MIAMI BEACH—Metastatic breast cancer is currently a lethal disease for the great majority of patients, but will it always be so? That was the subject of a provocative debate here at the Miami Breast Cancer Conference.
On the pro side, George W. Sledge, Jr, MD, Professor of Medicine and Chief of Medical Oncology at Stanford University School of Medicine, channeled his “inner Pollyanna,” as he put it, and argued that metastatic breast cancer is ultimately “just a disease,” and as such is ultimately amenable to human intervention.
Clifford A. Hudis, MD, Chief of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center, starting out by acknowledging himself as a “hard-bitten New Yorker,” pointed out that there has never been a study in which cure has been suggested as the result of treatment for metastatic breast cancer.
As with many medical debates, though, each side saw merits in the points of the other, and in the end both expressed hope for the future.
Sledge: ‘Embrace Your Inner Pollyanna’
Sledge opened with a downer, admitting that it would be easy to take the con position in this debate. “When I sit down with a patient with metastatic breast cancer, almost the first words out of my mouth are: ‘You have a disease that is likely to claim your life.’ That has not changed in 30 years, though we've certainly made many real improvements and delayed things.”
But then he asked the audience to “embrace your inner Pollyanna, and take a journey with me towards a cure, a journey towards a more positive future.”
Working definitions are always helpful, and Sledge provided three: “To a statistical purist, [a cure means] no one relapses and no one dies. For the patient there is the personal cure, to die of something else. And the corollary to that is the definition of the word ‘specialist’—a doctor who wants his patient to die of some other doctor's disease.”
He continued with the second definition as the more fruitful for his patients in the clinic. Some cases of metastatic breast cancer are already cured, Sledge said: in the adjuvant setting, where it is micrometastatic disease but still metastatic; and with oligometastatic breast cancer, as the CALOR (Chemotherapy for Isolated Locoregional Recurrence of Breast Cancer) trial has shown recently (Aebi et al. Lancet Oncology 2014;2:156-163).
“So the question is not why can't we cure, but rather why don't we cure more?” he said.
Clearly the size of the recurrence matters, he said, which the outcomes in the CALOR trial show—i.e., that the same chemotherapy given to a patient with a large tumor will not cure one that has micrometastases.
There may be a simple explanation, he said, that given a large enough tumor, there will be a number of mutational events that allow the development of resistant clones—and clearly biology in the form of drug resistance matters, he said.
To improve the cure rate, Sledge suggested undertaking a research program with three elements: find and treat smaller metastases; give the right drugs to the right patients; and then use new biology to develop new drugs.
Starting with the first element, Sledge said the CALOR trial suggests that it is possible to treat small-volume metastatic disease successfully: “I don't know any other rational explanation for the CALOR data. We gave up looking for low-volume metastatic disease in the 1990s, as a result of two studies from Italy that looked at surveillance screening and came to the same conclusion, that surveillance screening with the surveillance available at that time was not capable of finding tumors small enough to be cured.
“Maybe it's time to start looking at this question again, because we indeed have new technology. Imaging has increased steadily over the past two decades, in terms of being able to detect smaller and smaller lesions,” he said.
Circulating tumor cell technology certainly is capable of detecting small-volume disease, he said. And the increasingly exciting technology of circulating tumor DNA probably will make it possible to detect very small recurrences. “In a mouse model we are capable of finding a cancer lesion that is smaller than 300 microns,” he said, citing Branca et al: PNAS 2010;107:3693-3697.
“In the words of those who have reported this data: ‘With further optimization, even single cancer cells may become detectable.’ So we're going to reach a point in the relatively near future where we should be able to detect micrometastatic disease. And when we do so,” he said, “we'll need to shift the definition of what it means to have metastatic disease to be something much smaller and detectable earlier. Hopefully this will be more curable, as the CALOR trial suggests.”
‘The Right Patients’
For all of the patients treated and in whom there is a response, and for all the many in whom there is not a response, it is usually not possible to know ahead of time who will respond to what drug—“and that has been because biomarkers for drug response are not good. We need better biomarkers,” Sledge said.
“We certainly have learned so much in recent years about the genomics, proteomics, and epigenomics in cancers that it is reasonable to expect that sometime in the next decade we will have far better biomarkers—not just for whether or not you respond to chemotherapy, a la Oncotype, but whether or not you respond to a specific chemotherapy.”
