Real life efficacy of palbociclib and endocrine therapy in HR positive, HER2 negative advanced breast cancer.

BACKGROUND: Palbociclib is indicated for the treatment of hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC), in combination with endocrine therapy. Emerging real-life data suggest that the efficacy of a palbociclib-based therapy is highly conserved. We report the Institut Curie hospital experience. PATIENTS AND METHODS: We retrospectively reviewed all patients with HR + HER2- ABC treated with a palbociclib-based therapy as first or second line for ABC, with an initial prescription from November 2016 to December 2018. Clinical, laboratory and imaging data were retrieved from electronic records. Data lock was December 31st, 2019. Descriptive analyses, univariate and multivariate Cox regression analyses were performed. RESULTS: We included 310 consecutive patients. Median age was 61.8 years old. Palbociclib was prescribed in first line in 225 patients (72.6%). Before palbociclib-based therapy initiation, 122 patients (39.3%) were endocrine naive, 96 (31.0%) endocrine sensitive and 92 (29.7%) endocrine resistant. Median follow-up was 20.7 months. Median progression free survival (PFS) was 23.4 months (95%CI: 21.6-NR) in endocrine naive patients, 22.7 months (95%CI: 14.7-NR) in endocrine sensitive, and 13.4 months (95%CI: 10.7-20.8) in endocrine resistant. At 12 months from the initiation of palbociclib, 94.5% of patients were alive. By multivariate analysis, poor prognosis factors for PFS were identified in the endocrine naive/sensitive population: initial ECOG status 2, previous endocrine therapy for ABC, 3 metastatic sites or more. Toxicity profile was similar to previously published data. CONCLUSION: In a non-selected population of patients with HR + HER2- ABC, the efficacy and safety data are strikingly similar to those previously reported.

Use of computerized data listings and activity profiles of genetic and related effects in the review of 195 compounds.

Computer-generated listings of data from short-term tests for genetic and related effects (activity profile listings) were prepared for 195 compounds that included for each compound, the test system (identified by a three-letter code word), qualitative results and the lowest effective dose (LED) or highest ineffective dose (HID) tested. A corresponding bar or line graph (activity profile) was also generated, in which test systems are displayed along the x-axis and the LED or HID values along the y-axis. The listings were reviewed and the data summarized by an IARC Working Group. The methodology used to generate these listings and plots is described, and results are given for one compound, benzene. The entire data base contains approximately 7000 entries from 4000 references.

Response of experimental animals to human carcinogens: an analysis based upon the IARC Monographs programme.

Only the results of epidemiological studies can be used to establish a causal relationship between an exposure to an agent and human cancer; however, such studies often cannot be carried out due to limitations of population or latent period or to the presence of mixed exposures. It is essential, therefore, that the validity be established of extrapolating to humans the results obtained from long-term carcinogenicity tests in animals. The responses of experimental animals to known and suspected human carcinogens, as evaluated in the IARC Monographs series, were analysed as an indication of the sensitivity of animal tests for predicting human carcinogens. Although the response was high - 84% - it would have been even higher had all the compounds been adequately tested experimentally. An additional finding was that for many exposures causally related to human cancer, there is a target organ in common between humans and at least one animal species, despite many inherent physiological differences. These findings show clearly the importance of experimental carcinogenicity studies in the primary prevention of cancer.

Identification of chemicals carcinogenic to man.

Although both the epidemiologic and experimental studies have led to the identification of chemical carcinogens, the limitations in epidemiologic approaches and the need for primary prevention of cancer require a greater reliance on experimental studies. Long-term carcinogenicity studies in experimental animals have been instrumental in identifying chemicals with carcinogenic activity, and, in some cases, the experimental evidence has preceded the epidemiologic evidence (for 4-aminobiphenyl, aflatoxin B1, diethylstilbestrol, melphalan, mustard gas, and vinyl chloride). A better understanding of the multistage process of carcinogenesis and the findings from various short-term tests available more recently may provide a more solid basis for extrapolating experimental findings to man.

Mutagenicity of cancer chemotherapeutic agents in the Salmonella/microsome test.

Seventeen cancer chemotherapeutic agents were tested for their ability to mutate Salmonella typhimurium tester strains in the Salmonella/microsome mutagenicity test. There was a high correlation between the mutagenicity and carcinogenicity of a given agent. Carcinogens positive in the test were Adriamycin, daunomycin, 1-propanol-3,3'-iminodimethanesulfonate, cyclophosphamide, isophosphamide, hycanthone, chlornaphazin, nitrogen mustard, uracil mustard, melphalan, and thio-tepa. Two carcinogesn, actinomycin D and bleomycin, were not detected as mutagens. The presumptive noncarcinogen, methotrexate, was negative in the test. Tilorone and 6-mercaptopurine, tentatively classified as noncarcinogens, were mutagenic. The carcinogenicity of cis-dichlorodiammineplatinum(II), which was positive in the test, has not been determined.