HER2 Support Group Forums - View Single Post - Risk of Recurrent Disease in HER2-Positive Patients

Hopeful · 03-11-2010, 07:44 AM

Robert S. Mocharnuk, MD:
Mansell and colleagues^[33] presented data from a study that evaluates the influence of HER2 on recurrence patterns in estrogen receptor–positive early breast cancer (Capsule Summary).

William J. Gradishar, MD, FACP:
Mansell and colleagues^[33] analyzed prognostic factors in a dataset of 402 ER-positive patients with early-stage breast cancer and found that HER2-positive patients (12.7%) were at significantly increased risk of developing recurrent disease within 2.5 years after diagnosis compared to HER2-negative patients. In addition, at 2.5 years, DFS was 74.5% (95% CI: 68.4-80.6) in HER2-positive patients compared with 90.1% (95% CI: 88.5-91.7) in HER2-negative patients. Aromatase inhibitors were also found to reduce the risk of recurrence in HER2-positive patients.

This study demonstrated that HER2-positive patients developed recurrent disease at a peak of about 2.0-2.5 years, which is different than what we see with HER2-negative patients who had more of a consistent annual risk of recurrence during the study period. HER2-positive, ER-positive patients were at much higher risk of recurrence, which is supported by results of trials in similar patients with metastatic disease. Progression-free survival is much shorter in patients receiving hormonal therapy alone. These study findings support the idea of targeting both pathways and indicate that hormonal therapy will not suffice.

Paul E. Goss, MD, PhD, FRCPC, FRCP:
Only a small subset of ER-positive patients had HER2-positive tumors, but this is an important subset of patients. It is possible that HER2 positivity confers a degree of tamoxifen resistance; preclinical and other data suggest that the HER2 positivity may cause tamoxifen to behave like an estrogen, and actually drive breast cancer growth or at least be less effective. Blocking HER2 activity is important on ER-positive disease.

The findings in this study suggest that early use of an AI is strongly superior to tamoxifen, because it helps prevent the early recurrences to which HER2-positive patients are susceptible. However, neither of these treatments may be the optimal endocrine therapy because HER2 positivity confers ligand-independent signaling to the ER response element machinery. Consequently, fulvestrant, rather than tamoxifen or AIs, may be particularly useful in preventing the HER2 pathway from stimulating the ER pathway.

In general, ER-positive patients, if they are also HER2 positive, receive short-term anti-HER2 therapy and long-term antiendocrine therapy, and this may not be the optimal approach. Concurrent ongoing blockade of the HER2 pathway may be more fruitful. That may be in contrast to the situation with ER-negative patients, in whom short-term anti-HER2 therapy may be sufficient. I think these issues have yet to be confirmed in clinical trials.

Daniel F. Hayes, MD:
What I find interesting about this study is that with ER-positive cancer there is an ongoing risk of recurrence for a long period of time. It looks as though there is a secondary spike between 8 and 12 years. Dr. Goss did not necessarily agree with that, but there have been some reports of this, whereas in ER-negative patients, the tumor recurs within the first 5-7 years or it does not recur. But it seems as though the risk of recurrence after a long period of time diminishes, and in this way, HER2-positivity may make the tumor behave more like an ER-negative rather than an ER-positive tumor. I agree with the point Dr. Goss made that this study includes only 4 years of follow-up, and only very small numbers are included in the longer-term follow-up. Ultimately, this study may not help clarify what happens over the long term.

Paul E. Goss, MD, PhD, FRCPC, FRCP:
Dr. Hayes raises a very interesting point. The peak at 2.5 years in HER2-positive patients is valid, and there is unquestionably a sharp spike of recurrences early in ER-positive, HER2-positive breast cancer. That is the issue addressed in this paper. But what Dr. Hayes is suggesting is very interesting. HER2 positivity drives the risk of recurrence, even many years later during follow-up. However, I am not sure how dependent this result is on ER expression and how early anti-HER2 therapy may influence long-term recurrence risk.

