In Keynote Lectures during the 2013 ASCO Breast Cancer Symposium, experts George Sledge, MD, and Monica Morrow, MD, offered their opinions and outlook on how the medical and surgical management of breast cancer may continue to evolve over the next 5 to 10 years.1 Dr. Sledge is Chief of Oncology at Stanford School of Medicine, Palo Alto, California. Dr. Morrow is Chief of the Breast Surgical Service at Memorial Sloan-Kettering Cancer Center, New York, and the Anne Burnett Windfohr Chair of Clinical Oncology.
Medical Management: Five Emerging Trends
George Sledge, MD, first acknowledged that “making predictions is somewhat dangerous,” but said he feels confident that five emerging trends will shape breast cancer care within the next decade. These predictions are based on biology, technology, economics, and demography, all of which “intersect in the deep dark woods of the modern health-care system,” Dr. Sledge said.
Prediction #1: “The era of HER2 is almost over.” “We will always have patients relapsing with HER2-positive disease, and this will require novel therapies. But from a public health standpoint, I believe the era of HER2 is almost over,” said Dr. Sledge. This prediction is based on the fact that with adjuvant T-DM1 plus pertuzumab (Perjeta), 3-year disease-free survival may exceed 92% (according to the schema for the current trials). Surpassing this 92% disease-free survival benchmark makes HER2-positive breast cancer akin to testicular cancer, no longer thought of as a “public health issue.” With long-term disease-free survival accomplished, the research questions then become about toxicity and cost-effectiveness of treatment, and phase III trials will be too expensive to explore these remaining “fill in the blank” questions, Dr. Sledge said.
Prediction #2: “BRCA testing will become ubiquitous.” This will occur as a result of less expensive assays. The Supreme Court’s invalidation of the Myriad patent2 opened the door to market forces that will reduce the cost of testing to under $100, said Dr. Sledge. “When price is no barrier, we will likely see a surge in BRCA testing (possibly in all breast cancer patients), and the downstream effects of this will be more imaging, more prophylactic surgery, and a modest reduction in systemic treatment because of interventions that occur before the medical oncologist is needed,” he noted. “Mendeliome testing [genome-wide] will be next, and this will affect everyone’s practice.”
Prediction #3: “We will continue to target proliferation and survival pathways.” Recurrences are thought to be the result of proliferating micrometastases (especially in early recurrences) and activation of dormant cells (especially in late recurrences). “We haven’t gotten rid of this problem. It’s safe to say that targeting proliferation will continue to be important,” said Dr. Sledge. Novel pathway inhibitors, such as the experimental compound PD0332991 targeting cyclin-dependent kinases, affect cell-cycle progression and hold great promise.
Prediction #4: “Cancer genomics will become ubiquitous, but we won’t like what we find.” The cost of genomic testing will fall enough to make assays readily usable in the clinic, but the implications of this for patient management are concerning. Recent studies in breast cancer samples found driver mutations in at least 40 different cancer genes, with as many as six driver mutations in some tumors. This is daunting for treatment and for drug development. “In the history of cancer, we have never targeted six drivers intentionally,” he noted.
Beyond the “top fliers,” like p53 and PI3 kinase, most are rare mutations. “To think of treating these tumors in a way that has been successful, like targeting kinases, means we will have to be very clever,” said Dr. Sledge. Just as discouraging is the prospect of designing trials of relevant treatments for what becomes an orphan disease. In addition, rapid emergence of compensatory mechanisms of resistance to virtually all drugs, along with the expense and toxicity of combining several biologics, will create further hurdles.
Prediction #5: “We will need to do something different.” Relapses that occur beyond 5 years in estrogen receptor-positive patients are likely the result of dormant micrometastases. “This is a challenge for which we do not yet have good solutions,” said Dr. Sledge. The targeting of proliferating cells may not affect dormant cells; as agents are better able to suppress proliferating cells, dormant cells will become the major cause of breast cancer death and the remaining challenge in breast cancer, he predicted.
Dormancy could be addressed by increasing the duration of hormonal therapy, an approach recently validated by large endocrine therapy trials; by improving the detection and prediction of dangerous dormancy (for instance, by advancements in imaging, plasma DNA and RNA assays); and by developing novel therapies specifically against dormant cells, possibly through immune modulation. “Novel ways of targeting stem cells might not work in the overtly metastatic setting, but could possibly be game-changing in the adjuvant setting,” he suggested.
Key Challenges in the Surgical Management of Breast Cancer
“The ‘rules’ for surgery and radiotherapy in use for 30 years have served us well and have improved patient outcomes,” Dr. Morrow said in her presentation, “but very little of what we now believe about breast cancer biology was in place 30 years ago.” This new knowledge may alter locoregional management.
