Validation of late recurrence prediction by gene expression profiles and clinicopathological factors in estrogen receptor-positive breast cancer.

BACKGROUND: The mechanism of late recurrence (LR) of estrogen receptor (ER)-positive breast cancer remains unclear, as previous studies have separately investigated "gene expression profiles" and "clinicopathological factors." Thus, this study aimed to evaluate the predictive capability of LR by combining the two independent factors of gene expression profiles (42-gene classifier: 42GC) and clinicopathological factors (Clinical Treatment Score post-5 years: CTS5) in multiple large cohorts. METHODS: We analyzed microarray CEL file data downloaded from public databases of 28 global cohorts. A total of 2,454 patients with ER-positive breast cancer were analyzed for 42GC, and 1,263 of these, with complete clinicopathological data were analyzed for CTS5. RESULTS: In the analysis of recurrent patients, the 42GC LR and CTS5 low-risk group tended to have LR. Notably, in the analysis of patients with and without recurrence, the highest LR rate beyond 5 years was observed in the CTS5 high-risk group. The combination of the 42GC and CTS5 high-risk groups showed the highest LR rate (16.9%), significantly exceeding that of the 42GC non-LR (NLR) and CTS5 low-risk combination (5.41%) (p = 0.038, odds ratio = 3.53). Furthermore, incorporating a third factor, 95GC, potentially reduced the number of patients prioritized for extended hormonal therapy for approximately one-quarter of patients. CONCLUSIONS: Results confirmed that the two factors, gene expression profiles and clinicopathological factors, affect the time of recurrence. It also showed that the biological predisposition for LR (CTS5 low-risk) differed from the high LR rate (CTS5 high-risk). In clinical practice, patients with the 42GC LR and CTS5 high-risk combination should be prioritized for extended hormonal therapy. The addition of CTS5 and 95GC to 42GC allows for better risk classification of LR.

Investigation of recurrence prediction ability of EndoPredict® using microarray data from fresh frozen tissues in ER-positive, HER2-negative breast cancer and indication expansion of EndoPredict® from microarray data from fresh-frozen to FFPE tissues.

BACKGROUND: EndoPredict® (EP) is a multigene assay to predict distant recurrence risk in luminal breast cancer. EP measures the expression of 12 genes in primary tumor by qRT-PCR from formalin-fixed paraffin-embedded (FFPE) tissues and calculates EP risk score that indicates the risk of distant recurrence. We evaluated the performance of EP in predicting distant recurrence risk using microarray data from fresh frozen (FF) tissues. We also examined the applicability of EP to microarray data from FFPE tissues. METHODS: We analyzed the publicly available data of 431 node-negative and 270 node-positive patients with luminal breast cancer who received endocrine therapy alone. We evaluated the prognostic value of EP using microarray data from FF tissues. Next, we created an algorithm to calculate EP risk score using microarray data from FFPE tissues. We examined the correlation coefficient of EP risk score and concordance rate of EP risk high/low using microarray data from FFPE/FF tissue pairs in a validation set of 39 patients. RESULTS: In 431 node-negative patients, the distant recurrence-free survival (DRFS) rate was significantly worse in those with high EP risk scores (P = 3.68 × 10-6, log-rank). The 5-year DRFS was 95.2% in those with low EP risk score. In the validation set, the correlation coefficient of EP risk score was 0.93 and the concordance rate of EP risk high/low was 91.7%. CONCLUSIONS: EP using microarray data from FF tissues was useful in predicting distant recurrence risk in luminal breast cancer, and EP might be utilized in microarray data from FFPE tissues.

Multi-gene assay 95- and 155-gene classifiers for prognosis prediction and chemotherapy omission in lymphnode positive luminal-type breast cancer.

BACKGROUND: The prognosis of lymphnode positive breast cancer is worse than that of lymph node negative breast cancer but some cases may not require chemotherapy. We investigated the ability of the new multi-gene assays, 95GC and 155GC, to identify patients with lymphnode positive Luminal-type breast cancer whose chemotherapy can be omitted relatively safely. PATIENTS AND METHODS: We extracted 1721 cases of lymphnode positive Luminal-type breast cancer from 22 public database Caucasoid cohorts and 3 Asian cohorts, and performed recurrence prognosis analysis with 95GC and 155GC. RESULTS: Using 95GC, the cases were stratified as the high (n = 917) and low (n = 202) groups according to the prognosis of lymphnode positive Luminal-type endocrine only breast cancer. The 5 years DRFS in the low risk group was relatively good at 90%, and no additional effect of chemotherapy was observed, suggesting omission of chemotherapy. The recurrence prognosis was also significantly dichotomized into the high and low risks by 95GC in 21GC RS 0-25 cases. Here, we found a group with poor prognosis even in post-menopause RS 0-25 and requiring chemotherapy. Additionally, a group in which the prognosis was good in pre-menopause RS 0-25, and the omission of chemotherapy could be considered. Patients in the high-risk group at 155GC had poor prognosis after chemotherapy. 155GC also showed a group that chemotherapy alone was not sufficient. CONCLUSION: In this study, we demonstrated the possibility of accurately selecting patient groups for which chemotherapy can be omitted from lymphnode positive Luminal-type breast cancer.

