NEUROFIBROMIN 1 continued from page 8 bers of chromosomes, even within the same tumor (also a trait of human breast cancer tumors). To the researchers’ sur-prise, when partial exomic resequencing of these tumors was done, few somatic point mutations were observed in the targeted exon regions. The calculated mutation rate (~0.25 mutations/Mb) was not higher than the background rates ob-tained from other breast cancer genomic studies, implying that higher intragenic mutagenesis was not the primary mecha-nism for Chaos3 tumorigenesis. As a re-sult, the investigators also explored copy number alterations as potential carcino-genesis drivers. All Chaos3 tumors were analyzed by array comparative genomic hybridiza-tion. Of particular interest to the re-searchers were deletions observed on chromosome 11 of all Chaos3 mam-mary tumor cells. None of the Chaos3 nonmammary tumors had these same deletions. The genes included in these deletions were NF1, Omg (oligodendro-cyte myelin glycoprotein), Ksr1 (kinase suppressor of RAS), and Wsb1 (WD re-peat and SOCS Box-containinc Protein). Of this group of genes, the researchers thought NF1 was the most likely candi-date as a breast cancer tumor suppres-sor. Ksr1 is a promoter of oncogenic MAPK and RAS signaling, and thus loss of function would actually inhibit tumor growth, while Omg is required for my-elination of the CNS, and consequently is primarily expressed in neuronal tissues. As previously stated, neuroﬁbromin 1 is a negative regulator of RAS. In turn, RAS is a stimulator for the pro-growth factor mTOR (mechanistic target of ra-pamycin), thus one might postulate that tumor cells deﬁcient in NF1 may have both higher levels of activated-RAS as well as be sensitive to mTOR inhibitors such as rapamycin. This effect has been Continued on page 18 Approval of IBRANCE + letrozole is subject to the requirement to conduct an additional, adequate, well-controlled trial to verify the clinical beneﬁ t seen in PALOMA-1. Data from PALOMA-2 have not been reviewed by the FDA and are not included in the IBRANCE Prescribing Information (PI). Potential inclusion of these data in the IBRANCE PI has yet to be determined. PALOMA-2: Greater than 2 years of mPFS in ﬁ rst line In a double-blind, 2:1 randomized, Phase 3 trial of postmenopausal women with ER+/HER2-MBC (N=666) 2 IBRANCE + letrozole is the only treatment for HR+/HER2-MBC to demonstrate more than 2 years of mPFS in a Phase 3 trial Based on a MEDLINE® literature review for Phase 3 trials in HR+/HER2-MBC treatment as of October 2016. 100 90 PFS Probability (%) 80 70 60 50 40 30 20 10 0 0 3 6 Primary endpoint: PFS HR=0.58 (95% CI: 0.46–0.72) P <0.001 24.8 MONTHS with IBRANCE + letrozole (n=444) (95% CI: 22.1-NE) 14.5 months with placebo + letrozole (n=222) (95% CI: 12.9–17.1) Number of PFS events: 194 (43.7%) with IBRANCE + letrozole vs 137 (61.7%) with placebo + letrozole Secondary endpoints 9 12 15 18 Month 21 24 27 30 33 Number of Patients at Risk IBR+LET 444 395 360 328 295 263 238 154 69 PLB+LET 222 171 148 131 116 98 81 54 22 29 12 10 4 2 2 • ORR*: 55.3% with IBRANCE + letrozole vs 44.4% with placebo + letrozole in the measurable disease population (n=338 and 171, respectively; P =0.03) • OS: At the time of ﬁ nal analysis of PFS, OS data were not mature The most common adverse events ( ű 10%) of any grade reported in PALOMA-2 of IBRANCE + letrozole vs placebo + letrozole included neutropenia (80% vs 6%), leukopenia (39% vs 2%), fatigue (37% vs 28%), nausea (35% vs 26%), arthralgia (33% vs 34%), alopecia (33% vs 16%), diarrhea (26% vs 19%), cough (25% vs 19%), anemia (24% vs 9%), back pain (22% vs 22%), headache (21% vs 26%), hot ﬂ ush (21% vs 31%), constipation (19% vs 15%), rash (18% vs 12%), asthenia (17% vs 12%), thrombocytopenia (16% vs 1%), vomiting (16% vs 17%), pain in extremity (15% vs 18%), stomatitis (15% vs 6%), decreased appetite (15% vs 9%), dyspnea (15% vs 14%), insomnia (15% vs 12%), dizziness (14% vs 15%), nasopharyngitis (14% vs 10%), upper respiratory tract infection (13% vs 11%), dry skin (12% vs 6%), pyrexia (12% vs 9%), myalgia (12% vs 9%), urinary tract infection (12% vs 8%), abdominal pain (11% vs 5%), peripheral edema (11% vs 6%), dysgeusia (10% vs 5%), dyspepsia (9% vs 12%), and anxiety (8% vs 11%). CI=conﬁ dence interval; HR=hazard ratio; IBR=IBRANCE; LET=letrozole; NE=not estimable; PLB=placebo. Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 14 of ﬁ rst 2 cycles, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Pulmonary embolism (PE) has been reported at a higher rate in patients treated with IBRANCE plus letrozole in PALOMA-1 (5%) and in patients treated with IBRANCE plus fulvestrant in PALOMA-3 (1%) compared with no cases in patients treated either with letrozole alone or fulvestrant plus placebo. Monitor for signs and symptoms of PE and treat as medically appropriate. Based on the mechanism of action, IBRANCE can cause fetal harm . Advise females of reproductive potential to use eff ective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients with female partners of reproductive potential to use eff ective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.