Prognostic value of the 21-Gene Breast Recurrence Score® assay for hormone receptor-positive/human epidermal growth factor 2-negative advanced breast cancer: subanalysis from Japan Breast Cancer Research Group-M07 (FUTURE trial).

PURPOSE: This study aimed to determine whether the 21-Gene Breast Recurrence Score® assay from primary breast tissue predicts the prognosis of patients with hormone receptor-positive and human epidermal growth factor 2-negative advanced breast cancers (ABCs) treated with fulvestrant monotherapy (Group A) and the addition of palbociclib combined with fulvestrant (Group B), which included those who had progression in Group A from the Japan Breast Cancer Research Group-M07 (FUTURE trial). METHODS: Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test and Cox regression analysis based on original recurrence score (RS) categories (Low: 0-17, Intermediate: 18-30, High: 31-100) by treatment groups (A and B) and types of ABCs (recurrence and de novo stage IV). RESULTS: In total, 102 patients [Low: n = 44 (43.1%), Intermediate: n = 38 (37.5%), High: n = 20 (19.6%)] in Group A, and 45 in Group B, who had progression in Group A were analyzed. The median follow-up time was 23.8 months for Group A and 8.9 months for Group B. Multivariate analysis in Group A showed that low-risk [hazard ratio (HR) 0.15, 95% confidence interval (CI) 0.04-0.53, P = 0.003] and intermediate-risk (HR 0.22, 95% CI 0.06-0.78) with de novo stage IV breast cancer were significantly associated with better prognosis compared to high-risk. However, no significant difference was observed among patients with recurrence. No prognostic significance was observed in Group B. CONCLUSION: We found a distinct prognostic value of the 21-Gene Breast Recurrence Score® assay by the types of ABCs and a poor prognostic value of the high RS for patients with de novo stage IV BC treated with fulvestrant monotherapy. Further validations of these findings are required.

Changes in cell-free DNA after short-term palbociclib and fulvestrant treatment for advanced or metastatic hormone receptor-positive and human epidermal growth factor 2-negative breast cancer.

PURPOSE: Here, we investigated the potential predictive and elucidating efficacy of cell-free DNA (cfDNA) changes on clinical outcomes and biological effects, respectively, after short-term palbociclib and fulvestrant treatment for patients with hormone receptor (HR)-positive and human epidermal growth factor 2 (HER2)-negative advanced or metastatic breast cancer (ABC). METHODS: In this secondary analysis of the Japan Breast Cancer Research Group-M07 (FUTURE) trial, blood cfDNA was obtained before palbociclib treatment and on day 15 of cycle one (28-day cycle). Target enrichment was performed using next-generation sequencing; progression-free survival (PFS) was compared based on cfDNA changes between baseline and day 15 of cycle one after combination therapy. RESULTS: Fifty-six patients (112 paired blood samples) were examined. The median follow-up time was 8.9 months. PIK3CA (30.4%, 17/56), FOXA1 (30.4%, 17/56), and ESR1 (28.6%, 16/56) were most frequently mutated at baseline. The number of mutated genes was significantly decreased on day 15 compared with that at baseline (paired t test: P value = 0.025). No significant difference was observed in PFS (decrease group, 7.9 m vs the others, 9.3 m; log-rank P value = 0.75; hazard ratio, 1.13; 95% confidence interval, 0.53-2.41). Among patients without previous aromatase inhibitor treatment (n = 15), three (20%) had ESR1 mutations after progression to fulvestrant. CONCLUSION: No significant association was observed between changes in mutated genes after short-term palbociclib and fulvestrant treatment and disease progression; a significant reduction in cfDNA mutation level was observed on day 15 of cycle one. Clinical meanings of cfDNA should be investigated in the future trials.

Development of a Machine Learning-Based Prognostic Model for Hormone Receptor-Positive Breast Cancer Using Nine-Gene Expression Signature.

Background: Determining the prognosis of hormone receptor positive (HR+) breast cancer (BC), which accounts for 80% of all BCs, is critical in improving survival outcomes. Stratifying individuals at high risk of BC-related mortality and improving prognosis has been the focus of research for over a decade. However, these tools are not universal as they are limited to clinical factors. We hypothesized that a new framework for predicting prognosis in HR+ BC patients can develop using artificial intelligence. Methods: A total of 2,338 HR+ human epidermal growth factor receptor 2 negative (HER2-) BC cases were analyzed from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) cohorts. Groups were then divided into high- and low-risk categories utilizing a recurrence prediction model (RPM). An RPM was created by extracting nine prognosis-related genes from over 18,000 genes using a logistic progression model. Results: Risk classification by RPM was significantly stratified in both the discovery cohort and validation cohort. In the time-dependent area under the curve analysis, there was some variation depending on the cohort, but accuracy was found to decline significantly after about 10 years. Cell cycle related gene sets, MYC, and PI3K-AKT-mTOR signaling were enriched in high-risk tumors by the Gene Set Enrichment Analysis. High-risk tumors were associated with high levels of immune cells from the lymphoid and myeloid lineage and immune cytolytic activity, as well as low levels of stem cells and stromal cells. High-risk tumors were also associated with poor therapeutic effects of chemotherapy and endocrine therapy. Conclusions: This model was able to stratify prognosis in multiple cohorts. This is because the model reflects major BC therapeutic target pathways and tumor immune microenvironment and, further is supported by the therapeutic effect of chemotherapy and endocrine therapy.

