June 2018 Ask the Expert: Questions About Major Research From ASCO
The American Society of Clinical Oncology (ASCO) Annual Meeting provides healthcare providers, health advocates, people with cancer and the media direct access to presentations on the year’s leading cancer research. But sometimes, that research can be complex, or it can be hard to know whether it applies to treatment today.
Living Beyond Breast Cancer sends a staff member to ASCO each year to report on the latest findings. If you followed our daily posts or breaking news from other sources, you may have read about the landmark trials TAILORx, PERSEPHONE and ASTRRA as well as studies on new and upcoming medicines.
This June, LBBC expert Pallav K. Mehta, MD answered your questions about these trials, including how they might change treatment, who they impact, and what they mean for you.
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While there exists an ethical and professional obligation to publish completed clinical trial results for studies involving human subjects in any field of medicine, this does not always happen. Issued in 2016, the final rule of Section 801 of the FDA Amendments Act makes this standard official.
When looking at breast cancer abstracts presented at the annual ASCO conferences from 2009 to 2011, only about 77 percent of the randomized and 52 percent of the non-randomized trials were published by 2015. This means almost one quarter of randomized trials are not getting published. The decision to publish is often influenced by many variables including the size of the trial, whether it's randomized or not, the results, who's sponsoring it, etc. In terms of exactly when a trial will get published in relation to when it was presented, it's often quite difficult to know, though the more mature the data, the sooner it would occur. I assume the question is referring to the PERSEPHONE trial, which is more than likely to ultimately be published given the large size (4,000+ patients), multicenter participation and highly relevant results.
Since the approval of trastuzumab for adjuvant (post-surgery) treatment in 2006, the optimal duration of treatment was determined to be 1 year. The recent PERSEPHONE trial was a 4000+ person trial looking to determine whether 6 months may be just as good — "non-inferior" — to 12 months. The results were positive, meaning that women who received 6 months had similar outcomes as those who received 12, and a few less heart related issues. While it may ultimately be practice changing, with large trials such as this, we really need to be careful in implementing changes too quickly. We will be digging deeper once it is published to look at multiple factors such as statistical design, methodology, and the different subgroups to see who really benefits from this approach.
The class of drugs known as the CDK4/6 inhibitors, of which palbociclib was the first approved by the FDA, has been found to be quite effective in metastatic estrogen receptor-positive, HER2-negative breast cancer both as first and second line therapy. They work by inhibiting proteins involved in cancer cell growth that appear to be produced in much higher amounts in these types of patients. The hormone receptors and the HER2 receptor are completely different and when activated, can stimulate cancer cell growth in different ways. It’s not that we don’t use estrogen and estrogen receptor blockers in HER2-positive cancer and vice versa, it’s just that we only want to use drugs that are appropriate for the specific targets that are present on the cancer we’re treating. It’s also true that cancers that express both estrogen receptors and HER2 may have different mechanisms of growth and resistance to treatment so drugs that target estrogen receptors may not work as well in these patients as they do in patients where estrogen is the primary driver of the disease.
As a result of the benefits seen in this setting, there are many trials now recruiting patients looking at these CDK 4/6 inhibitors (there are now 2 others, ribociclib [Kisqali] and abemaciclib [Verzenio]) in various other situations such as before surgery (neoadjuvant), after surgery (adjuvant), and in HER2-positive metastatic breast cancer. The PATRICIA trial is one of those trials and the interim analysis of the first 15 patients was presented at ASCO this year. While this is too small a number of patients, and too early in the trial to make any definitive statements, it seems about 20 percent (3/15) patients did have some sort of a response. All this really tells us is that there is enough of a signal here to continue recruiting for the trial. So stay tuned!
There were several studies presented at the 2018 ASCO meeting that will impact breast cancer care, but the two that may rise to the level of practice changing in the near term are TAILORx and PERSEPHONE.
