Cyclin-dependent kinase 4/6 inhibitors (CDK4/6iss) are widely used in first-line metastatic breast cancer. For patients with progression under CDK4/6is, there is currently no standard treatment recommended at the category 1 level in international guidelines. The purpose of this article is to review the cellular mechanisms underlying the resistance to CDK4/6is, as well as treatment strategies and the clinical data about the efficacy of subsequent treatments after CDK4/6is-based therapy. In the first part, this review mainly discusses cell-cycle-specific and cell-cycle-non-specific resistance to CDK4/6is, with a focus on early and late progression. In the second part, this review analyzes potential therapeutic approaches and the available clinical data on them: switching to other CDK4/6is, to another single hormonal therapy, to other target therapies (PI3K, mTOR and AKT) and to chemotherapy.

Abstract BACKGROUND AIs are the milestone adjuvant treatment for postmenopausal early HR+ BC pts. Non-steroidal AIs induce a significant oestrogen deprivation, responsible in approximately 40% of the pts for muscle-skeletal adverse events (MSKs) and for discontinuation in 25%. The present study aims to evaluate the impact of the diagnosis communication and of the need for AI therapy on the future development of MSKs events in a prospective cohort of EBC pts. PATIENTS AND METHODS The analysis of patients’ psychological attitude was conducted by using 3 different tests: SCL 90-r for psychological symptoms, SF-36 for the self-perception of the health status and COPE-NVI for evaluation of coping. After a full explanation of the AIs potential adverse events by the oncologist, the questionnaires were self-administered with the support of a dedicated psychologist at the moment of the first visit (T0). For the future correlation between baseline psychological attitude and the development of AI-related events, the presence and the intensity of pain were measured by NRS 11-points scale and by Tender Points (TPs) evaluation. Pearson correlation analysis was used to calculate correlations between Pain Scale, Physical Synthetic Index of Sf-36 and NRS/TRPs scores. Wilcoxon’s Test was used to compare baseline scores with subsequent ones. RESULTS From October 2012 to April 2013, 70 EBC pts entered the study. Exclusion criteria included severe osteoporosis or other co morbidities that contraindicate therapy with AIs and documented diagnosis of psychosis or cognitive deterioration. Median age was 64.8 years (43-88). The vast majority of the pts (584.3%) presented stage IA-IIA disease. Fifteen pts aged less than 55 years were menopausal, 13 have previously received chemotherapy as part of the planned adjuvant programme. Thirty-four pts (48.6%) had a baseline NRS>0 and 18 NRS>5; 26 pts presented at least 1 positive TP. Regarding the SCL 90-r analysis, all the pts have reported standardized scores within the normal ranges for somatization, anxiety and phobic anxiety. The analysis of SF-36 questionnaires indicated that pts showed a significant lower score in comparison to the reference population in the ISF Index (44.17 vs 48.7) and in the Physical Health Scale (47.5 vs 74.13). These differences could suggest a greater difficulty to do daily activities and a worse global index of self physical perception At baseline, there was a statistically significant correlation between Physical Pain Scale of SF-36 and NRS Pain score (p=0.001) and between Physical Synthetic Index of SF-36 and NRS Pain Score (p<0.001). No differences have been observed in the COPE NVI questionnaires between the studied population and the reference one. CONCLUSION Early BC pts who are candidate for endocrine adjuvant therapy with AIs often present an impairment in terms of physical activity (daily and working) and perception of physical pain. The analysis of these parameters along the 1st year of AI therapy and their correlation with MSK adverse events onset is ongoing. Citation Format: Marina E Cazzaniga, Annalisa Valentini, Francesca Gallina, Francesca Riva, Alessandra Crippa, Marco Tagliabue, Federica Cicchiello, Diego Cortinovis, Paolo Bidoli. Psychological status of early breast cancer (EBC) patients (pts) after surgery and before the starting of aromatase Inhibitors (AIs). Results of a single-institution, prospective study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-12-05.

Introduction: Erlotinib is useful in advanced non-small cell lung cancer although compliance and efficacy are diminished by skin rash in a high proportion of patients, often necessitating dose reduction or drug withdrawal. No effective treatment for the rash is available.Methods: We carried out a preliminary investigation on isotretinoin and clindamycin. Among 56 advanced lung cancer patients treated with erlotinib, 31 (53%) developed rash. Seven (35%) of the 20 G2/G3 cases agreed to treatment with clindamycin (450 mg/d, days 1-10; 300 mg/d, days 11-20) plus isotretinoin (20 mg/d, days 11-20) after being informed of the experimental nature of the combination.Results: In 6 of 7 (86%) patients, the rash resolved (G1/G0) without dose reduction; in the other patient (G3), the erlotinib dose also had to be reduced. Median time to resolution was 14 days (range 7-20 days). No rash-treatment adverse events occurred during 20 days of administration.Conclusions: Isotretinoin plus clindamycin promises to be the first effective treatment for erlotinib rash and is being tested further.

e19551 Background: Oral tyrosine kinase inhibitors are useful in advanced NSCLC although compliance and efficacy are diminished by skin rash which develops in about 75% of patients. Skin rash is the main cause of dose reduction and therapy withdrawal, and is no specific treatment is available. Clindamycin modulates the chemotaxis of polymorphonucleocytes, while isotretinoin has favorable effects on cell proliferation and differentiation, and inflammatory mediators. We therefore assessed the efficacy of isotretinoin plus clindamycin in erlotinib-induced skin rash. Methods: We treated 56 patients with advanced NSCLC from April 2008 to September 2009 with erlotinib (150 mg/day) mainly as 2nd/3rd line therapy. Consenting patients who developed symptomatic cutaneous rash (G2/ G3) were started on clindamycin (450 mg/day days 1 to 10; 300 mg/day days 11 to 20) plus isotretinoin (20 mg/day days 11 to 20). Clinical examination with photographic documentation was performed on days 0, 15 and 30. Results: Thirty-one (53%) patients developed rash: 12 (20%) G2 and 8 (14%) G3. However only 7/20 (35%) consented to receive clindamycin plus isotretinoin after being informed of possible side effects of isotretinoin (particularly liver damage and photosensitivity) and lack of experience with the combination. The treatment was effective in 6 (86%) patients with resolution of rash to G1/G0; in the other patient (G3) it was also necessary reduce the erlotinib to 100 mg/day. Median time to rash resolution was 14 days (range 7-20) in these 7 patients. No adverse events associated with clindamycin plus isotretinoin were observed during the 20 days of treatment. Cutaneous rash (all grades) was related to erlotinib activity: 89% of patients with radiological response developed rash, while 52% of those with progressive disease did not develop rash. Conclusions: Isotretinoin plus clindamycin promises to be effective for managing erlotinib-induced skin rash, allowing maintenance of effective erlotinib dose in order to maximize clinical efficacy. A randomized phase II study, to further explore the efficacy of isotretinoin plus clindamycin, is planned. No significant financial relationships to disclose.