When that comes to be the case, he said, perhaps we will do a better job of erasing metastatic breast cancer.
Part of this approach, he said, is embodied in the National Cancer Institute's Exceptional Responders Initiative, launched last September, as an attempt to understand the molecular underpinnings of exceptional responses to treatment, primarily via chemotherapy, in cancer patients. The starting assumption is that there is a certain percentage of patients in every Phase II trial with a new agent, no matter how small, who respond, and respond for years.
“We don't know who or why people respond currently,” Sledge said. “But with whole-exome sequencing among these exceptional responders, maybe we'll know more and maybe we will be able to offer our patients more.”
‘The Right Drugs’
Using the right drug in the right patient matters in the metastatic setting, Sledge said, referring to the TNT trial reported at last year's San Antonio Breast Cancer Symposium, which randomized patients with advanced triple-negative or BRCA1/2-positive breast cancer to carboplatin or docetaxel (OT 2/25/15 issue).
He said the outcomes of TNT demonstrate compelling evidence that even within a subtype such as triple-negative breast cancer, some patients will do specifically better, based on whether or not the patient has a BRCA1 or 2 mutation—“Certainly we should be able to increasingly use these sorts of approaches to give the right drug to the right patient,” he said.
We are still improving on existing therapies—for example, for estrogen receptor-positive disease and HER2-positive disease, the overall survival curves are getting better, Sledge continued. “In HER2-positive disease now, some trials show outcomes of 56.5 months overall survival for frontline therapy—compare this with the situation for those of you like me who were practicing in the 1990s, when a HER2-positive patient with metastatic disease might live, on average 15 or 16 months.”
Big Problem is Resistance
The big problem, Sledge said, is the rapid emergence of compensatory mechanisms of resistance, where tumor heterogeneity has impeded most of what has been done in the metastatic setting.
“In multiple areas of human cancer we are seeing a renaissance in terms of immuno-oncologic approaches in treating the disease. This has come about as a result of more sophisticated understanding of how the immune system works. We can now identify the on and off switches for immune activation compounds, such as the molecules CTLA-4, such as PD-1, PDL-1.”
In diseases such as metastatic melanoma, there are populations of patients treated with ipilimumab who are now five and 10 years out from diagnosis and doing well.
An immuno-oncologic approach would certainly appear to be promising, he said, and triple-negative breast cancer may be “low hanging fruit,” because it is highly mutagenized with lots of antigens on the surface that would be good targets in the immune system.
The very first of these studies, a Phase I trial, was presented at last year's San Antonio Breast Cancer Symposium (OT 2/10/15 issue), he noted. “One never wants to make too much of one patient in five in a trial responding, but some of the patients on this trial have been responding for close to a year or more. Are we beginning to see what we've seen in melanoma—a population of patients who are going to be long-term survivors by engaging the body's immune system? It may be that 20 years from now, when Cliff and I are brought back in wheelchairs to this meeting, some of those patients will still be around and their chest x-ray may still show the lump.”
Sledge anticipated Hudis's obvious question: Is this really a cure? “I can promise you that the patient won't care; they'll still be here,” Sledge said.
The Case of the Naked Mole Rat
Sledge concluded his talk with a slide of “the ugliest mammal in existence—the naked mole rat, which lives its entire life underground, slithering around in holes underground, but on average they live about 40 years and never, ever, ever die of cancer.
“Never, okay?” he said. “You can radiate them, give them carcinogens, transplant tumors into them, and they just simply won't die of cancer. Why not?”
As he further explained in a column in OT last fall (10/25/14 issue), the microenvironment does not permit it. The animals create a form of high molecular weight hyaluronic acid that walls off cancer cells immediately, and simply won't die of cancer.
“I ask you, are we really not smarter than naked mole rats?” Sledge concluded. “Join the crusade to cure metastatic cancer, never give up, learn from the naked mole rats and the exceptional responders, or perhaps even the melanoma doctors among us. Don't be a cynical, hard-bitten New Yorker. Embrace your inner Pollyanna!”
