Expert Point of View: Stephen R.D. Johnston, MD

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Is this a game-changer? I think it probably is. The thorny issue is how to integrate these data into clinical practice.
— Stephen R.D. Johnston, MD

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“These results apply to about two-thirds of women with advanced breast cancer, ie, those with hormone receptor–positive metastatic breast cancer,” noted the formal discussant of this paper, Stephen R.D. Johnston, MD, of the Royal Marsden Hospital, London. “At present with first-line endocrine therapy, median progression-free survival in this group of women ranges from 10 to 13 months. The question is can we do better,” Dr. Johnston said.

Several studies have now demonstrated improved outcomes in hormone receptor–positive advanced breast cancer with the addition of new therapies to standard hormonal therapy. They include the present trial—MONALEESA-2—the FALCON trial (fulvestrant [Faslodex] plus letrozole), and PALOMA-2 (palbociclib [Ibrance], another CDK4/6 inhibitor, plus letrozole).

Resistance vs Sensitivity

A key issue is whether some patients can be effectively treated with hormonal therapy such as an aromatase inhibitor (ie, letrozole or anastrozole) or a selective estrogen receptor downregulator (ie, fulvestrant) alone, whereas others may do better with a combination of a CDK 4/6 inhibitor such as ribociclib or palbociclib added to hormonal therapy, Dr. Johnston continued. “We need prognostic/predictive markers and markers of sensitivity or resistance to CDK4/6 inhibitors,” he told listeners.

Dr. Johnston distinguished between endocrine resistance (early relapse on hormonal therapy) and endocrine sensitivity (late relapse on hormonal therapy). “How to use this in clinical practice is probably a gray area. Long disease-free interval and endocrine-naive status may predict a good clinical response to to endocrine therapy alone, as well to combination therapy,” he added. “We need to stratify for prior adjuvant endocrine therapy and disease-free interval to tease out resistance vs sensitivity.”


Three different CDK4/6 inhibitors are being rapidly developed: abemaciclib, palbociclib, and ribociclib.

PALOMA-2 compared palbociclib plus letrozole vs letrozole alone in a comparable patient population as in ­MONALEESA-2 and has reported similar results, with a significant improvement in progression-free survival. The benefit of palbociclib was observed across all subgroups, regardless of the disease-free interval, the site of metastatic disease, and the use of prior ­treatment.

“Both studies show impressive data, with a separation of [progression-free survival] curves observed early,” he noted.

­“MONALEESA-2 showed a clinically meaningful and statistically significant improvement in [progression-free survival] with ribociclib added to letrozole,” Dr. Johnston continued. “Is this a game-changer? I think it probably is. Now two randomized studies in a similar population show a substantial improvement in [progression-free survival] with the addition of a CDK4/6 inhibitor to letrozole. The thorny issue is how to integrate these data into clinical practice,” he said.

To help resolve the question of which is best for first-line therapy—endocrine therapy alone or the combination of CDK4/6 inhibitor plus letrozole—better biomarkers are needed. For now, the only biomarker for CDK4/6 is estrogen receptor positivity itself. Dr. Johnston suggested that endocrine resistance vs endocrine sensitivity may inform the choice of first-line therapy, with resistant patients given the combination and sensitive patients given endocrine therapy alone. ■

Disclosure: Dr. Johnston has received research grants or personal fees from AstraZeneca, Novartis, Pfizer, Eli Lilly, and Pfizer.

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