“In the past, we believed that bigger is better and it cured more cancers. We got slightly away from that after six randomized controlled trials showed that breast-conserving therapy was equivalent to mastectomy, but it has recently become clear that we haven’t totally gotten rid of the ‘bigger is better’ idea,” said Dr. Morrow.
For example, the reigning thought for triple-negative breast cancer is that “bigger surgery will perturb the bad biology,” in spite of several studies showing that the increased rate of local recurrence in triple-negative cancers is not improved through more extensive surgery, i.e., wider margins or mastectomy, Dr. Morrow noted.
“Although many people envision the ideal future of breast cancer management as one that includes no surgery, this remains a fantasy for the foreseeable future,” she said. Instead, the immediate quest is to address key challenges: how to appropriately individualize surgery in response to advances in our understanding of tumor biology, and how to redefine surgery’s role in reducing disease burden in an era of increasingly sophisticated imaging technology that allows visualization of diffuse microscopic disease in patients previously thought to have small, localized primary tumors.
Targeted Therapies Can Improve Local Outcomes
It is increasingly apparent that targeted therapy improves local therapy outcomes, as illustrated in patients with HER2-overexpressing tumors who receive adjuvant trastuzumab (Herceptin). But efforts to identify genetic signatures that define patients at higher risk of local recurrence after breast-conserving therapy than after mastectomy have been unsuccessful, said Dr. Morrow.
Encouragingly, emerging evidence suggests that within molecular subtypes, genetic profiling may reveal some of this risk and potentially allow for tailoring of local therapy. The implication of recent studies3,4 is that postmastectomy irradiation might be avoided in patients with one to three involved nodes (or even four or more) and a low 21-gene recurrence score, she said.
Role of Surgery in Reducing Disease Burden
The ACOSOG Z0011 trial5 was “a watershed in our thinking” regarding the need for surgical removal of all clinically evident disease in the multidisciplinary era, showing that T1/2 clinically node-negative patients with sentinel node metastases could safely avoid axillary completion dissection. “These results illustrate the ability to change standard surgical paradigms based on the use of multimodal therapy,” said Dr. Morrow.
ACOSOG Z0011 and similar studies are opening the door to the possibility that less surgery in the breast—for example, removal of only the gross tumor without “obsessive concern for margins”—could result in high rates of local control in selected subgroups, Dr. Morrow suggested.
On the other hand, the increasing use of magnetic resonance imaging preoperatively is leading to the identification of cancer not otherwise found, and this is increasing the mastectomy rate (without reducing re-excision rates), according to a recent meta-analysis she co-authored6.
Looking Forward: One Size Does Not Fit All
Looking to the future, Dr. Morrow said, there is a need to recognize that small differences in local recurrence (< 5%) are unlikely to impact survival, and that adding more treatment adds toxicity, making it necessary to ask what old treatments can be reduced as new ones are added. She predicted an increasing appreciation that both local and distant outcomes vary according to breast cancer subtypes. Studies will need to evaluate the benefit of less extensive surgery and radiotherapy, as well as effective new systemic therapies, in the face of favorable biology, she said.
Unfortunately, “The low rate of locoregional recurrences, coupled with the reluctance of physicians to enter patients into trials of less therapy, will make progress difficult,” she added. Dr. Morrow further suggested that patient-reported outcome measures add important information to the overall framing of preference-sensitive decisions and should be incorporated into future trials.
“Looking ahead, the one thing that is clear is that the ‘one size fits all’ approach to local therapy that has served us well for the past 30 years is not the path to future success,” Dr. Morrow concluded. ■
Disclosure: Drs. Sledge and Morrow reported no potential conflicts of interest.
References
1. Sledge G, Morrow M: How will we be treating breast cancer in 5 to 10 years? 2013 Breast Cancer Symposium September 9, 2013.
2. Supreme Court Ruling, June 13, 2013. http://www.supremecourt.gov/opinions/12pdf/12-398_1b7d.pdf. Accessed September 23, 2013.
3. Mamounas EP, Tang G, Fisher B et al: Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor-positive breast cancer: Results from NSABP B-14 and NSABG B-20. J Clin Oncol 28:1677-1683, 2010.
4. Mamounas EP, Tang G, Paik S et al. Prognostic impact of the 21-gene recurrence score on disease-free and overall survival of node-positive, ER-positive patients with breast cancer treated with adjuvant chemotherapy: Results from NSABP B-28. 2012 AACR-CTRC-San Antonio Breast Cancer Symposium. Abstract 1. Presented September 13, 2011.
5. Giuliano AE, Hunt KK, Ballman KV et al. Axillary dissection vs. no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 305:569-575, 2011.
6. Houssami N, Turner R, Morrow M. Preoperative magnetic resonance imaging in breast cancer: meta-analysis of surgical outcomes. Ann Surg 257(2):249-255, 2013.
