JC 9.18.17 – HERA trial w/ Drs. Jae Sim, Nagalla, Sadeghi, and Dowell

We had an awesome oncology-themed Journal Club with Dr. Jae Sim presenting the landmark HERA trial (Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer), which was published in NEJM in 2005. This study showed significant improvement in disease-free survival among women with HER2-positive breast cancer treated with 1 year of adjuvant trastuzumab after chemotherapy.

A special thank you to our faculty discussants: Dr. Nagalla at CUH, Dr. Sadeghi at Parkland, and Dr. Dowell at the VA for leading such wonderful discussions!

Below is a summary of the questions/discussions from all 3 sites:

  • Q: Why is this trial special?
    • Dr. Nagalla: It is very unusual in oncology to have a therapy that makes a HUGE difference. More commonly, you have trials showing a small benefit here or there, but nothing as slam-dunk as this trial. When HERA trial was presented at ASCO in 2005, the audience stood up and gave a standing ovation. I had never seen such a thing before. This trial was a huge step forward in the field.
  • Q: How did they come up with the name “trastuzumab” and how do they name these antibodies?
    • Dr. Nagalla:
      • “-mab” stands for monoclonal antibody.
      • The letters preceding the “-mab” tell you where the antibody is coming from. For example, “xi” means xeno and “zu” means humanized.
      • The letters preceding this can tell you about the class of drug. For example, “tu” = tumor, “li” = immunologic system, “ci” = cardiovascular directed antibody.
      • Therefore, tras-Tu-Zu-Mab = tumor-directed, humanized, monoclonal antibody
  • Q: What is HER?
    • Dr. Nagalla: HER stands for human epidermal growth factor receptor. There are 4 classes of HER (1, 2, 3, 4).
  • Q: Why is HER2 unique/interesting?
    • Dr. Nagalla: Interstingly, HER2 does not have a ligand! To form a signal it has to either homo-dimerize or hetero-dimerize, then it signals through tyrosine kinases. The dimerization is crucial to the signaling so drugs that attach to and disrupt the dimerization domain interferes the signaling pathway.
  • Q: What are other ways of interfering with the signaling pathway?
    • Dr. Nagalla: You can either use other drugs that interfere with the dimerization of HER2 (such as pertuzumab) or you can interfere with the downstream tyrosine kinase – Lapatinib is a HER2 tyrosine kinase inhibitor (TKI).
  • Q: Why did they use disease free survival instead of overall survival?
    • Dr. Dowell: Survival benefit takes years to obtain and that would mean a long follow up with the study, extra money, and a lot of work on the patient’s part. Disease free survival is a good marker in this case because it has shown to correlate with overall survival
  • Q: Is the fact that the study was not blinded considered a limitation in this study?
    • Dr. Dowell: Well, the problem with blinding is that nobody really wants to sign up for fake infusions of trastuzumab. Blinding is much more important with softer endpoints. For example, if you asking “Do you feel better?” then not blinding will likely affect the results. However, this study uses hard endpoints like disease free survival and death. Not blinding does not really affect these outcomes. You are either alive or dead or have disease free or have recurrence. So in this study, open label likely did not affect the results as compared with other studies
  • Q: What is the benefit of having such a diverse population?
    • Dr. Dowell: The good thing about the study is the diversity of the patients. This allows for the study to be more generalizable. If you do a study with only blue eyed, left handed, Irish males, this is likely not generalizable to the general population. The diversity improves generalizability.
    • Dr. Sadeghi: Breast cancer treatment nowadays is more homogenous than it was before. During the time of the advent of traztuzumab, treatments were more heterogeneous. The fact that the effect of traztuzumab was present in the setting of all prior treatment reassured the investigators that the effect was specific to traztuzumab and not necessarily to some specific chemo regimen in combination with traztuzumab.
  • Q: Future studies showed a survival of 73% compared with 69% at 12 years, which was significant, but why is it narrow?
    • Dr. Dowell: Well, the important thing to remember is that after the initial study, people who had not received trastuzumab are now eligible to receive it. This likely narrows the survival advantage. For example, if you forbid patient in the “observation” group from ever getting trastuzumab, then the survival at 12 years would likely have been wider.
  • Q: What was the major potential drawback of early release of the interim data?
    • Dr. Sadeghi: Early release of the interim data permitted cross-over from the observation arm to the 1-year treatment arm. When cross-over is allowed, an intention-to-treat analysis may underestimate the effect of the treatment. In other words, the outcomes of the observation arm may begin to look somewhat similar to the treatment arm when crossover occurs because both observation and treatment arms are getting the intervention. As a result, there may be a false null-result. This was not the case in this study, even when re-analysis without intention to treat occurred.
  • Q: What is the cardiac toxicity of trastuzumab vs. drugs like doxorubicin?
    • Dr. Dowell: Remember that trastuzumab, as opposed to Doxorubicin, causes cardiomyopathy in an idiosyncratic way and is usually reversible. Anthracyclines like doxorubicin are dose-dependent and many times irreversible
  • Q: What considerations do you take into account with industry sponsorship when interpreting a paper?
    • Dr. Sadeghi: To get a sense of the effect of sponsorship, one can examine the extent to which the sponsor was involved in the development of the paper. If the sponsor is heavily involved in the steering committee and has significant input into the drafting of the manuscript, the decision to publish the results, the decision on when to release the data, on how the data is stored, then some caution should be taken. However, if this is not the case and the methods are clear, the sponsorship may not result in as much bias.
  • Q: Why was one of the outcomes looking at other malignancies?
    • Dr. Nagalla: Some of the treatments, particularly topoisomerase II inhibitors (Adriamycin) and alkylating agents are associated with things like leukemias and MDS. You typically develop malignancies 2-3 years after Adriamycin and 5-7 years after alkylating agents so the timing is helpful to determine the cause.
  • Q: How do you choose what to treat patients with breast cancer with? What are the options?
    • Dr. Nagalla: There are different types of drugs. SERMS (selective estrogen receptor modulators) like tamoxifen, SERDs (selective estrogen receptor downregulators), aromatase inhibitors (AI) like anastrazole, letrozole, exemestane. AIs inhibit estrogens coming from adrenals and fat. In premenopausal women, most of the estrogens are coming from the ovaries, so AI does not have a role in treating premenopausal women. They are great for postmenopausal women.

Thank you for joining us!

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