Living with HER2-positive metastatic disease and its consequential anxieties is not a cure. I believe it is theoretically possible to cure metastatic breast cancer. We just aren’t there yet.
—Clifford A. Hudis, MD
We gave up looking for low-volume metastatic disease in the 90s. Maybe it’s time to look at this question again.
—George W. Sledge, Jr, MD
Can metastatic breast cancer ever be cured? This issue was debated at the 32nd Annual Miami Breast Cancer Conference by two experts in the field: George W. Sledge, Jr, MD, Professor of Medicine at Stanford University Medical Center, Palo Alto, California, and Clifford A. Hudis, MD, Chief of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center and Professor of Medicine, Weill Cornell Medical College, New York.
Not Much Has Changed in 30 Years
“This has been a disease for which I sit with the patient, and almost the first words out of my mouth are, ‘You have a disease that’s likely to claim your life,’” Dr. Sledge said. “This conversation has not changed in 30 years.” Despite this discouraging, repetitive dialogue, Dr. Sledge maintained that the field of oncology is “journeying toward a cure and a more positive future.”
Dr. Hudis agreed that the future may be brighter but said the present is still fairly dire. “Don’t mistake my position for pessimism over the ability to prolong life and palliate symptoms. We are doing better,” he acknowledged. “We continue to make remarkable progress. Death rates are falling. But when we focus on metastatic breast cancer, and not all breast cancer, the results are somewhat less impressive,” he indicated.
Steep declines in overall mortality owe more to early detection of nonmetastatic disease, as a result of massive screening programs, Dr. Hudis said. And although patients with de novo metastatic disease and those relapsing after treatment do have somewhat different long-term outcomes, both groups of patients have “a steady progression toward death,” he added.
“Living with disease and the risk of relapse is the definition of not being cured,” Dr. Hudis countered. “I believe, at present, the reality is that we cannot cure metastatic breast cancer.”
What Does ‘Cure’ Really Mean?
Drs. Sledge and Hudis agreed that these two perspectives may relate to how one defines “cure.” With a “statistical cure,” no patient relapses and no patient dies. To the patient, a “personal cure” means death from something other than breast cancer, Dr. Sledge said, adding, “The latter definition is the fruitful one for the patient.”
According to Dr. Sledge, metastatic breast cancer is already being cured. “We cure it in the adjuvant setting when it’s micrometastatic. We cure some patients with oligometastatic breast cancer. We also do a good job with locoregional recurrence,” he indicated, citing data from the recent CALOR trial, which showed an advantage for adjuvant chemotherapy in patients with isolated locoregional recurrence.1
“There are already patients we are curing with metastatic breast cancer,” emphasized Dr. Sledge. “There are patients who, despite my lecture that their disease will take their life, keep coming back and coming back without disease. We all see patients like these.” To Dr. Sledge, the question is not why metastatic breast cancer cannot be cured but why more patients cannot be cured.
Dr. Hudis, on the other hand, cited the “crowd-sourced” definition of cure as “the end of a medical condition” and emphasized that when chronic diseases like diabetes and hypertension are well controlled, they are not believed to be “cured.” The same is true with metastatic cancer, he said.
“Unless we change our definition of cure, the successes described by Dr. Sledge—now and in the future—technically do not fit the bill,” he maintained. “Patients living well with breast cancer are still being treated for breast cancer. A remission is a temporary end to the medical signs and symptoms of an incurable disease.”
Dr. Hudis also offered an anecdote from 1992—a patient with a lesion on the inner surface of the thoracic pleura that was consistent with primary breast cancer. After resection, she received an experimental regimen of interleukin-6, doxorubicin, and thiotepa. “That was her last medical intervention,” he noted.
“The personal cure George described might aptly describe her outcome. It was remarkable, so much so that we have gone back and rechecked her biopsy. But she continues to be in the hands of a medical oncologist, who monitors her for relapse potential,” he said. The patient with an incurable disease has an ever-present risk for relapse, no matter how long the duration of remission, he reiterated.
“If cure is the end of a medical condition, we are, unfortunately, far from this. If we want to label ‘remission’ as a cure and call living with disease and its threat a cure, then Dr. Sledge and I are closer to this issue,” he concluded.
How to ‘Cure’ More Patients
Aside from the nuances of the definition, it is likely that more “cures” are possible. Dr. Sledge proposed three means through which this could happen: finding and treating small metastases, giving the right drugs to the right patients, and using “new” biology to develop new drugs.
The CALOR trial suggested that small (localized) metastatic disease can be successfully treated, he noted, “but we gave up looking for low-volume metastatic disease in the 90s,” after surveillance screening proved incapable of finding small-enough tumors to made a difference in survival.
“Maybe it’s time to look at this question again,” Dr. Sledge suggested, as the definition of “metastasis” shifts downward. New and evolving technology allows for the identification of ever-smaller tumors, including advanced imaging, circulating tumor cells, and circulating tumor DNA. Hopefully, more easily detectable metastatic disease will translate into more curable disease, he said.
Treating the right patient with the right drug “may matter in the metastatic setting,” continued Dr. Sledge. This imperative will become easier, once better biomarkers are discovered.
Part of this challenge is embodied in the National Cancer Institute’s “Exceptional Responder Initiative.” The initiative is collecting cases in which patients have dramatic and long-lasting responses to standard and experimental treatments that were not seen in similar patients on the same treatment. Insights regarding underlying molecular mechanisms of response should be gained from this program, Dr. Sledge suggested.
Finally, it will be important to use “new” biology to develop more effective drugs. A well-established example of this is the identification of HER2 and the development of trastuzumab (Herceptin), which improved median survival from 16 months to 56.5 months. “We simply got better in treating these patients,” noted Dr. Sledge.
But a vexing problem is the emergence of compensatory mechanisms of resistance. “This heterogeneity has defeated much of what we have done in the metastatic setting,” he noted. In tackling this problem, emerging immunotherapies hold promise.
Dr. Hudis agreed that emerging approaches will yield more successes, as more is learned about the heterogeneity of breast cancer at the population and individual levels. Whether they will be “cures” is another matter, he added, noting that tumor biology was not predictive of response to everolimus (Afinitor) in the BOLERO-2 trial.2
“We continue to struggle with the simple idea of targeted therapy and in whom it works,” he commented. “We don’t understand as much about the biology and compensatory mechanisms as we would like.” In Dr. Hudis’ opinion, extending remissions through better science and drugs is more likely to be “delaying the inevitable.”
He noted that even in the HER2 setting, with the unprecedented overall survival improvement gained by combining pertuzumab (Perjeta) with trastuzumab in CLEOPATRA,3 “those patients are on ongoing and, parenthetically, expensive therapy and live with a constant ongoing risk, if not certainty, of eventual progression and continued medical care until their death, potentially from their disease.”
“Living with HER2-positive metastatic disease and its consequential anxieties is not a cure. Waiting for the next shoe to drop is not a cure,” offered Dr. Hudis. “I believe it is theoretically possible to cure metastatic breast cancer. We just aren’t there yet.” ■
Disclosure: Drs. Sledge and Hudis reported no potential conflicts of interest.
1. Aebi S, Gelber S, Anderson SJ, et al: Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): A randomised trial. Lancet Oncol 15:156-163, 2014.
2. Hortobagyi GN, Piccart-Gebhart MJ, Rugo HS, et al: Correlation of molecular alterations with efficacy of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer: Results from BOLERO-2. 2013 ASCO Annual Meeting. Abstract LBA509. Presented June 3, 2013.
3. Swain SM, Baselga J, Kim SB, et al: Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724-734, 2015.