Tumor Biology Is Critical to Making Chemotherapy Choices

Hope Rugo, MD

The key to advancements in chemotherapy treatment for patients with metastatic breast cancer most likely will come through a better understanding of their underlying tumor biology, according to Hope S. Rugo, MD. Rugo discussed some of the issues concerning the use of chemotherapy in her presentation at the 30th Annual Miami Breast Cancer Conference (MBCC).

“We understand now that there are differences in terms of what our standards should be based on the tumor biology,” Rugo said in an interview at MBCC. Yet Rugo, who is director of Breast Oncology and Clinical Trials Education at the UCSF Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, said important questions remain unanswered.

Managing first-line chemotherapy for patients with HER2-positive disease or slow-growing, hormone-responsive tumors is fairly straightforward, Rugo indicated, but the choices become more complex when the malignancy is more invasive.

“For patients who have more aggressive, more rapidly growing, upfront hormone-resistant or triple-negative disease, the choice of chemotherapy may be more important, and I don’t think we really know the answer to that yet,” Rugo said.

“It does appear that, in those patients, it’s better to start with an intravenous chemotherapy, particularly if there is rapidly advancing disease and you want to see a rapid response,” she said. “The choice of therapy is going to depend on what a patient had in the adjuvant setting and how long their disease-free interval is.”

Overall, Rugo noted, there are many areas of controversy regarding the use of chemotherapy in metastatic disease. “I don’t think that we know that combination chemotherapy is better for any one group than single-agent therapy when you can administer many different single agents sequentially,” she said. “If you have limited options, there are situations where combination chemotherapy is better because you can only give treatment in the first or second line.”

Other issues include how best to sequence drugs; how to decide the schedule and duration of therapy; whether a “treatment holiday” would be beneficial; and how to proceed in maintenance settings.

These questions stem in part from the manner in which clinical trials historically have been designed. “We studied everybody together, so it was a one-size-fits-all” approach, with past data “muddied” by the comparatively better outcomes of HER2-positive patients and potentially by longer survival of hormone-responsive patients, Rugo said.

For more than a decade, median survival for patients with advanced breast cancer has remained stable at approximately 2.5 years from start of chemotherapy, Rugo said.

“Moving forward, we really need to understand these biologic subsets in our clinical trials, so that we can potentially identify if one group benefits more than another from a specific chemotherapy,” she said in the interview.

Additionally, Rugo said investigators want to determine whether newer chemotherapy agents that may offer fewer toxicities and a better quality of life can be employed earlier in the treatment timeline.

Although researchers are moving in that direction, the questions that remain are complex. In summary, Rugo said, “We know a lot about chemotherapy, we have a lot of options, and we’re pretty good about understanding how to use it in the safest ways. What we don’t know is the optimum sequencing, dosing, and combinations. Those are some big questions, and it’s really because we haven’t looked at the biologic subsets as carefully as we might. It remains to be seen whether or not we’ll be able to do so because these are difficult questions to ask.”

Indeed, she said, researchers may learn the most by first evaluating chemotherapy agents in clinical trials in the neoadjuvant setting, and then applying those lessons to metastatic disease, instead of the traditional paradigm of testing drugs first in patients with advanced breast cancer.