Hudis: ‘Living with Metastatic Breast Cancer Is Not A Cure’
In Hudis's presentation, he acknowledged that the con position, that there will never be a cure for metastatic breast cancer, is not an easy position to take, despite his being “a hard-bitten, cynical New Yorker,” as Sledge had called him jokingly for the purposes of the debate: “It isn't what I believe in terms of a long-term future, but I do believe that at the present, the reality is that we can't cure metastatic breast cancer.”
The difference in the two speakers' approaches to this topic may be subtle, Hudis said, but it does boil down to the definition of cure: “The Wikipedia definition of cure is the end of a medical condition,” Hudis said. “We don't cure diabetes, we control it. We don't cure hypertension, we control it, and nobody runs around saying that we've cured those chronic illnesses. So unless we change the definition of cure, the successes that George appropriately described now and in the future, technically don't fit the bill.
“People who are living well with breast cancer are being treated for breast cancer, they are part of the medical system, day in and day out. And while they may not die of the disease, they're very much living with it.”
The definition of a remission is a temporary end to the medical signs and symptoms of an incurable disease, Hudis said. “And that's what George just described.”
The problem with an incurable disease is the there is always a chance that that patient may relapse, no matter how long the patient has been in remission.
Hudis related an anecdote of his own, from the pre-modern era, in 1992: “We were randomizing patients on Bill Peters' high-dose chemotherapy trial for high-risk adjuvant therapy in patients with 10 or more positive lymph nodes. In those days we were screening intensively to put these patients on the trial, and I had a middle-aged woman who had a single, pedunculated lesion on the inner surface of her thoracic pleura.”
The woman underwent a vast procedure, and the lesion was dissected and proven to be metastatic breast cancer, consistent with her ER-positive primary, Hudis continued. “She had 12 positive nodes and was disqualified from the adjuvant transplant trial. She then got three or four doses of an experimental IL-6-Adriamycin combination with thiotepa, hated it, and then quit and went on tamoxifen.
“And that is the last medical intervention that was ever performed on her. Nothing else has ever happened. So the personal cure that George described quite happily described her outcome. It's really remarkable. So much so, that over the years we've gone back and rechecked that last procedure biopsy.
“On the other hand, she very much continues now, decades later, to be in the hands of a medical oncologist who constantly monitors her for both toxicity of her ongoing treatment, and potential for relapse. It is that distinction I'm focusing on here: saying, for the purposes of our discussion, that we will not cure a metastatic breast cancer.”
Make no mistake, Hudis said, death rates are falling. But in metastatic breast cancer, as opposed to all of breast cancer, the results are somewhat less impressive.
“But do not mistake my position for pessimism about the benefits of therapy, and the ability to prolong life, or to palliate symptoms, all of which I think we continue to make remarkable progress in. But again, living with disease and living with the risk of relapse is a definition of not being cured.
“And yes, we've done better, we have changed the median survival, and the expectation of duration of life is improved for these patients. But it's very hard for me to look at this incremental improvement and say that we're curing any of these patients. We are hopefully delaying something that was inevitable, and I think that is as much as we can say.”
Survival Is Improving
Hudis cited a recent trial led by Sandra M. Swain, MD, showing what he called an unprecedented improvement in overall survival for patients with HER-2 positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel (NEJM 2015; 372:724-734).
“It's a highly effective therapy, but those patients are on an ongoing—and I'll add parenthetically, expensive—therapy. And they live with constant ongoing risk, if not certainty, of eventual progression and continued medical care, until eventually perhaps death from disease. And I will take a clear exception to George's definition at the beginning, but living with disease and all of its consequential anxieties is not cure.
“And living with metastatic HER2-positive breast cancer, waiting for that next shoe to drop, is not cure. It is living, which is a success. But it is certainly not what I think what we were charged with.
“If cure is the end of the medical condition and the patient walks away and doesn't have to worry about their doctor and his ugly office anymore, then unfortunately we're far away from curing metastatic disease. If you want to label remission as cure, and call living with disease and its threats cure, then I actually would agree with George that we're closer to it than ever before.”
Hudis concluded by saying that as a medical oncologist, though, he knows things could change: “I do believe that it's theoretically possible to cure metastatic breast cancer, just as it is theoretically possible to cure any number of other disseminating diseases. We're just not there yet.”