Finally! Data in Low-Risk HER2 Breast Cancer
Finally! Data in Low-Risk HER2 Breast Cancer
Dr. Krop: From a practical standpoint, therefore, we felt that a randomized trial was not possible. However, we had the idea for a single-arm study, which was led by Sara Tolaney. It was a single-arm study in which all patients received trastuzumab and weekly paclitaxel for 12 weeks, followed by completion of a year of trastuzumab monotherapy. So basically, it is the ACTH regimen (doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab) without the AC.
Dr. Miller: Yes-- just start in the middle.
Dr. Krop: The idea was that we know that trastuzumab is effective in these HER2-positive cancers. There are data from preoperative studies showing that the paclitaxel/trastuzumab regimen has efficacy. Perhaps you don't need all of the chemotherapy because you are starting with lower-risk patients. That was the statistical design of the study, given that it was a single-arm study: to show that with this treatment, we could exclude a felt-to-be unacceptable rate of recurrence, which was around 9%, and a successful study would show that the recurrence rate was in the 5% range or less.
Dr. Miller: How did we do?
Dr. Krop: The data that Sara presented were quite compelling. The endpoint of the study was disease-free survival, and the 3-year disease-free survival rate in the overall population was 98.7%. There were 10 events, and 8 of those were local or locoregional recurrence or contralateral disease. If you take out the contralateral disease, the disease-free survival at 3 years was more than 99%. So virtually no recurrences; there were 2 distant recurrences out of more than 400 patients who were enrolled.
It's not a randomized study. You can't say that the regimen given to these patients made any difference. Some of them were likely to do well without any treatment, but given that more than one half of the patients had cancers that were larger than 1 cm and 10% had cancers that were larger than 2 cm, compared with historical data, you would expect these patients to have significant rates of recurrence. Yet, with this regimen, there were virtually no recurrences.
Dr. Miller: It allows us to have a very different discussion with patients. Whereas I can't share randomized data with them, in reality, before this trial, I didn't have any data to share with them. We could talk about the pathology series suggesting that their risk was not quite as low as the small tumor size might suggest, but I couldn't extrapolate any treatment data directly to them. So at least now, we have data on 400 patients, to be able to say, "Treated this way, here is what you might expect, good and bad." This is a huge advance, honestly, from where we were for this group of patients.
Dr. Krop: We see it the same way. They are not randomized data; there are caveats to that. It is very reassuring, however, to tell a patient that with this regimen, if you fit into the patient population of this trial, your risk for recurrence is extremely low. That is important information, and our opinion is that these data are practice-changing in that respect. For a patient who fits the criteria of the trial -- a node-negative patient with a small cancer (up to 3 cm) -- this regimen is relatively well tolerated and is associated with an extremely favorable outcome.
It doesn't mean that every patient with a small HER2-positive cancer needs to have treatment. A patient with T1A breast cancer (a cancer that is ≤ 5 mm) may not need any treatment, but for a cancer that you as the physician believe needs to have some treatment, these data are compelling.
Phase 2, Single-Arm Study Changes Practice
Dr. Krop: From a practical standpoint, therefore, we felt that a randomized trial was not possible. However, we had the idea for a single-arm study, which was led by Sara Tolaney. It was a single-arm study in which all patients received trastuzumab and weekly paclitaxel for 12 weeks, followed by completion of a year of trastuzumab monotherapy. So basically, it is the ACTH regimen (doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab) without the AC.
Dr. Miller: Yes-- just start in the middle.
Dr. Krop: The idea was that we know that trastuzumab is effective in these HER2-positive cancers. There are data from preoperative studies showing that the paclitaxel/trastuzumab regimen has efficacy. Perhaps you don't need all of the chemotherapy because you are starting with lower-risk patients. That was the statistical design of the study, given that it was a single-arm study: to show that with this treatment, we could exclude a felt-to-be unacceptable rate of recurrence, which was around 9%, and a successful study would show that the recurrence rate was in the 5% range or less.
Dr. Miller: How did we do?
Dr. Krop: The data that Sara presented were quite compelling. The endpoint of the study was disease-free survival, and the 3-year disease-free survival rate in the overall population was 98.7%. There were 10 events, and 8 of those were local or locoregional recurrence or contralateral disease. If you take out the contralateral disease, the disease-free survival at 3 years was more than 99%. So virtually no recurrences; there were 2 distant recurrences out of more than 400 patients who were enrolled.
It's not a randomized study. You can't say that the regimen given to these patients made any difference. Some of them were likely to do well without any treatment, but given that more than one half of the patients had cancers that were larger than 1 cm and 10% had cancers that were larger than 2 cm, compared with historical data, you would expect these patients to have significant rates of recurrence. Yet, with this regimen, there were virtually no recurrences.
Dr. Miller: It allows us to have a very different discussion with patients. Whereas I can't share randomized data with them, in reality, before this trial, I didn't have any data to share with them. We could talk about the pathology series suggesting that their risk was not quite as low as the small tumor size might suggest, but I couldn't extrapolate any treatment data directly to them. So at least now, we have data on 400 patients, to be able to say, "Treated this way, here is what you might expect, good and bad." This is a huge advance, honestly, from where we were for this group of patients.
Dr. Krop: We see it the same way. They are not randomized data; there are caveats to that. It is very reassuring, however, to tell a patient that with this regimen, if you fit into the patient population of this trial, your risk for recurrence is extremely low. That is important information, and our opinion is that these data are practice-changing in that respect. For a patient who fits the criteria of the trial -- a node-negative patient with a small cancer (up to 3 cm) -- this regimen is relatively well tolerated and is associated with an extremely favorable outcome.
It doesn't mean that every patient with a small HER2-positive cancer needs to have treatment. A patient with T1A breast cancer (a cancer that is ≤ 5 mm) may not need any treatment, but for a cancer that you as the physician believe needs to have some treatment, these data are compelling.