Success rates for lumpectomies or mastectomies are high with respect to survival, with up to 98% long-term survival rates for surgery and/or radiotherapy, but what if similar results could be achieved by substituting targeted medications for therapy?
Henry M. Kuerer, MD, PhD, FACS
American women undergo 60,000 lumpectomies or mastectomies each year to remove ductal carcinoma in situ (DCIS). Success rates for these procedures are high with respect to survival, with up to 98% long-term survival rates for surgery and/or radiotherapy, but what if similar results could be achieved by substituting targeted medications for therapy?
Henry M. Kuerer, MD, PhD, FACS, discussed the first tenuous steps in that direction during his presentation, “Neoadjuvant Strategies in DCIS.”
“No one is forgoing surgery yet, not even for research, but trials have found some promising results when agents such as tamoxifen are used before surgery,” said Kuerer, professor and director of the Breast Surgical Oncology Training Program at The University of Texas, MD Anderson Cancer Center, in an interview in advance of his presentation.
Investigators from the University of California at San Francisco (UCSF), for example, tested preoperative tamoxifen and letrozole to determine whether or not such treatments result in detectable histologic alterations.
Premenopausal women in the study group received tamoxifen; postmenopausal women received letrozole. Researchers evaluated pathologic markers of proliferation, inflammation, and apoptosis at baseline and at 3 months. They then compared results from the treatment group to those of a control group that received nothing before surgery.
Among those who received a neoadjuvant agent, predominant morphologic changes included increased multinucleated histiocytes and degenerated cells, a decrease in the proliferation marker Ki-67, and immune infiltration into the lesions — all consistent with a treatment effect.
Indeed, results were promising enough that a phase II trial of letrozole for postmenopausal women is now open with the Alliance cooperative group.
“Studies like this provide an incredible opportunity for us to learn about the effects of the treatment because the normal standard of care, which still gets followed, is to remove the entirety of the affected area,” Kuerer said. “Researchers thus get to see, almost in real time, exactly how well any treatment regimen performs against the DCIS.”
The idea for neoadjuvant treatment of DCIS arises naturally from other areas of invasive cancer care, where using medications before surgery can consistently lessen the extent of tissue removal, improve results, or both.
It also makes sense in light of studies showing that treatment with tamoxifen can reverse atypical ductal hyperplasia, the presumed precursor to DCIS.
Indeed, Kuerer believes the idea of neoadjuvant DCIS treatment makes so much sense that it would have been investigated some time ago but for the fact that current standards of care provide a very good prognosis for newly diagnosed patients.
Even for patients who choose lumpectomy and radiation rather than the more effective mastectomy and reconstruction, recurrence rates range only from 5-25%, depending on patient demographics, margin status, and cancer biology.
Recurrences, moreover, can usually be treated successfully, either with mastectomy or some other therapy.
Yet Kuerer argued that trials of neoadjuvant DCIS treatment constitute important research that should, at the very least, reduce the amount of tissue removed during surgery and might even eliminate the need for thousands of surgeries per year.
“If the researchers develop preoperative treatments that consistently eliminate malignancies in the neoadjuvant studies, then the next step would be trials that use the preoperative treatments, skip the actual operations, and follow the subjects very closely,” Kuerer said.
“If those studies go well, then standards of practice might shift from surgery to targeted medications, at least for some patient groups with some types of malignancies.”
Any such change to existing standards would take years, Kuerer cautioned, but the mere possibility of such a breakthrough has spurred a surge in DCIS research that Kuerer’s presentation explored.
Several projects mirror the UCSF study, but focus on different carcinoma types or different medications or both. Kuerer and several colleagues at MD Anderson Cancer Center ran one of those projects, investigating the effect of one dose of trastuzumab, given 2 or 4 weeks before surgery, in HER2+ DCIS.
They compared tissue and blood from before treatment, and after surgery, they found no overt histologic changes, alterations in Ki-67 levels, or differences between apoptosis (cleaved caspase-3) in the treatment and control groups.
However, they found that trastuzumab significantly augmented antibody-dependent cell-mediated cytotoxicity in 100% of patients, an effect that was demonstrated to be mediated through natural killer cells.
Researchers at the University of Pennsylvania, meanwhile, undertook a markedly different approach to neoadjuvant treatment of DCIS. They tried to stimulate immune response by removing malignant cells, combining them with peptides and some of each patient’s immune cells and then injecting it all back into the patient as a vaccination.
Kuerer’s presentation examined the results of both studies, plus the UCSF study, as well as trials currently under way. “The paradigm of preoperative therapy has been steadily spreading over the past few years, so it was natural that it would spread to DCIS,” Kuerer said.
“Will it radically reduce deaths? That seems unlikely. The overall survival rate is already 98%. Bringing it to 99% would be very hard,” he said.
“But any substantial reduction in surgeries would be a significant step forward. Even barring that, merely reducing amount of tissue to be removed in many surgeries would benefit patients. Plus, the technique that’s being used to do this research, because it provides such a quick look at the effect of the treatment, may allow for a more rapid way to test medications in general,” Kuerer continued. “It’s definitely an interesting area to follow.”