Destiny Breast 04 was presented at the American Society of Clinical Oncology (ASCO) Annual Meeting on June 5, 2022, as part of the Plenary Session — cancer’s biggest stage. The clinical trial enrolled patients with metastatic (StageIV) “Her2-low” (more on that soon) breast cancer that had previously progressed on both endocrine therapy AND one or two lines of chemotherapy and randomized them to either “usual chemotherapy” or a novel antibody drug conjugate, Trastuzumab Deruxtecan. And the results changed the very foundation of how we treat breast cancer. So, let’s break this down slowly in plain talk.

  • Metastatic breast cancer/Stage IV: This is breast cancer that has spread outside the breast or the lymph nodes to somewhere else in the body. This is breast cancer that is not curable.
  • Hormone receptor positive: Breast cancer that is positive for Estrogen Receptor (ER) or Progesterone Receptor (PR)
  • Hormone receptor negative: Negative for ER and PR. When patients are negative for the hormone receptor AND Her2, this is classically when we use the phrase “triple negative breast cancer.”
  • Her2 Low: This part is brand new. This is the earth-shattering part. We have never defined breast cancer like this before. Before Destiny Breast 04, breast cancer was binary — positive or negative. But the devil is in the details. We typically use a test called Immunohistochemistry (IHC) to score breast cancer on a scale of 0 – 1 – 2 -3. On this scale 0- 1 are negative, 2 gets extra testing, 3 is positive. The extra test for 2 is an ISH (in situ hybridization) and is either positive or negative—so you can be 2 and ISH negative, thus negative for Her2 or 2 and ISH positive, thus positive for Her2. BUT NOW, we have patients that are her2 0 (negative), her2 1 or Her2 2 ISH negative (Her2 Low), or Her2 2 ISH positive or Her2 3 (positive). Clear as mud, right?
  • The usual chemotherapy included the treating physician’s choice of capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel. These are great drugs and a very typical trial design that allows the physician and patient to choose based on side effects and dosing schedule what makes the most sense for each patient.
  • An antibody drug conjugate is a chemotherapy (drug) connected via a linker (conjugate) to an antibody — a target-seeking compound that specifically targets a cancer. In the case of trastuzumab deruxtecan, the antibody is Her2. And this drug has already been approved for the treatment of metastatic Her2+ breast cancer in the practice-changing trial Destiny Breast 03.

So what happened?

Dr. Shanu Modi presented data that showed that Trastuzumab Deruxtecan (“TDxd” for short) improved both progression-free survival and overall survival as compared to chemotherapy of physician’s choice for Her2 low breast cancer for both Hormone receptor positive and Hormone receptor negative breast cancer. The data was reported, due to the statistical design (that’s probably a separate blog post!), as hormone receptor positive disease and all-comers (hormone receptor positive and hormone receptor negative together).

In hormone receptor positive, Her2-low metastatic breast cancer, patients who were treated with trastuzumab deruxtecan saw the time until their cancer started to grow improved (“progression free survival”) by 4.7 months, and lived 6.4 months longer (overall survival). Among the all-comer group, the trastuzumab deruxtecan treated patients saw slower time to cancer growth by 4.8 months and lived 6.6 months longer (overall survival). Inflammation of the lungs occurred in 12.1% of patients in the trastuzumab deruxtecan treated patients, although most of it was mild. Nausea was another common side effect. This all means that patients with Her2-low breast cancer, a new subgroup of breast cancer, live longer when treated with this new drug which is a practice-changing response

Now what?

This work was published simultaneously in the New England Journal of Medicine and most breast experts an approval from the FDA to follow. Meanwhile, trastuzumab deruxtecan (Enhertu®) is being explored in clinical trials in earlier phases of disease across numerous definitions of disease, including curable, early-stage settings, and asking for and participating in clinical trials with this drug are an exciting option for patients. Importantly, all breast cancer patients should get curious about the details of their Her2 status beyond the binary status of “positive” and “negative” to know where they fall on the Her2 spectrum.



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