Detection of high-risk patients resistant to CDK4/6 inhibitors with hormone receptor-positive HER2-negative advanced and metastatic breast cancer in Japan (KBCSG-TR-1316).

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) improve the prognosis of hormone receptor-positive HER2-negative advanced/metastatic breast cancer (HR+/HER2- mBC). However, some cancers show resistance to CDK4/6i and have a poor prognosis. The non-luminal disease score (NOLUS) was developed to predict non-luminal disease using immunohistochemical analysis. METHODS: The association between the efficacy of CDK4/6i and NOLUS was investigated by evaluating pathological and clinical data, including real-world progression-free survival (rw-PFS) and overall survival (OS). Real-world data of patients with HR+/HER2- mBC who received CDK4/6i therapy [palbociclib or abemaciclib] as first- or second-line endocrine treatments was obtained. NOLUS was calculated using the formula: NOLUS (0-100) = - 0.45 × estrogen receptor (ER) (%) - 0.28 × progesterone receptor (PR) (%) + 0.27 × Ki67(%) + 73, and the patients were divided into two groups: NOLUS-positive (≥ 51.38) and NOLUS-negative (< 51.38). RESULTS: Of the 300 patients, 28 (9.3%) were NOLUS-positive, and 272 (90.7%) were NOLUS-negative. The expression rates (%) of ER and PgR in NOLUS-positive patients were lower than those in NOLUS-negative patients (p < 0.001). Ki67 expression was higher in NOLUS-positive patients. There were statistically significant differences in prognosis (rw-PFS and OS) between the two groups. Moreover, NOLUS-negative patients showed statistically better rw-PFS with first-line therapy than second-line therapy. However, NOLUS-positive patients showed poor prognoses with both the first and second therapeutic lines, suggesting CDK4/6i inefficacy for NOLUS-positive patients. CONCLUSIONS: The efficacy and prognosis of CDK4/6i significantly differed between the NOLUS-positive and NOLUS-negative patients. This feasible method can predict patients with HR+/HER2- mBC resistant to CDK4/6i and help select a better therapeutic approach to overcome resistance.

[Concurrent COVID-19 and Pneumocystis Jirovecii Pneumonia in a Patient with Breast Cancer Receiving Adjuvant Dose-Dense Chemotherapy].

A 49-year-old woman had been treated with adjuvant dose-dense chemotherapy for left breast cancer pT2N2aM0, Stage ⅢA. She developed a fever of over 38°C on day 13 of the third course of dose-dense doxorubicin/cyclophosphamide (AC)chemotherapy. She was started on oral levofloxacin, but the fever did not resolve. COVID-19 PCR test was positive and chest CT scan showed bilateral ground-glass opacities. She was diagnosed with COVID-19 pneumonia and hospitalized. The fever did not resolve even after sotrovimab and remdesivir were administered. On the 5th hospital day, the serum ß-D-glucan level was found to be elevated(81.7 pg/mL), and she was diagnosed with concurrent COVID-19 and Pneumocystis jirovecii pneumonia(PCP). After the start of sulfamethoxazole-trimethoprim(TMP-SMX), the fever resolved quickly. After discharge from hospital, ground-glass opacities had disappeared. She resumed dose-dense chemotherapy with TMP-SMX and completed without fever. In immunosuppressed patients with cancer drug therapy, it is necessary to make a differential diagnosis of various types of pneumonia and to consider the different types of pneumonia may occur simultaneously.

[A Case of Successful Surgical Treatment for Paraaortic Lymph Nodes Recurrence of Gallbladder Cancer].

Cholecystectomy with gallbladder bed resection and regional lymphadenectomy was performed in a 75-year-old man with advanced gallbladder cancer. Pathological examination revealed adenocarcinoma in the gallbladder with regional lymph node metastases. Cancer recurrence was found in paraaortic lymph nodes behind the duodenum 9 months after the surgery. Although chemotherapy using S-1 was initiated, the lymph nodes remained the same size after 2 courses without any new recurrent regions. Lymphadenectomy was then performed as a curative surgery. The patient has remained alive without recurrence for 46 months after the second surgery.

A small-molecule inhibitor of SMAD3 attenuates resistance to anti-HER2 drugs in HER2-positive breast cancer cells.

PURPOSE: Resistance against anti-HER2 drugs in HER2-positive breast cancer is a major obstacle to the improving prognosis. Transforming growth factor ß (TGFß) is a cytokine involved in the acquisition of more malignant phenotypes through epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties. The aim of this study was to investigate the effects of TGFß and its downstream SMAD pathway on resistance to anti-HER2 drugs. METHODS: HER2-positive breast cancer cell lines were stimulated with TGFß for 14 days. Then, the sensitivity to trastuzumab and lapatinib and the expression levels of various EMT and CSC markers were examined. The correlation of nuclear SMAD3 expression in untreated breast tumor tissues with trastuzumab efficacy in neoadjuvant settings was examined. The effect of a small-molecule inhibitor of SMAD3 (SIS3) on resistance to anti-HER2 drugs was explored. RESULTS: We found that continuous activation of the TGFß-SMAD3 pathway induced resistance to anti-HER2 drugs and CSC traits in HER2-positive breast cancer cells. The induction of drug resistance by TGFß required strong activation of SMAD3. In fact, activated SMAD3 regulated multiple genes that harbor SMAD-binding elements and are involved in trastuzumab resistance. Nuclear SMAD3 expression in tumor tissue was inversely correlated with sensitivity to neoadjuvant treatment with trastuzumab. SIS3 not only prevented the acquisition of resistance to anti-HER2 drugs but also restored trastuzumab sensitivity in trastuzumab-resistant cells. CONCLUSIONS: This study indicates that the TGFß-SMAD3 pathway plays an important role in the induction and maintenance of resistance to anti-HER2 drugs. Thus, SMAD3 is a potential therapeutic target that can inhibit resistance and restore sensitivity to anti-HER2 drugs.