Adverse independent prognostic effect of initial lung cancer on female patients with second primary breast cancer: a propensity score-matched study based on the SEER database.

OBJECTIVE: To investigate the prognostic impact of initial lung cancer (LC) on second primary breast cancer after LC (LC-BC) and further develop a nomogram for predicting the survival of patients. METHODS: All patients diagnosed with LC-BC and first primary BC (BC-1) during 2000-2017 were collected from Surveillance, Epidemiology, and End Results database. Pathological features, treatment strategies and survival outcomes were compared between LC-BC and BC-1 before and after propensity score matching (PSM). Cox regression analysis was performed to identify the prognostic factors associated with LC in patients with LC-BC. Additionally, least absolute shrinkage and selection operator regression analysis was used to select clinical characteristics for nomogram construction, which were subsequently evaluated using the concordance index (C-index), calibration curve and decision curve analysis (DCA). RESULTS: 827 429 patients with BC-1 and 1445 patients with LC-BC were included in the analysis. Before and after PSM, patients with BC-1 had a better prognosis than individuals with LC-BC in terms of both overall survival (OS) and breast cancer-specific survival (BCSS). Furthermore, characteristics such as more regional lymph node dissection, earlier stage and the lack of chemotherapy and radiation for LC were found to have a stronger predictive influence on LC-BC. The C-index values (OS, 0.748; BCSS, 0.818), calibration curves and DCA consistently demonstrated excellent predictive accuracy of the nomogram. CONCLUSION: In conclusion, patients with LC-BC have a poorer prognosis than those with BC-1, and LC traits can assist clinicians estimate survival of patients with LC-BC more accurately.

PKCßII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis.

The accumulation of lipid peroxides is recognized as a determinant of the occurrence of ferroptosis. However, the sensors and amplifying process of lipid peroxidation linked to ferroptosis remain obscure. Here we identify PKCßII as a critical contributor of ferroptosis through independent genome-wide CRISPR-Cas9 and kinase inhibitor library screening. Our results show that PKCßII senses the initial lipid peroxides and amplifies lipid peroxidation linked to ferroptosis through phosphorylation and activation of ACSL4. Lipidomics analysis shows that activated ACSL4 catalyses polyunsaturated fatty acid-containing lipid biosynthesis and promotes the accumulation of lipid peroxidation products, leading to ferroptosis. Attenuation of the PKCßII-ACSL4 pathway effectively blocks ferroptosis in vitro and impairs ferroptosis-associated cancer immunotherapy in vivo. Our results identify PKCßII as a sensor of lipid peroxidation, and the lipid peroxidation-PKCßII-ACSL4 positive-feedback axis may provide potential targets for ferroptosis-associated disease treatment.