Proton Pump Inhibitors and Cyclin-Dependent Kinase 4/6 Inhibitors in Patients With Breast Cancer.

BACKGROUND: Proton pump inhibitors (PPIs) reduce the bioavailability of several anticancer drugs. The impact of PPIs co-administered with cyclin-dependent kinase 4 and 6 inhibitors is controversial. We aimed to clarify whether the concomitant use of PPIs impacts palbociclib and abemaciclib effectiveness in breast cancer treatment. PATIENTS AND METHODS: This multicenter, retrospective, observational study, conducted across 4 medical institutions in Japan, consecutively included patients with endocrine-resistant metastatic breast cancer, receiving palbociclib or abemaciclib between December 2017 and August 2022. Propensity score-matched analyses were performed. Treatment efficacy and safety with and without PPIs were compared. Progression-free survival and overall survival were estimated using the Kaplan-Meier method and compared using a log-rank test. A Cox proportional hazards model was used to estimate the hazard ratio. RESULTS: The study included 240 patients. After 1:1 matching, 112 patients were treated with and without PPIs. The median progression-free survival period was 1.2 years in the PPI group and 1.3 years in the non-PPI group (hazard ratio, 1.19; 95% CI, 0.70-2.02). The median overall survival period was 3.6 years in the PPI group, whereas it was not reached in the non-PPI group (hazard ratio, 1.23; 95% CI, 0.61-2.47). Consistent results were obtained for subgroups receiving palbociclib (n = 177) and abemaciclib (n = 63) without propensity score matching. Adverse event incidence and severity were similar in both groups. CONCLUSION: The effectiveness of cyclin-dependent kinase 4/6 inhibitors is unlikely to be affected by concomitant PPI use. Future prospective pharmacokinetic studies are warranted.

Bird's eye view analysis of in situ cholesterol metabolic pathways in breast cancer patients and its clinicopathological significance in their subtypes.

Obesity has been known to increase the risks of breast cancer (BC) development and also to be associated with adverse clinical outcome of the patients. Abnormalities of cholesterol metabolism are not only related to obesity but also to biological or clinical behavior of BC patients. However, which metabolites or pathways of cholesterol metabolism could represent the characteristics of BC patients have remained virtually unknown. Therefore, in this study, we attempted to perform bird's eye view or comprehensive analysis of in situ or intra-tumoral cholesterol metabolic pathways using the multimodal approaches in order to elucidate the possible significance of cholesterol metabolites and its metabolic enzymes including CYP27A1, CYP7A1, and CYP46A1. GC-MS study using BC specimens was first performed in 60 BCE patients to evaluate cholesterol metabolism from cholesterol through oxysterols in both BC and normal tissues. Results of those analyses above lead to evaluating immunoreactivity and mRNA expression of CYP27A1, CYP7A1 and CYP46A1 in 213 and 153 BCE cases, respectively. Results of comprehensive GC-MS analysis did reveal that three oxysterols, 27-HC, 7α-HC and 24-HC were all related to malignant phenotypes in BC. 27-HC abundance was significantly associated with higher tumor stage (P = 0.0475) of BC patients. Luminal B type BC patients harboring high CYP27A1, the enzyme responsible for production of 27-HC were significantly associated with worse disease-free survival than those with low CYP27A1 (P = 0.0463). 7α-HC tended to be more abundant in HER2 positive and TNBC subtypes and higher levels of 7α-HC were also significantly associated with higher Ki-67 labeling index (P = 0.0022) and histological grade (P = 0.0286). CYP7A1, the enzyme involved in production of 7α-HC, was significantly more abundant in TNBC than other subtypes (vs Luminal A; P = 0.0321, vs Luminal B; P = 0.0048, vs HER2; P = 0.0103). The levels of 24-HC in BC were lower than normal breast tissues regardless of its subtypes. CYP46A1, the enzyme involved in the production of 24-HC, was detected only in 33 (15.5%) out of 213 BCE cases examined in this study. Results of our bird's eye view analysis of in situ or intra-tumoral cholesterol metabolism in BC patients did firstly reveal BC subtype dependent involvement of its different pathways. Results also indicated the therapeutic possibility of subtype dependent modification of cholesterol metabolizing pathways in BC patients.

Targeting Amino Acid Metabolic Reprogramming via L-Type Amino Acid Transporter 1 (LAT1) for Endocrine-Resistant Breast Cancer.

The PI3K/Akt/mTOR pathway has been well known to interact with the estrogen receptor (ER)-pathway and to be also frequently upregulated in aromatase inhibitor (AI)-resistant breast cancer patients. Intracellular levels of free amino acids, especially leucine, regulate the mammalian target of rapamycin complex 1 (mTORC1) activation. L-type amino acid transporters such as LAT1 and LAT3 are associated with the uptake of essential amino acids. LAT1 expression could mediate leucine uptake, mTORC1 signaling, and cell proliferation. Therefore, in this study, we explored amino acid metabolism, including LAT1, in breast cancer and clarified the potential roles of LAT1 in the development of therapeutic resistance and the eventual clinical outcome of the patients. We evaluated LAT1 and LAT3 expression before and after neoadjuvant hormone therapy (NAH) and examined LAT1 function and expression in estrogen deprivation-resistant (EDR) breast carcinoma cell lines. Tumors tended to be in advanced stages in the cases whose LAT1 expression was high. LAT1 expression in the EDR cell lines was upregulated. JPH203, a selective LAT1 inhibitor, demonstrated inhibitory effects on cell proliferation in EDR cells. Hormone therapy changed the tumor microenvironment and resulted in metabolic reprogramming through inducing LAT1 expression. LAT1 expression then mediated leucine uptake, enhanced mTORC1 signaling, and eventually resulted in AI resistance. Therefore, LAT1 could be the potential therapeutic target in AI-resistant breast cancer patients.

[A rare case of lymphangitis carcinomatosa of the lung due to primary pulmonary adenocarcinoma with intestinal differentiation successfully treated with chemotherapy].

We report a rare case of lymphangitis carcinomatosa in a 66-year-old man with a relatively long survival of 18 months following chemotherapy.The patient initially presented with dyspnea and lower abdominal pain.Subsequent colonoscopy detected adenocarcinoma of the descending colon, and computed tomography (CT) demonstrated indications of lymphangitis carcinomatosa of the lung.Therefore, the patient was diagnosed with pulmonary metastasis due to colon cancer and administered chemotherapy.The performance status (PS) of patients with lymphangitis carcinomatosa is usually dismal.This patient's PS was also poor, but dyspnea markedly improved following chemotherapy, and a subsequent CT revealed disappearance of radiological findings of lymphangitis carcinomatosa.However, subsequent immunocytochemistry analysis using the cell transfer method in bronchoalveolar lavage fluid specimens revealed diffuse positivity for cytokeratin (CK) 7, while the colon carcinoma was negative for CK7.The difference in CK7 immunoreactivity between the bronchoalveolar lavage fluid and biopsy specimen of the colon indicated that the lymphangitis carcinomatosa in this patient could be reasonably postulated to be caused by a synchronous primary pulmonary adenocarcinoma with intestinal differentiation.However, an autopsy could not be performed to test this hypothesis.