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ORLANDO – Breast cancer guidelines from the National Comprehensive Cancer Network (NCCN) now include the targeted agent palbociclib (Ibrance), paired with letrozole (Femara) or fulvestrant (Faslodex), for the treatment of postmenopausal patients with advanced or recurrent disease.

Results from the PALOMA trials "led us to have a great deal of enthusiasm for this class of drugs," said NCCN committee chair , of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago. at the . The cyclin-dependent kinase 4/6-retinoblastoma inhibitor (CDK 4/6) was given a category 1 designation (highest clinical evidence).

Gradishar said the committee members were particularly impressed that in the PALOMA 2 trial, the combination of palbociclib and letrozole led to a doubling of median progression-free survival (PFS) in advanced cancer(10.2 months with letrozole alone versus 20.2 months with the combo).

Other changes to the guidelines include:

• "Preoperative endocrine therapy alone may be considered for patients ER-positive disease based on comorbidities or low-risk luminal biology."
• In premenopausal women, "Selective ER modulators (tamoxifen or toremifene [Fareston]) or ovarian ablation or suppression plus endocrine therapy as for postmenopausal women."

Gradishar said that it is likely that future iterations of the guidelines will include ribociclib (Kisqali), based on its performance in the MONALEESA trials, where the CDK 4/6 inhibitor plus letrozole was compared with letrozole alone in women with advanced breast cancer. In the phase III MONALEESA-2 trial, the addition of ribociclib reduced the risk of progression or death by 44% during follow-up, and median PFS was 25.3 months with the combination versus 16 months with letrozole alone.

Another novel agent moving forward is abemaciclib in the , he said, adding that early research with single-agent abemaciclib showed a roughly 20% response rate in heavily pretreated patients.

Gradishar noted that "CDK 4/6 inhibitor wars" are highly likely. "You can anticipate that the marketing people will be at your doorstep to describe the distinctions between these drugs and the results of these trials" he said. He noted that while all of the drugs are from the same class, they have distinct efficacy and safety profile.

But as is generally the case with new agents, Gradishar cautioned that there are still many unanswered questions, such as who are the exceptional responders to endocrine therapy; can biomarkers be identified to define optimal therapy; can CDK 4/6 inhibitors be used sequentially; and what is the optimal sequence or combination of targeted therapy with endocrine therapy.