Laura Esserman and Ian Thompson Discuss Strategies for Screening and Treatment of Early-Stage Cancers, and How Clinicians Can Learn From Each Other’s Experiences

Oncology (Williston Park). 30(9):770, 785-786.

Laura J. Esserman, MD, MBA

Ian M. Thompson, Jr, MD

1. Earlier this year, both the US Preventive Services Task Force and the American Cancer Society changed their recommendations, saying that women should begin annual breast cancer screening at age 45, instead of 40. Is there concern that this change will affect early detection and, subsequently, outcomes for the disease?

Dr. Esserman: These guidelines make sense for the average woman. The data support these changes to the guidelines. However, there is a lot of anxiety on the part of women that this kind of change will leave them at risk. The lack of consensus on the guidelines contributes to this concern. The task force guidelines recommend that women in their 40s have a conversation with their primary physician to assess their risk, as well as discuss the pros and cons of screening, and make an informed choice. The problem is that we do not have standards for breast cancer risk assessment. One size does not fit all! We now know that breast cancer is not one disease, but rather many diseases-some that grow quickly and others that are so slow growing that they may never come to clinical attention. We do not treat these conditions the same, so it does not make sense that we screen for them in the same way. However, today, the only real risk stratification we use is age. What we need is a modern-era trial that helps us build the evidence for the optimal screening method. The WISDOM study (Women Informed to Screen Depending On Measures of risk; ClinicalTrials.gov identifier: NCT02620852) is a Patient-Centered Outcomes Research Institute–funded effort from the Athena Breast Health Network that is comparing personalized screening (based on inherited factors-including 9 genes and about 200 single nucleotide polymorphisms-breast density, exposures, and lifestyle) with annual screening starting at age 40. In the personalized arm, we will assign women based on their risk, an age to start and stop, and frequency and modality for screening. We will learn who is at risk for what kind of cancer, and determine if this new approach is just as safe, less morbid (fewer recalls, false-positive biopsies), preferred by women, and whether it promotes prevention. This is an important step forward. It will be open to women across California this year, and across many sites in the United States the following year.

Dr. Thompson: In prostate cancer, there has been a similar controversy, largely due to the high frequency of small tumors in healthy men, which commonly do not grow or cause problems in a man’s lifetime. If screening with the prostate-specific antigen (PSA) blood test is conducted, and all men with any degree of suspicion undergo biopsy, and then if all these men are treated, there will almost certainly be men in whom a prostate cancer death will be prevented, but far more men will be treated unnecessarily. However, with the development of methods to incorporate a range of factors (eg, age, family history, PSA, rectal examination findings, other more sophisticated detection tests, and even genomic factors), we can better predict who is most likely to harbor an aggressive tumor, then perform a biopsy, and, if an aggressive tumor is confirmed, treat him to prevent death. The previous large-scale screening studies showed a reduction in mortality (in the European study[1]), but no change in the US trial, probably due to the high PSA testing rate in men who were not in the PSA testing arm of the US study.[2] What we simply don’t know now is whether implementing screening and treatment, targeted for tumors that are most likely to take a man’s life, will maintain the dramatic fall in prostate cancer death rates that we’ve seen over the past 20 years. Ideally, a study similar to the WISDOM study in breast cancer ought to be conducted for prostate cancer.

2. Lately, there has been a lot of discussion around reclassifying certain early-stage cancers, so that they aren’t actually considered “cancer” anymore. How do you currently approach these indolent tumors in your practice?

Dr. Esserman: We have validated an “ultra-low-risk” threshold on the 70-gene test for invasive cancers in postmenopausal women that shows that there are tumors with very low risk of metastatic recurrence after surgical excision alone. This is for cancers that appear as clinical masses. Finding these early would not improve the chance of survival, since the survival rate of these cancers is already high. So, precursors of these cancers certainly do not need to be found early. It is likely that many cases of ductal carcinoma in situ (DCIS) are precursors of such cancers. DCIS is certainly not an emergency, and depending on the clinical circumstance (if it is hormone receptor–positive), it is possible to try alternatives to surgical excision as a first step. These include watchful waiting or endocrine risk reduction (tamoxifen, if premenopausal, or raloxifene or an aromatase inhibitor, if postmenopausal). There are a number of trials starting around the world (LORD and LORIS in the Netherlands and the United Kingdom, respectively, and COMET in the United States, as well as a registry through the Athena Breast Health Network[3-5]) that are testing alternative approaches to surgery. We have treated DCIS the same way for over 2 decades and have not made much progress in advancing treatment options. We need to learn a lesson from our colleagues in prostate cancer, who took low-risk prostate cancer and offered watch-and-wait options with excellent results at 10 years, changing the standard approach to the management of Gleason 3+3 prostate cancer. The lesson is that if you don’t try a different approach, you can not improve treatment options.

Dr. Thompson: In prostate cancer, we have seen a dramatic change in the management of early-stage tumors. Low-grade, low-volume tumors, which are the most common in American men, are increasingly managed with active surveillance. In this approach, low-grade tumors are monitored carefully, and treatment is reserved for those men who develop signs suggesting that the tumor may cause them harm. In so doing, over half of men may be spared treatment. Increasingly, we are also developing methods, similar to those for screening, which incorporate a range of factors that will predict high-risk tumors, and will personalize follow-up to the tumor’s risk in an individual patient. As such, follow-up may be more intense in a younger man and less frequent in an older man in whom the risk of disease progression at 15 to 20 years is a lesser concern.

