Carlson, Robert H.
SAN FRANCISCO—It was with rapt attention that the audience here at the Breast Cancer Symposium listened to the two keynote lectures. The two noted experts were attempting to answer the question “How Will We Be Treating Breast Cancer in Five to 10 Years?”
George Sledge, MD, Professor and Chief of the Division of Oncology at Stanford University School of Medicine, took on the role of futurist for Medical Oncology.
Monica Morrow, MD, Chief of the Breast Service in the Department of Surgery and Chair of Clinical Oncology at Memorial Sloan-Kettering Cancer Center, gave her predictions from the viewpoint of Surgical Oncology.
Each began with the disclaimer that no one can predict the future—Sledge even quoting Yogi Berra (who quoted Niels Bohr), that “Prediction is difficult—especially about the future.”
George Sledge: Predictions from a Medical Oncologist's Perspective
George Sledge began his lecture with a list of erroneous past predictions, possibly to the chagrin of some in the audience who once held these disproven views, that:
- adding more chemotherapy drugs will cure cancer;
- high-dose chemotherapy will cure breast cancer;
- hormonal therapy is static, not cytotoxic, so it will not work as adjuvant therapy;
- adjuvant hormonal therapy will not work in premenopausal women;
- monoclonal antibody therapy will not work; and
- anti-angiogenic therapy will cure cancer because it targets the host, and host tissues won't develop resistance.
His next slide listed reasons those predictions failed:
- Predictions fail because one dumb cancer is worth 10 smart oncologists;
- Predictions are based on unsubstantiated bias, which we mistake for hypotheses; and
- We lack imagination to know what's coming ahead of us.
Then he bravely made predictions of his own—based, he said, on perhaps “little imagination,” but certainly on currently available data:
- HER2 is (almost) over;
- BRCA testing will become ubiquitous;
- We will continue to target proliferation and survival pathways;
- Cancer genomics will become ubiquitous, but we won't like what we find so we'll need to do something else.
HER2 Is (Almost) Over
He called HER2 almost over from a public health standpoint because HER2 treatments are so successful. An indication of this can be seen, he said, in a new adjuvant treatment study comparing trastuzumab emtansine (T-DM1) plus pertuzumab with trastuzumab-pertuzumab. The primary endpoint is disease-free survival, and the disease-free-survival target is an increase from 88 to 92 percent.
“Assuming the trial works, then somewhere north of 92 percent disease-free survival becomes the new benchmark in the adjuvant setting for HER2-positive disease,” he said. “Then HER2-positive disease suddenly becomes testicular cancer in terms of long-term disease-free survival.”
If this comes about, pharmaceutical companies and the National Cancer Institute will have to seriously question whether HER+ breast cancer continues to be a significant public health issue, he said. Phase III trials of HER2+ breast cancer at that point would become prohibitively large and expensive, he said.
“In testicular cancer, when disease-free survival went over 90 percent, the study questions became ‘fill in the blank’ questions, about reducing toxicity, or getting rid of chemotherapy, or cost effectiveness.”
BRCA Testing, and Diagnosis, Will Become Ubiquitous
For more than a decade, BRCA testing in the U.S. has used a 10 percent risk of having the mutation as an arbitrary cutoff point before testing would be done, he said. “Ten percent is a nice round number, but there is nothing logical or magical about it that makes it different from a nine percent or 11 percent risk. By and large, [the fixed cutoff] was driven by the fact that the cost of testing was held captive to market forces that gave a patent to a single company.”
Since that patent was recently invalidated, Sledge predicted that BRCA testing would soon become routine at a cost of less than $100: “We're going to be seeing a surge in BRCA1/2 diagnosis over the next year or so. Downstream that will mean more breast MRIs, and patients will be having more prophylactic surgery.”
It will also mean fewer patients going for systemic adjuvant chemotherapy because their problem would be taken care of before that point, he said.
Genetic testing would next become routine, he said, a full panel of genetic tests at a reasonable price—“That will affect everyone's practice in how mutational events are managed.”
Continue Targeting Proliferation and Survival
Research that targets proliferation and survival will continue to be important as new pathways and agents targeted at them are discovered, Sledge said, calling this prediction a no-brainer. Also obvious is that cancer genomics will become ubiquitous as the price of genomic testing drops in cost, whether this ends up being whole genome sequencing, whole exxome sequencing, or hot gene sequencing that looks only at a few hundred genes.
But what those genomics assays will show will be daunting, he predicted, citing a study last year in Nature (2012;486:400-404) that analyzed the genomes of 100 breast cancers. The results found driver mutations—a subset of mutations that confer clonal selective advantage on cancer cells—in at least 40 different cancer genes and in 73 different combinations.
There was only one driver mutation in 28 of the cancers, but some cancers had as many as six. “We have never targeted six drivers!,” Sledge said (adding, though, that this may have happened unintentionally since some of the kinase inhibitors are promiscuous).
Sledge said countering the rapid emergence of compensatory mechanisms of resistance is like a “Whac-a-Mole” game played with kinase inhibitors.
In the future, he said, dormant cells may become the major cause of breast cancer death as therapies targeting proliferating cells improve—“The good news is that there will be many molecular targets and new antimetastatic drugs.”
