NEUROFIBROMIN 1 continued from page 7 NF1 gene as a driver in breast cancer ( Genetics 2012;192,385-396). Until that point, intragenic mutations and loss of heterozygosity had been noted for the NF1 gene in breast cancer cases. Women with neuroﬁbromatosis type 1 (i.e., those who have an inherited mutation or loss of gene from their germline cells) have a higher association with or risk for breast cancer. When these researchers screened the breast cancer patient data available at the time from The Cancer Genome Atlas, they found 27.7 percent of the patients had NF1 deletions or mutations, and of these, the majority was heterozygous. Additionally, more than 40 percent of the HER2-overexpressed or basal tumor subtypes showed NF1 mutation or loss. In their study, Schimenti, et al uti-lized the C3H-Mcm4 Chaos3/Chaos3 mouse tumor model (hereafter abbreviated Chaos3 ) to examine potential drivers because: • tumors can arise efﬁciently from this model due to genomic instability induced by a point mutation in the minichromo-some maintenance 4 ( Mcm4 ) gene; and • the mammary tumors in this model were shown via tumor differentiation score analysis to most closely resemble mature human luminal cells, a rare but very important property among mouse models for the study of the most fre-quent form of human breast cancer. By using this particular model, the in-vestigators hoped the controlled genetic makeup and single tumor etiology might make it easier to identify recurring muta-tion events that are likely to be tumorigen-esis drivers. This line of mice has thus found to have more than 80 percent of the nul-liparous females develop mammary-based adenocarcinomas exclusively. The Chaos3 tumors isolated in the study had a large number of cells with varying num-Continued on page 9 What could longer PFS in ﬁ rst line mean for your patients? PALOMA-1: 10-month improvement in median PFS (mPFS) in ﬁ rst line In an open-label, 1:1 randomized, Phase 2 trial of postmenopausal women with ER+/HER2-MBC (N=165) 1 Primary endpoint: PFS with letrozole alone (95% CI: 13.8-27.5 vs 5.7-12.6); MONTHS HR=0.488 (95% CI: 0.319-0.748); number of PFS events: 41 (48.8%) vs 59 (72.8%) 20.2 IBRANCE + letrozole vs 10.2 months Secondary endpoints • Overall response rate (ORR)*: 55.4% with IBRANCE + letrozole vs 39.4% with letrozole alone in the measurable disease population (n=65 and 66, respectively) * ORR was deﬁ ned as the number (%) of patients with complete response or partial response. 3 • Overall survival (OS): At the time of ﬁ nal analysis of PFS, OS data were not mature with 37% of events The most common adverse reactions ( ű 10%) of any grade reported in PALOMA-1 of IBRANCE + letrozole vs letrozole alone included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%), diarrhea (21% vs 10%), thrombocytopenia (17% vs 1%), decreased appetite (16% vs 7%), vomiting (15% vs 4%), asthenia (13% vs 4%), peripheral neuropathy (13% vs 5%), and epistaxis (11% vs 1%). PALOMA-1 and PALOMA-2 studied IBRANCE 125 mg PO once daily taken 3 weeks on, 1 week off + letrozole 2.5 mg PO once daily vs letrozole alone or placebo + letrozole, respectively. 1,2 Recommended treatment option by the National Comprehensive Cancer Network® (NCCN®) 4 RECOMMENDED Palbociclib (IBRANCE) + letrozole for ﬁ rst-line treatment of postmenopausal women with HR+/HER2-MBC (category 2A)† † Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. This category 2A recommendation is based on data from PALOMA-1, the Phase 2 trial presented in the IBRANCE Prescribing Information. 4 Indication IBRANCE is indicated for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (MBC) in combination with letrozole as initial endocrine-based therapy in postmenopausal women. The indication in combination with letrozole is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon veriﬁ cation and description of clinical beneﬁ t in a conﬁ rmatory trial. Important Safety Information Neutropenia was the most frequently reported adverse reaction in PALOMA-1 (75%) and PALOMA-3 (83%). In PALOMA-1, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (56%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in about 1% of patients exposed to IBRANCE. One death due to neutropenic sepsis was observed in PALOMA-3. Inform patients to promptly report any fever. Please see Important Safety Information throughout, followed by Brief Summary.