Take that, Mike Adams! The TAILORx study vs. the alt-med stereotype of oncologists anxious to administer toxic chemotherapy

I didn’t attend the this year’s ASCO (American Society of Clinical Oncology) meeting, which wraps up today. The reason is simple. I had attended the Society of Surgical Oncology (SSO) and the American Association for Cancer Research meetings in March and April, respectively. ASCO was just one meeting too many in too short a time. Also, I’m a surgeon, and ASCO tends to be a bit more medical oncology-oriented, with lots of presentations of trials testing this chemotherapy regimen against that chemotherapy regimen for cancers I don’t treat, like the various leukemias. Still, this year, I kind of wish I had attended, because the results of a trial (the TAILORx trial) were being presented, and those of us who specialize in breast cancer have been waiting for a long time. I also wanted to discuss the results of this trial as a rebuke to certain alternative medicine mavens who claim that all we cancer doctors want to do is to cut, poison, and burn—but especially poison. After all, if you peruse certain websites, you might get the idea that oncologists are anxious to poison people with cancer using toxic chemotherapy regimens. Basically, the TAILORx trial has defined a rather large subgroup of breast cancer patients who do not benefit and therefore do not require chemotherapy. The details will follow, but first let’s back up a bit.

I’ve discussed the difference between primary treatment and adjuvant treatment with chemotherapy on a number of occasions. Indeed, confusing the difference is one of the main reasons why testimonials for cancers treated primarily surgically can sound convincing to those not familiar with cancer biology and treatment. Basically, curative chemotherapy is administered as a primary treatment for a specific cancer. Leukemias and lymphomas tend to be treated primarily with chemotherapy ± radiation (in the case of lymphomas, mainly). Organ tumors, like colorectal cancer, breast cancer, and the like, tend to be treated primarily surgically by extirpation of the cancer and part or all of the affected organ. Through decades of clinical trials for such cancers, it’s been shown that the addition of adjuvant chemotherapy after surgery can decrease recurrence and increase the rate of overall survival. In other words, chemotherapy is “icing on the cake” that decreases the chance of the cancer coming back and killing the patient. This is why so many alternative cancer cure testimonials can sound convincing. When, for instance, Christ Wark beat colon cancer or Suzanne Somers or Hollie Quinn did well after treating their breast cancers with “holistic” treatments, in reality, it was the surgery that they both underwent that “cured” them. Refusing adjuvant therapy, be it chemotherapy in Wark’s case or Tamoxifen in Suzanne Somers’ case, only increased their risk of recurrence. They were lucky enough, however, that that increased risk didn’t manifest itself in a recurrence in their specific cases.

So how does this relate to the TAILORx trial, which was reported over the weekend at ASCO and published early in the New England Journal of Medicine? The stereotype among alt med mavens of oncologists just drooling at the prospect of injecting cancer patients with all manner of horrific toxic chemotherapies feeds into the reasons why patients above were susceptible to the siren songs of quacks and decided to eschew evidence-based treatment for their cancers. Of course, part of the problem with adjuvant chemotherapy for breast cancer is that most of the women who receive it don’t benefit from it. If you take two large groups of women with breast cancer, well-matched for age, tumor type, race, and other factors relevant to how well they do with breast cancer, and then randomize them either to receive chemotherapy or not after their curative surgery for breast cancer, on the whole, the group receiving chemotherapy will have better five year and ten year recurrence-free and overall survival. However, most of those women would have done well anyway, and some would die regardless if they had chemotherapy or not. In only a relatively small percentage of them does chemotherapy make the difference between living and dying. That percentage depends on the pre-chemotherapy risk of recurrence, such that the absolute percentage of women saved by chemotherapy increases in nastier cancers, where the risk of recurrence is higher, but that doesn’t change the essential problem. Toxic therapy is being administered to some women without benefit. Despite this problem, most women for whom chemotherapy is recommended do undergo the treatment, even when the expected survival benefit is in the single digit percentages. It’s also hard to argue with results. Over the last 30 years, mortality from breast cancer has declined by nearly 40%, thanks in large part to better adjuvant treatment regimens after surgery. The authors note the problem the study was designed to address:

Hormone-receptor–positive, axillary node–negative disease accounts for approximately half of all cases of breast cancer in the United States.2 Adjuvant chemotherapy reduces the risk of recurrence,3-5 with effects that are proportionally greater in younger women but that are little affected by nodal status, grade, or the use of adjuvant endocrine therapy.6,7 These findings led a National Institutes of Health consensus panel to recommend adjuvant chemotherapy for most patients,8 a practice that has contributed to declining breast cancer mortality.9 However, the majority of patients may receive chemotherapy unnecessarily.

Yes, one of the most pressing questions in breast cancer for the last few decades has been how to identify which patients will and won’t benefit from chemotherapy, or at least to develop predictive tests that make our assessments of who will and won’t benefit from adjuvant chemotherapy more reliable and accurate. That’s what TAILORx is about. Before you can understand TAILORx, you need to understand a bit about estrogen receptor-positive, HER2-negative, node negative breast cancer, which makes up roughly half of all breast cancer cases diagnosed, and the OncoType DX test (also known as the 21-gene recurrence score assay). This particular assay has revolutionized the treatment of this form of breast cancer, which can be treated by hormonal therapy to block estrogen activity with drugs such as Tamoxifen or aromatase inhibitors.