Sledge ended with a quote from Arthur C. Clarke: “If an elderly but distinguished scientist says that something is possible, he is almost certainly right; but if he says that it is impossible, he is very probably wrong.”
To which Sledge added, “You will notice that in the course of my talk I said nothing is impossible.”
Monica Morrow: Predictions from a Surgical Oncologist's Perspective
Local therapy to prevent local breast cancer recurrence was the theme dominating Monica Morrow's lecture. The attitude toward local therapy is changing, she said.
“In the past there was a wall between local therapy to control disease in the breast and chest wall, and systemic therapy to improve survival. That wall has come down a little because we clearly recognize that local therapy, when inadequate, does have a survival impact—the Oxford Overview shows us that—and that systemic therapy actually plays a much bigger role than we ever imagined.”
Another concept undergoing change is that bigger surgery is better surgery. “In the multimodality era today, it's recognized that microscopic disease does not always require surgical excision,” she said. “The challenge for the future will be to define safe residual burden, and that is likely to vary among subgroups.”
She warned that in the future more and more drug therapy will be used in an effort to achieve cure, even though that potentially means more and more toxicity. “The question for those of us who do local therapy is, how do we leverage the benefits of systemic therapy on local control to decrease morbidity for our patients?,” she asked.
No Role for Neoadjuvant Therapy
In the evolution of thought in local therapy, breast cancer has gone from being one disease with one set of rules for selecting patients for breast conservation or delivering radiotherapy—a single box—to several boxes representing several diseases based on ER and HER status—“But we still have a single set of rules,” Morrow said.
She predicted that in the future breast cancer will be treated as many diseases, multiplying those boxes by genomic signatures, each with a treatment tailored for it.
Neoadjuvant therapy, though, will not have a role in that mix, Morrow predicted. “Neoadjuvant therapy may be the future of drug development, but for me it's definitely not the future of local therapy. It doesn't improve survival compared with standard adjuvant therapy. And, at least in the U.S., we don't see that many patients with inoperable breast cancer where neoadjuvant therapy is mandatory.”
She said that in this era of screening, the majority of women diagnosed with breast cancer are candidates for breast conservation, “or they don't want breast conservation anyway.”
How Much Tumor Can Be Controlled Without Surgery?
“We have an increasingly schizophrenic relationship with residual disease burden,” Morrow said, illustrating her point with the issue of adequate negative margins. In a 2005 study, she said, only 11 percent of 318 surgeons thought ink not touching tumor was an adequate margin for a 60-year-old woman with an 8 mm triple-negative cancer. And only 45 percent of North American radiation oncologists and 25 percent of European radiation oncologists thought ink not touching the tumor was an adequate margin.
The confusion regarding tumor burden, and the definition of adequate margins, will only get worse with the increasing use of MRI and other expensive imaging modalities to look for subclinical disease, which will lead to bigger surgery.
“We now perform re-excisions in approximately one-quarter of women with technically negative margins to obtain more widely-clear negative margins, with the net result that across the U.S. the mastectomy rate is increasing.”
There is no doubt that systemic therapy reduces local recurrence, and that better systemic therapy reduces local recurrence more, Morrow said. Hormonal therapy and chemotherapy increase both disease-free and overall survival while producing a corresponding decrease in local recurrence.
That effect of systemic therapy on local recurrence is independent of the type of surgery, she added, noting that a joint Society of Surgical Oncology-ASTRO multidisciplinary consensus conference was held recently to develop guidelines and “restore some sense of what we were doing to the question of margins.”
The conference produced a meta-analysis of 33 studies with 28,162 patients, which Morrow said would be published soon. The key finding was that negative margins with no ink on tumor optimize local control, but that wider margins do not significantly improve local control.
“Therefore, the routine practice in your tumor board of saying all patients must have [margins of] 1 mm, 2 mm, 5 mm—whatever your favorite number is—is not indicated,” she said.
Moving into the future means “recognizing that small differences in local recurrence—less than five percent, probably less than 10 percent—are unlikely to impact survival, and we need to stop obsessing about them. We must also recognize that added treatment equals added toxicity. If we do nothing but add and add and add [new therapies], all we are doing is increasing the burden of treatment for our patients.”
And because breast cancer subtypes vary in both local and distant outcomes, Morrow said, studies must be designed to address the issue of decreasing the extent of surgery and radiotherapy—And that is “either in the face of favorable biology or effective systemic therapy.”
Questions to be answered, she said, would include whether the need for post-mastectomy radiotherapy is reduced in ER+ patients with favorable molecular profiles; does multiple HER2 blockade alter the need for post-mastectomy radiotherapy; and do all patients need radiotherapy after breast-conserving surgery?
Keeping clinical studies of manageable size in the face of declining recurrence rates, and getting clinicians to enroll patients in trials of less therapy, will be two major challenges, she said, pointing to two recent major trials, ACOSOG Z11 and IBCSG 2301, both of which failed to accrue. “And we need to start thinking more about incorporating patient-reported outcomes in these trials. Because as we talk about differences in outcomes of a couple of percentage points based on adding treatments, patient attitudes towards the toxicity of those treatments becomes increasingly important in overall framing of preference-sensitive decisions.”
Morrow closed with a reminder that the rules for surgery and radiotherapy in use for the past 30 years have served us well and improved patient outcomes—“but very little of what we believe about breast cancer biology now was in place 30 years ago.”