By: Diana Swift
Questions remain about whether there is any benefit to removing an intact primary tumor
About 6% of newly diagnosed breast cancer patients present at initial diagnosis with de novo metastatic disease and an intact primary tumor. Understandably, many such patients will want to have that tumor removed at the outset. Over the past 2 decades, however, the approach has increasingly been not to undertake surgery, but to instead keep the focus on increasingly effective medical therapies to control distant disease.
So while systemic therapy remains the treatment cornerstone for this population, some — mostly restrospective — research suggests that locoregional treatment may offer improved survival for certain patient subgroups. Randomized trials, however, have provided conflicting data.
One earlier retrospective analysis reported reduced mortality risk with extirpation of the primary tumor.
“In this patient population, there’s long been interest in seeing if there’s a clear role for surgery,” Anita Mamtani, MD, a breast surgeon at Memorial Sloan Kettering Cancer Center in New York City, told MedPage Today. “There’s been a lot of research and a lot of controversy.” Three or four large randomized controlled trials since the early 2000s have overwhelmingly found no survival improvement with surgery, she added.
The driver of treatment has become the biology of the distant disease and how to control it with effective medical therapy, Mamtani said. “The metastasis is almost a different biological beast. That’s what determines the patient’s outcome, and in most instances there’s no value added by removing the primary tumor.”
Palliative surgery, however, in the event of fungating tumors and wound infection is the exception, she explained. “We do palliative surgery if the patient has a locally aggressive tumor causing a wound and compromising quality of life. In this case, it’s a mixed-team decision made on a case-by-case basis, and the scenario is much more selective than it would have been even 10 years ago.”
Emily K. Robinson, MD, professor of surgery at McGovern Medical School at the University of Texas Health Science Center at Houston, said she also typically discourages patients with stable tumors from having surgery. “The main issue is this: if you interrupt treatment to take the patient to surgery and she has some surgical misadventure such as a wound infection, that will only delay the life-saving systemic therapy,” Robinson told MedPage Today.
She acknowledged, however, that advising against surgery can be difficult when you have an anxious patient sitting in front of you who has heard about upfront surgery for the primary tumor and would prefer to have it out. “A nuanced conversation is needed here,” Robinson said. “I tend to say not ‘no’ but rather ‘not now,’ and I refer them to the medical oncologist for further evaluation.”
Clearly, evolving endocrine, targeted, and now immune-directed therapies are what’s lengthening the lives of stage IV patients, but some researchers are taking a closer look at subsets who might benefit from excising the primary tumor.
In a Turkish randomized trial of de novo stage IV breast cancer published in 2018, Soran and colleagues found no improvement in survival 36 months after upfront surgery, but in longer follow-up (median of 40 months) noted a statistically significant improvement in survival.
In addition, subgroup analyses showed a statistically lower risk of death after surgery in patients who were estrogen receptor (ER)- and progesterone receptor (PR)-positive and HER2-negative. Also benefiting from surgery were women younger than 55 and those with solitary bone-only metastases.
Similarly, researchers publishing results earlier this year reported a survival benefit of primary tumor surgery in patients with bone metastases. The finding came from an analysis of 3,956 breast cancer patients with bone metastases in the NCI’s Statistics, Epidemiology, and End Results database during 2010-2016. Bone is the most common site of breast malignancy spread, affecting as many as 6% of de novo stage IV patients at diagnosis.
Also in 2021, Shen and colleagues published results suggesting a survival benefit by adding surgery to systemic therapy in stage IV patients. Analyzing data on 12,838 stage IV breast cancer patients with known hormone receptor and HER2 status in the National Cancer Database from 2010 to 2015, the researchers found that the sequence of chemotherapy in relation to surgery was significant, with the greatest survival advantage in recipients of neoadjuvant chemotherapy.
The team concluded that surgery should be considered after chemotherapy for those with ER-positive, PR-positive, or HER2-positive disease.
Mamtani urged caution in interpreting the Shen et al. study, however: “This is a highly selected population of patients, including those who are HER2-positive — the most chemosensitive subgroup of cancers at this time — and for whom we have a host of effective systemic therapies. In addition, the majority of patients had single-site metastasis.”
The study also excluded those who died within 6 months of diagnosis, effectively implementing a selection bias in which the more aggressive cancers were already excluded, Mamtani added.
“The benefit seen in this study is most likely a product of favorable tumor biology that is responsive to the systemic therapies, and a selected good-risk group that sees an improved survival overall to which surgery appears to contribute. We would need to see more clear and again randomized data before this could be broadly applied,” she said.
While individualized and targeted systemic treatments remain the therapeutic mainstay, future studies may establish a clearer role for early local surgery in subsets of patients with newly diagnosed stage IV disease, but the decision-making will be complex.
Ultimately the decision to include surgery in the equation must be reached in subtle, multidisciplinary ways, said Soran and co-authors: “When locoregional treatment in de novo stage IV breast cancer is discussed with the patient as an option, practitioners must consider age, performance status, comorbidities, tumor type, and metastatic disease burden.”
Equally needing consideration is that taking the patient to surgery may delay or interrupt the more consequential systemic therapies that are extending the lives of so many metastatic breast cancer patients.
Barbara Jacoby is an award winning blogger that has contributed her writings to multiple online publications that have touched readers worldwide.