3. Treating breast cancer and prostate cancer no longer follows a one-size-fits-all approach, given the recent advances in genetics and genomics. In what areas do you think additional progress toward individualized therapy is still needed?

Dr. Esserman: We need to find better treatments for the highest-risk breast cancers. Women who have fast-growing cancers are not helped with screening. These cancers often arise between normal screens. Thus, we have to optimize treatment. One way of doing so is to start with systemic therapy first (neoadjuvant therapy), learning how tumors respond to treatment. In this setting, new agents can be introduced in the neoadjuvant period, and evaluated for the likelihood of improving the chance that the tumor will completely disappear with treatment. If tumors are eradicated in this treatment period, the chance of survival is much higher. The I-SPY 2 Trial is an example of how to accelerate that chance by testing new agents and combinations in the early high-risk setting[6,7] to discover which tumor types will benefit from which regimens, and therefore will have the greatest chance of success in a small targeted, confirmatory, phase III trial. Once we have improved treatments and better understand the pathways that are targeted, we can work on prevention (by learning who is at risk for what kind of cancer, eg, in the WISDOM study).

Dr. Thompson: In prostate cancer, unlike breast cancer, while there appears to be genetic risk factors, there seems to be a broad range of genetic variants that play a role. More common variants may only slightly increase the risk, and those variants that may have a higher risk are generally seen in only a small percentage of the population. A better method may not be the traditional constitutional genetic approach, but rather to assess genetic changes within the prostate. Even more impressive than our growing ability to examine circulating DNA is our ability to capture prostatic cells from voided urine and then perform detailed genetic analyses. These new methods must be incorporated into carefully designed early detection clinical trials to avoid the substantial biases that are often seen in studies that use “samples of convenience,” which are often collected without regard for selection biases that can confound conclusions.

4. Despite evidence that many early-stage breast tumors are not aggressive, many women are still choosing to have mastectomies in order to prevent future disease recurrence. What do you think is the main reason for patients making this kind of treatment decision, and how can clinicians help their patients avoid overtreatment?

Dr. Esserman: Women are mostly motivated by fear. They are afraid that not taking action will result in them dying of their disease. As we develop better markers that can help us classify tumors as ultra-low-risk, and as we have more confidence in such tests, clinicians can help women feel more comfortable being less aggressive in their treatment selection. Initially, this may be difficult to change, because such an approach is time intensive and most physicians are rewarded for intervening and not taking any risk. However, when the risk is very low, we do a disservice to our patients by not pushing for better, more tailored treatments. Why not just do everything? Because all treatments have complications and side effects. A mastectomy can be psychologically difficult for women, complications from surgery can lead to chronic pain, and reconstructions can result in complications as well, and rarely look as good as the native breast. If treatment is not needed, all of the complications can be avoided. We can learn from the experiences of our colleagues in prostate cancer and perhaps use that to help us make a change in breast cancer.

Dr. Thompson: A man with a low-grade, low-volume prostate cancer, when sitting in a physician’s office, may hear the words, “your biopsy showed prostate cancer,” and ignore the remainder of the conversation as they think about the impact of their cancer diagnosis. What many of us incorporate into our practice is a discussion of the possible outcomes of biopsy before it is performed. Thus, a man who receives the information is pre-educated that one of the outcomes could be a low-grade, low-volume tumor, which is often optimally managed with surveillance. Because of the sexual, urinary, gastrointestinal, and other side effects that can be seen with treatment, it is imperative that, at every step along the way in early detection of disease, men undergoing screening are aware of the implications of the findings beforehand. This approach mitigates the cancer anxiety and allows a better-educated patient to use his own priorities to make an informed decision that is best for him.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet. 2014;384:2027-35.

2. Shoag JE, Mittal S, Hu JC. Reevaluating PSA testing rates in the PLCO trial. N Engl J Med. 2016;374:1795-6.

3. Elshof LE, Tryfonidis K, Slaets L, et al. Feasibility of a prospective, randomised, open-label, international multicentre, phase III, non-inferiority trial to assess the safety of active surveillance for low risk ductal carcinoma in situ-The LORD study. Eur J Cancer. 2015;51:1497-510.

4. Francis A, Thomas J, Fallowfield L, et al. Addressing overtreatment of screen detected DCIS; the LORIS trial. Eur J Cancer. 2015;51:2296-303.

5. Patient-Centered Outcomes Research Institute. Comparison of Operative versus Medical Endocrine Therapy for Low Risk DCIS: the COMET trial. http://www.pcori.org/research-results/2016/comparison-operative-versus-medical-endocrine-therapy-low-risk-dcis-comet. Accessed August 19, 2016.

6. Park JW, Liu MC, Yee D, et al. Adaptive randomization of neratinib in early breast cancer. N Engl J Med. 2016;375:11-22.

7. Rugo HS, Olopade OI, DeMichele A, et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. 2016;375:23-34.