better.

DR LOVE: Did she experience any side effects? Hand-foot syndrome?

DR ZELKOWITZ: She’s had some hand-foot that’s evolved over time, but no major toxicity. I very infrequently use doublets, but she was sick enough to warrant the doublet, and she got better.

DR LOVE: What happened?

DR ZELKOWITZ: About six to eight weeks later, she felt better and we had approval for bevacizumab. At that point, I wanted to do a CAT scan to confirm that she was responding and, sure enough, she was. Her effusions and mediastinal adenopathy were smaller. Her nodules appeared smaller, and she had what the radiologist described as a pulmonary embolism. She had received her first dose of bevacizumab right before her CAT scan. So she was admitted to the hospital for anticoagulation. She switched from heparin to warfarin, and then the decision was whether or not to continue the bevacizumab.

DR LOVE: Rowan?

DR CHLEBOWSKI: Would a pulmonary embolus be more likely to be a bleeding site? I’d probably have to say yes, so I’d be reluctant to continue the bevacizumab or would try to find out whether somebody’s done that before.

DR LOVE: Vicente?

DR VALERO: You just started the bevacizumab, so the benefit was with the docetaxel/capecitabine combination. It would be hard to defend using bevacizumab because she has thrombosis and you’re going to use anticoagulation. What are the safety data for that setting? I would just continue what you were doing before.

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