William J. Gradishar, MD, FACP:
This paper may encourage long-term study of different durations of anti-HER2 therapy

03-11-2010, 07:44 AM	#2
Hopeful Senior Member Join Date: Aug 2006 Posts: 3,380	Re: Risk of Recurrent Disease in HER2-Positive Patients Robert S. Mocharnuk, MD: Mansell and colleagues^[33] presented data from a study that evaluates the influence of HER2 on recurrence patterns in estrogen receptor–positive early breast cancer (Capsule Summary). William J. Gradishar, MD, FACP: Mansell and colleagues^[33] analyzed prognostic factors in a dataset of 402 ER-positive patients with early-stage breast cancer and found that HER2-positive patients (12.7%) were at significantly increased risk of developing recurrent disease within 2.5 years after diagnosis compared to HER2-negative patients. In addition, at 2.5 years, DFS was 74.5% (95% CI: 68.4-80.6) in HER2-positive patients compared with 90.1% (95% CI: 88.5-91.7) in HER2-negative patients. Aromatase inhibitors were also found to reduce the risk of recurrence in HER2-positive patients. This study demonstrated that HER2-positive patients developed recurrent disease at a peak of about 2.0-2.5 years, which is different than what we see with HER2-negative patients who had more of a consistent annual risk of recurrence during the study period. HER2-positive, ER-positive patients were at much higher risk of recurrence, which is supported by results of trials in similar patients with metastatic disease. Progression-free survival is much shorter in patients receiving hormonal therapy alone. These study findings support the idea of targeting both pathways and indicate that hormonal therapy will not suffice. Paul E. Goss, MD, PhD, FRCPC, FRCP: Only a small subset of ER-positive patients had HER2-positive tumors, but this is an important subset of patients. It is possible that HER2 positivity confers a degree of tamoxifen resistance; preclinical and other data suggest that the HER2 positivity may cause tamoxifen to behave like an estrogen, and actually drive breast cancer growth or at least be less effective. Blocking HER2 activity is important on ER-positive disease. The findings in this study suggest that early use of an AI is strongly superior to tamoxifen, because it helps prevent the early recurrences to which HER2-positive patients are susceptible. However, neither of these treatments may be the optimal endocrine therapy because HER2 positivity confers ligand-independent signaling to the ER response element machinery. Consequently, fulvestrant, rather than tamoxifen or AIs, may be particularly useful in preventing the HER2 pathway from stimulating the ER pathway. In general, ER-positive patients, if they are also HER2 positive, receive short-term anti-HER2 therapy and long-term antiendocrine therapy, and this may not be the optimal approach. Concurrent ongoing blockade of the HER2 pathway may be more fruitful. That may be in contrast to the situation with ER-negative patients, in whom short-term anti-HER2 therapy may be sufficient. I think these issues have yet to be confirmed in clinical trials. Daniel F. Hayes, MD: What I find interesting about this study is that with ER-positive cancer there is an ongoing risk of recurrence for a long period of time. It looks as though there is a secondary spike between 8 and 12 years. Dr. Goss did not necessarily agree with that, but there have been some reports of this, whereas in ER-negative patients, the tumor recurs within the first 5-7 years or it does not recur. But it seems as though the risk of recurrence after a long period of time diminishes, and in this way, HER2-positivity may make the tumor behave more like an ER-negative rather than an ER-positive tumor. I agree with the point Dr. Goss made that this study includes only 4 years of follow-up, and only very small numbers are included in the longer-term follow-up. Ultimately, this study may not help clarify what happens over the long term. Paul E. Goss, MD, PhD, FRCPC, FRCP: Dr. Hayes raises a very interesting point. The peak at 2.5 years in HER2-positive patients is valid, and there is unquestionably a sharp spike of recurrences early in ER-positive, HER2-positive breast cancer. That is the issue addressed in this paper. But what Dr. Hayes is suggesting is very interesting. HER2 positivity drives the risk of recurrence, even many years later during follow-up. However, I am not sure how dependent this result is on ER expression and how early anti-HER2 therapy may influence long-term recurrence risk. William J. Gradishar, MD, FACP: This paper may encourage long-term study of different durations of anti-HER2 therapy