Stretching PFS in ER-Positive Metastatic Breast Cancer

Kate Johnson


December 21, 2016

Editor's note:
In a plenary presentation at the San Antonio Breast Cancer Symposium, Stephen R.D. Johnston, MD, of the Royal Marsden Hospital and Institute of Cancer Research in Chelsea, London, United Kingdom, highlighted recent findings and best practices regarding adjuvant endocrine therapy in metastatic breast cancer.

The refinement of endocrine therapy, one of the main pillars of hormone-positive breast cancer treatment, has enabled great strides in the management of postmenopausal patients with metastatic disease. First-line aromatase inhibitor (AI) treatment can delay disease progression for up to 14 months—and new guidelines from the American Society of Clinical Oncology suggest sequential AIs are preferred.[1]

"If a patient responds to first-line, they have a good chance of responding to second- or even third-line therapy," Dr Johnston noted.

But this approach presents the risk for acquired AI resistance, he said.

Ultimately, we all want to know and understand the optimal sequence for endocrine therapy in metastatic breast cancer.

"Ultimately, we all want to know and understand the optimal sequence for endocrine therapy in metastatic breast cancer."

A patient's sensitivity to endocrine therapy in the metastatic setting hinges in part on whether she has been exposed to it in the adjuvant setting, Dr Johnston explained.

Historically, studies of first-line AI for metastatic disease yielded fairly low rates of progression-free survival (PFS), "probably because they didn't take into account prior endocrine therapy given in the adjuvant setting, and what we understand as endocrine responsiveness. It's becoming increasingly important to try and work this out."

Current guidelines recommend that first-line treatment choices should take into consideration whether a patient is endocrine-naive as well as the length of their disease-free interval, which can suggest whether they have primary or secondary AI resistance, Dr Johnston said. Patients with secondary, or "acquired," resistance, who experience relapse after some degree of benefit from endocrine therapy, "may well be sensitive to further endocrine approaches," he explained.

The combination of AIs with therapies targeting growth factor and cell cycle pathways can further delay the development of endocrine resistance and "already yields us 2 years of PFS in the first-line setting," he said. In particular, putting cancer cells into a type of "arrest or senescence" with cyclin-dependent kinase (CDK) 4/6 inhibitors "is perhaps a more ubiquitous target" and could be "a game-changer," he suggested.

With two CDK 4/6 therapies (ribociclib, abemaciclib) in clinical trials and one (palbociclib) already in clinical practice, "the acquisition of data for these agents has been breath taking, particularly in the past 2 years," he noted.

We now can achieve 14-16 months of PFS with endocrine therapy.

"We now can achieve 14-16 months PFS with endocrine therapy—we might have reached a ceiling there—and combination approaches with CDK4/6 inhibitors can now improve that to nearly 2 years."

But should CDK inhibitors in combination with AIs be a new standard of care as first-line therapy for all patients with estrogen receptor (ER)-positive metastatic disease?

"We've got to be aware that we will create a new problem, which is resistance to these therapies. Do we create a more aggressive disease? Do we create a disease that could still be endocrine responsive?" Early work in this area "suggests these cells are plastic, adapt to treatment, and rewire," Dr Johnston warned.

The use of biomarkers to predict response or resistance to endocrine and targeted therapy combinations could offer valuable insight, but thus far work in this area has not yielded much, he said. Genetic alterations detected in primary tumor specimens have not been shown to predict response to CDK inhibitors in the PALOMA-2 and PALOMA-3 trials[2,3] and the BOLERO-2 study[4] could not find gene alterations that predicted response.

"Although it's all very well going back to the primary tumor, it's archival and it's old, and biology changes over time," said Dr Johnston. Enter "real-time biology" in metastatic cancer, the use of circulating tumor DNA or the "liquid biopsy" to monitor response, by detecting new mutations as they occur during treatment.

"Many of the mutations in ER-positive breast cancer remain stable between the primary and metastatic disease, but there is one exception: the estrogen receptor gene," he said. "The frequency of mutation is low in the primary tumor but rises to more than 20% in the resistant setting. This mutation is acquired through therapy in the metastatic setting, particularly during exposure to AIs."

Work by his group has recently shown that ESR1 mutations detected in plasma could identify a group less likely to respond to exemestane in the SOFEA study.[5]

If we select the right patients, we can breach 20 months of PFS in the first-line setting.

Finally, data from the FALCON study[6] suggest the benefit of another endocrine monotherapy—the selective estrogen-receptor downregulator fulvestrant (500 mg). "If we select the right patients, we can breach 20 months of PFS in the first-line setting," he added. "The issue is then whether we use a second-line AI or a CDK inhibitor to get up to nearly 30 months."

What's important for patients is that these first-line therapies will ultimately delay the start of chemotherapy, said Dr Johnston. The issue of which approaches will best affect overall survival is still to be determined. "In the second-line setting, we've definitely made good progress in the recent 5 years. We now have PFS of up to 9 months, and there are many targets still being investigated."

Dr Johnston has disclosed that he receives consulting fees from AstraZeneca, Novartis, Roche/Genentech and OBI. He also disclosed that he does contracted research for Pfizer. These relationships do not affect his ability to present an unbiased presentation.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.