Optimal Treatment of Hormone Receptor-positive Advanced Breast Cancer Patients With Palbociclib.

BACKGROUND/AIM: Palbociclib was the first cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved worldwide. Currently, CDK4/6 inhibitors are strongly recommended for endocrine therapy in the first or second line with hormone receptor-positive advanced breast cancer. It is expected the use of CDK4/6 inhibitor will further increase. Therefore, the aim was to investigate and better understand the use of palbociclib. PATIENTS AND METHODS: We retrospectively analyzed the data of patients with advanced breast cancer who were treated with palbociclib in three hospitals between 2018 and 2022. Clinical data were obtained from the patients' medical electronic records. RESULTS: A total of 143 patients were enrolled. The median age was 66 years (range=33-89), and the majority (90.9%) were postmenopausal patients. In total, median time-to-treatment discontinuation (TTD) (95% confidence interval, CI) was 7 (6-10) months. Median TTD (95% CI) was 13 (7-20) months for the first or second line, and significantly prolonged compared to TTD for the third or later lines with palbociclib (p<0.0001). The importance of front-line use was indicated. Multivariate analyses showed that no visceral metastasis or first or second line therapy influenced the longer TTD. Between patients above or below 70 years of age, older age did not negatively affect TTD, though there were significantly more cases of dose reduction or withdrawal in patients over 70 years old. The variation of adverse events (AEs) among hospitals was very large (9.0%, 31.3%, 4.5%). We found that understanding of AE management was important. CONCLUSION: This study showed that dose reduction or withdrawal of palbociclib had no harmful effects in Japanese patients. Efficacy was also high in older patients. It is important to manage palbociclib administration more safely and appropriately. A combination of dose reduction and withdrawal is key to this therapeutic strategy.

Concurrent trastuzumab deruxtecan-induced interstitial lung disease and COVID-19 in the treatment of advanced breast cancer.

Patients with cancer are at an increased risk of developing coronavirus disease 2019 (COVID-19) infection. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) against epidermal growth factor receptor 2 (HER2)-positive cancer, known to cause drug-induced interstitial lung disease (DILD), including drug-induced pneumonitis. A 60-year-old woman with breast cancer developed a fever during treatment with T-DXd and was diagnosed with COVID-19. The fever persisted for approximately 3 weeks, and chest computed tomography showed multiple consolidations with bilateral peripheral predominance. Since the clinical course was atypical for COVID-19 due to the long duration of the fever and the CT pattern was frequently seen in T-DXd-induced ILD, the patient was diagnosed with T-DXd-induced ILD, following which, prednisolone was started, leading to improvement in the symptoms and fading of shadows. Even in patients suspected of COVID-19 pneumonia, physicians should consider the possibility of DILD, particularly in patients undergoing cancer treatment.

Everolimus for Treating Hormone Receptor-positive Metastatic Breast Cancer Previously Treated With Cyclin-dependent Kinase 4/6 Inhibitors.

BACKGROUND/AIM: Cyclin-dependent kinase (CDK) 4/6 inhibitors have become the standard of care as the first- and second-line treatments for hormone receptor-positive (HR+) or human epidermal growth factor receptor 2 (HER2)-negative metastatic and recurrent breast cancers. Although CDK 4/6 inhibitors can markedly prolong progression-free survival, there is no clear evidence of their post-treatment effects. The option of developing mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, has been discussed as a post-treatment option for such patients. This study aimed at determining everolimus' efficacy as a post-treatment option following CDK4/6 inhibitor administration in clinical settings. PATIENTS AND METHODS: Thirteen patients who received everolimus as a post-treatment after CDK4/6 inhibitor therapy from December 2017 to July 2021 were retrospectively reviewed. The primary endpoint was progression-free survival; the secondary endpoints were overall response rate, clinical benefit rate, and overall survival. RESULTS: The median patient age, progression-free survival, and overall survival were 59 years (range=44-76 years), 9.1 months (95% confidence interval=2.3 to not reached), and 37.4 months (95% confidence interval=12.3-37.4), respectively. The overall response rate and clinical benefit rate were 15.3% (2/13) and 46.2% (6/13), respectively. CONCLUSION: Considering there is a mechanism of resistance to CDK4/6 inhibitors, everolimus would be important as an effective post-treatment for HR+ or HER2-negative metastatic and recurrent breast cancers treated with CDK4/6 inhibitors in clinical settings.