Basically, the OncoType test is a PCR-based test that measures the levels of 21 genes in the tumor. The genes measured involve estrogen signaling, control of proliferation, and housekeeping genes for normalization. The history of how this test was developed and validated is too long and complex for purposes of this discussion; so I’ll boil down the results. Based on the levels of the various genes, a “recurrence” score is calculated ranging from 0-100 from which the patient’s risk of distant recurrence (metastasis) within 10 years can be estimated. (Note that this estimate assumes that the patient receives adjuvant hormonal therapy, either Tamoxifen or an aromatase inhibitor). The bottom line is that patients with a low recurrence score (17 or lower, and definitely 10 or lower) do not benefit from adjuvant chemotherapy, while those with a high recurrence score (31 or greater) do. The problem is that what to do with patients with an intermediate recurrence score (18-30), which is a large number of patients. Chemotherapy is usually recommended for most of these women. Now here’ the thing. Even with these limitations, the adoption of Oncotype testing has already decreased the use of chemotherapy in this patient population quite markedly. (Take that, Mike Adams!)

Enter TAILORx, which was designed to answer the question of where the OncoType recurrence score cutoff should be for recommending chemotherapy. TAILORx is a four-arm clinical trial, in which women were assigned to groups this way after surgery:

  • Recurrence score of 10 or lower (low risk): Hormonal therapy only.
  • Recurrence score of 26 or higher (high risk): Chemotherapy and hormonal therapy.
  • Recurrence score 11-25 (intermediate risk): Randomize to either (1) hormonal therapy only or (2) hormonal therapy and chemotherapy.

Here is the way patients were assigned:

TAILORx design

TAILORx design

So, based on the 10,273 subjects who were assigned or randomized, here is the result:

TAILORx results

TAILORx results


There you have it. There was no difference in disease-free survival or distant recurrence. None, nada, zip:

In the intention-to-treat population, endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease–free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval [CI], 0.94 to 1.24; P=0.26) (Figure 2A). Endocrine therapy was likewise noninferior to chemoendocrine therapy in the analyses of other end points, including freedom from recurrence of breast cancer at a distant site (hazard ratio for recurrence, 1.10; P=0.48) (Figure 2B), freedom from recurrence of breast cancer at a distant or local–regional site (hazard ratio for recurrence, 1.11; P=0.33), and overall survival (hazard ratio for death, 0.99; P=0.89).

And:

In this prospective, randomized trial, we found that among 6711 women with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer and a midrange recurrence score of 11 to 25 on the 21-gene assay, endocrine therapy was not inferior to chemoendocrine therapy, which provides evidence that adjuvant chemotherapy was not beneficial in these patients. This finding contrasts those of previous biomarker validation studies that were performed retrospectively with the use of archival tumor specimens, in which a substantial benefit for the prevention of distant recurrence has been found for the combination of chemotherapy and endocrine therapy in patients with a recurrence score of 26 or higher.12,13 The 9-year rate of distant recurrence in women with a recurrence score of 11 to 25 in our trial was approximately 5%, irrespective of chemotherapy use, a finding consistent with that predicted from the original report showing a significant treatment interaction between chemotherapy benefit and a recurrence score of 26 or higher.14 Updated results for patients with a low recurrence score of 10 or less, who were previously reported as having a 1% distant recurrence rate at 5 years in our trial,18 now indicate a 9-year rate of distant recurrence of approximately 3%.

The authors also did some exploratory subgroup analyses to determine if there might be benefit due to chemotherapy in specific subgroups. They did find that younger women with a recurrence score less than 25 might still benefit from chemotherapy under certain conditions:

The results of our trial suggest that the 21-gene assay may identify up to 85% of women with early breast cancer who can be spared adjuvant chemotherapy, especially those who are older than 50 years of age and have a recurrence score of 25 or lower, as well as women 50 years of age or younger with a recurrence score of 15 or lower. Ongoing clinical trials are obtaining additional information on the clinical usefulness of the 21-gene assay in women with hormone-receptor–positive breast cancer and positive axillary nodes33 and evaluating the clinical usefulness of the 50-gene assay in this context.34

That’s right. Oncologists and scientists already have their eyes on another group of women who might be able to forego chemotherapy after surgery for breast cancer, women with cancer in one or two lymph nodes, all of whom currently receive a recommendation for chemotherapy now, barring medical contraindications. There’s also another test out there (the MINDACT) that used a different gene test, the MammaPrint. It’s not as widely used as OncoType (yet), but has the advantage of having been validated for more than just hormone receptor-positive cancers. I discussed the MINDACT trial back when it was published in 2016.

The bottom line is that, contrary to the stereotype quacks promote of oncologists, we don’t like the status quo, in which many women who won’t benefit from chemotherapy receive it anyway because we know chemotherapy saves the lives of some women but haven’t had good tests to predict which women will benefit and which women will not. As I’ve said before, while it is true that there are a lot of women who receive chemotherapy who probably didn’t need it, it’s not because oncologists want to give lots of chemotherapy, and it’s not based on profit motive. It’s because we couldn’t predict which of these women will benefit from chemotherapy. Gene tests like the OncoType and MammaPrint are now changing that. At the very least, we can now predict, albeit not 100% by any means, which individual women are highly unlikely to benefit from chemotherapy, and oncologists are acting on that knowledge. And guess what? Oncologists don’t mind at all. In fact, they like it. It turns out that cancer doctors don’t like to administer chemotherapy to women who are very unlikely to benefit from it and continue to work on ways to reduce that number and make sure only the women who are likely to benefit from chemotherapy receive it. As a result of TAILORx, thousands of women who would have received a recommendation for chemotherapy in the past will be able to forego chemotherapy.

Take that, Mike Adams!