Yes – It Is Time to Consider a Paradigm Shift.
In stage IV breast cancer, local therapy is not considered important except for controlling symptoms. But recent large-scale retrospective studies tell us that, if you follow enough women long enough, you see a difference in survival related to control of local disease. These emerging data tell us it’s time to consider a paradigm shift in the treatment of stage IV breast cancer.
Researchers are finding that primary site treatment regimens are important because an intact primary tumor can serve as a continued source of new metastatic lesions. There is reason, therefore, to believe that treating these can prolong life.
First explored by Dr. Larry Norton and Joan Massagué, Ph.D., (Nature Med. 2006;12:875-8), the concept of cancer self-seeding holds that cells from the primary tumor not only travel unidirectionally to seed metastases but also return to the primary tumor, self-seeding it and helping it to grow even more.
This view incorporates the microenvironment of the primary tumor. Here, fibroblasts and other cells – particularly mesenchymal stem cells derived from bone marrow – may play a very important role, creating a reactive stroma that seems to release growth-promoting substances that increase the metastatic efficiency of the circulating cells.
Robert A. Weinberg, Ph.D., published data showing that these mesenchymal stem cells are pluripotent progenitor cells. When weakly metastatic human breast cancer cells were mixed with these stem cells, the cancer cells’ metastatic potential greatly increased. The breast cancer cells then stimulated the stem cells to secrete a chemokine which – in turn – enhanced the cancer cells’ motility and their ability to invade and metastasize (Nature 2007;449:557-63). In effect, the primary tumor acts like a filling station, giving these tumor cells more energy to go out and metastasize in different sites.
Although such studies remain animal models, I think we can say there is a basis for primary tumor therapy in the metastatic setting. A dozen or more retrospective studies of large institutional series, cancer databases, and population-based studies have examined outcomes in women treated with and without surgical resection. Data on about 30,000 women have been published, with about 50% receiving some form of primary tumor therapy. The survival benefit across them is quite consistent, with the hazard ratio of death over a given time period reduced from 30% to 50%.
These studies do demonstrate selection bias: Women treated with surgical removal were more likely to be young, white, married, with smaller tumors and a lower burden of disease, and it is possible that they would have done better anyway. Studies have also shown that better survival, even in stage IV cancer, occurs in women who have a therapeutic target (that is, hormone receptors or HER2). But there was still a significant survival benefit for surgery.
Surgical resection may also confer benefit by preventing the primary tumor in the breast from becoming a quality of-life problem. At Northwestern Memorial Hospital, Chicago, we conducted a study that showed the odds of symptomatic chest wall disease were far lower in the surgical group, compared with the nonsurgical group. In this 2008 study, we found that women with good local control– surgical or systemic - did better. Time to first progression was prolonged by 50% in the surgical group, while chest wall control was associated with a 60% improvement in overall survival, regardless of whether surgical resection was performed (Cancer 2008;113:2011-9).
So the question is, do we need a randomized trial? My unbiased answer is that we do – and I am the principal investigator of such a trial open to all U.S. and Canadian institutions (NCT01242800). The end points are survival, local control, and quality of life. In addition, the trial will provide an opportunity to answer biological questions regarding the relationship between the primary tumor and metastatic site. Only when we have samples of primary and metastatic tumors can we settle this continuing debate.
Dr. Khan is the Bluhm Family Professor of Cancer Research at the Lurie Comprehensive Cancer Center, Chicago.
No – Case Selection Bias Is Behind the Survival Advantage.
It’s true that some studies show an increase in stage IV breast cancer survival after primary site resection – but this more likely reflects a bias of case selection than a true benefit of local therapy.
Any findings of positive benefit other than case selection must be biologically plausible. The suggestion that the primary tumor releases some sort of growth-promoting substance that is gone when you remove the tumor, inhibiting metastatic disease has not yet been proven in humans; nor has the proposition that continued cell shedding might further metastasis.