TAILORx was a large trial designed several years ago that is looking at using a 21 gene (the genes of the cancer, not the genes you can pass on to your children) signature known as Oncotype DX to determine the role of chemotherapy in early-stage, lymph node-negative, hormone receptor-positive, HER2-negative breast cancer. While this may sound like a narrow population to study, in fact this represents a large number of patients seen by oncologists every day in clinical practice. Oncotype DX reports a Recurrence Score (RS), which has been used since 2004 to both predict the likelihood of metastasis in the next decade after diagnosis and support chemotherapy or not. The Recurrence Score cutoffs have been broken down into three categories: high risk scores are those greater than 30; intermediate risk scores are 19 to 30; low risk scores are under 19. Oncologists have generally been giving chemo to high risk patients and avoiding it in low risk ones. The management of intermediate risk patients has been somewhat difficult, so the TAILORx trial was designed to answer the question. Of note, in TAILORx, so as not to miss patients that may have a small benefit from chemo, the Recurrence Score cutoffs were shifted to the left and the “new” intermediate risk patients were now defined as those given a Recurrence Score of 11 to 25. In TAILORx, women with a recurrence score lower than 11 only received hormonal therapy and those with a recurrence score over 25 received both chemotherapy and hormonal therapy. More than 6,000 women with a Recurrence Score from 11 to 25 were randomized to hormonal therapy alone or both chemo and hormonal therapy. The results of the low risk population were published previously and confirm that chemo is not needed for these women. The results from the intermediate risk population were presented at ASCO 2018 and reveal that chemotherapy is not beneficial for any woman with a recurrence score under 16. Age was an important factor here though, as women over the age of 50 did not benefit from chemo at all in the recurrence score 11 to 25 group. Women under age 50, however, seemed to have slightly different results as there appeared to be a benefit to chemo in these younger women for recurrence scores above 15. That benefit seemed to increase with higher RS, which makes those results that much more believable.
The other trial likely to affect practice is the PERSEPHONE trial which looked at the optimal duration of trastuzumab (Herceptin) in early-stage, HER2-positive breast cancer. The standard of care based on a few trials that were initially presented almost 15 years ago is 1 year. While trastuzumab does not generally result in chemotherapy-like side effects, there is a small risk of reversible damage to the heart muscle. There have been two previous trials, HOG and PHARE, looking at reducing the duration of trastuzumab treatment to 6 months but the results from both of those trials supported the full 12 months. PERSEPHONE was a greater-than-4,000 patient trial looking at 6 months versus 12 months of adjuvant trastuzumab. The results demonstrated that there was no difference in disease-free survival in either group and there was a lower cardiac risk in the group that received it for 6 months versus 12 months. Some valid criticisms however included the fact that our treatment of HER2-positive breast cancer has changed: Over half the patients in the study got trastuzumab after chemotherapy (which is not how we treat patients in the U.S.), and that the follow up for the study is only 4 years right now, which may be too short to see any differences. While this would not yet be considered standard of care for everyone, for patients in whom oncologists are worried about heart function, older patients, or those that are having side effects to trastuzumab, this trial supports shorter therapy.
For background on the PERSPHONE trial, see my response to the question above on practice-changing trials. Given that two previous trials looking at 6 versus 12 months supported the longer duration, we have to be a bit more cautious about applying these results to all early-stage, HER2-positive patients. There are likely subsets that were more appropriate for 6 months and others for whom 12 months was still necessary. I think several questions arise from this, particularly how we interpret this data in an era where a large percentage of HER2-positive patients are getting neoadjuvant chemo (before surgery) and often with an additional agent – pertuzumab (Perjeta) – that may now be continued in the adjuvant (after surgery) setting. And to complicate matters further, there is an oral HER2 drug – neratinib (Nerlynx) – that has shown benefit in HER2-positive patients who take it for 1 year after completing 1 year of trastuzumab. Finally, in those patients whose HER2-positive cancer recurs, it can often take several years and the PERSEPHONE trial for now only has 4 years of follow up which may be too short to see these recurrences.
If chemotherapy has already started, it’s likely your oncologist has already determined for you whether the Oncotype DX study was appropriate. While there is a large population of patients for whom the test is used, there are still many patients – e.g., lymph node positive, hormone receptor-negative, HER2 positive – for whom the test is either not reliable, not appropriate, or simply not needed. You may want to ask why Oncotype DX was or was not ordered to get some clarification.
It seems that while women over the age of 50 did not benefit from the addition of chemotherapy to hormonal therapy with a Recurrence Score of 11 to 25, the same could not be said for women under age 50. It appears that even for a Recurrence Score as low as 16, there was a benefit to chemotherapy and that benefit increased with the higher scores. One plausible explanation, though not looked at in this study, is that chemotherapy in younger women resulted in menopause, and we know from the previous data from the SOFT/TEXT trials that stopping ovarian function improves outcomes in premenopausal women. It’s important to remember, however, that decisions for chemotherapy are never black and white. There are many variables an oncologist considers when making this decision, and we should not use this Recurrence Score in a vacuum. The benefit to chemotherapy in young women with scores from 16 to 25 does not appear to be nearly as great as in the original data with Recurrence Scores above 30, so the discussion around risk and benefit is vital. For more on TAILORx, see my response on the biggest news out of ASCO above.