Impact of systemic dexamethasone dosage on docetaxel-induced oral mucositis in patients with breast cancer.

Oral mucositis (OM) is a common adverse effect of docetaxel-containing treatment. This study aimed to assess whether dexamethasone (DEX) dose-dependently attenuates docetaxel-induced OM and dysgeusia. We retrospectively analyzed medical records of patients with breast cancer receiving docetaxel-containing regimens at Hokkaido University Hospital between June 2015 and June 2022. The patients were divided into low-dose and high-dose groups (DEX 4 or 8 mg/day on days 2-4, respectively), and incidence of OM and dysgeusia, and risk factor(s) for OM incidence were evaluated. The incidence of all-grade OM in the first cycle was 57.8% in the low-dose group and 19.2% in the high-dose group (P = 0.0002), which met our primary endpoint. The incidence of OM in all treatment cycles was also significantly lowered by DEX-dose increase (P = 0.01). In contrast, the incidence of dysgeusia was similar between the two groups in the first and all cycles (P = 0.50 and P = 0.28, respectively). These results were also confirmed in a propensity score-matched population. Multivariate logistic regression analysis also suggested that lower DEX dosage was a singular risk factor for all-grade OM incidence. In conclusion, our study suggests that DEX dose-dependently reduces the incidence of OM in docetaxel-containing regimens for breast cancer treatment.

High dose of dexamethasone attenuates docetaxel-induced fluid retention in breast cancer treatment.

Docetaxel-induced fluid retention (DIFR) cumulatively occurs and is one of the most troublesome adverse effects. This study aimed to determine whether high dose dexamethasone (DEX) could prevent DIFR during breast cancer treatment. Breast cancer patients receiving docetaxel (75 mg/m2)-containing regimens were divided into 4 and 8 mg/day DEX groups, with each DEX dose administered on days 2-4 and retrospectively assessed. Incidence of greater than or equal to grade 2 DIFR was significantly lower in the 8 mg group (13.0%) compared to the 4 mg group (39.6%, P = 0.001). All-grade DIFR was also less in the 8 mg group (P = 0.01). Furthermore, the maximum variation of body weight was significantly lower in the 8 mg group (P = 0.0003). These results were also confirmed in the propensity score-matched population. Additionally, time-related DIFR incidence was also significantly delayed in the 8 mg group (P = 0.0005). Our study revealed that high dose DEX prevents DIFR. Therefore, further studies on its management are required for less onerous chemotherapy provision with better DIFR control.

Dexamethasone dose-dependently prevents taxane-associated acute pain syndrome in breast cancer treatment.

PURPOSE: Taxane-associated acute pain syndrome (T-APS) is one of the most bothersome adverse effects caused by taxanes. We have previously reported the attenuating effect of dexamethasone (DEX) on T-APS and its risk factors under DEX prophylaxis. However, the appropriate DEX dosage administration remains unclear. Therefore, this study aimed to investigate whether DEX dose-dependently prevents T-APS in breast cancer patients. METHODS: We retrospectively evaluated patients with breast cancer who received docetaxel (75 mg/m2)-containing chemotherapy without pegfilgrastim and regular non-steroidal anti-inflammatory drugs. The patients were divided into 4 mg/day and 8 mg/day DEX groups, with each DEX dosage on days 2-4 (n = 68 for each group). Primary endpoint was the comparison of all-grade T-APS incidence between the groups. Propensity score-matching was performed to adjust the baseline factors between the groups, and outcomes in the matched-population were also assessed. RESULTS: The incidence of all-grade T-APS was 72.1% in 4 mg/day group and 48.5% in 8 mg/day group, which was significantly lowered by higher DEX dosage (P = 0.008). The severity of T-APS was also significantly reduced in 8 mg/day group (P = 0.02). These results were confirmed in the propensity score matching. Multivariate logistic analysis showed that higher DEX dosage was an independent T-APS preventive factor, whereas age < 55 years was a risk factor. Moreover, DEX-dosage-associated adverse effects similarly appeared in both groups. CONCLUSION: Our study suggested that DEX dose-dependently prevents T-APS in breast cancer treatment. As understanding of the nature of T-APS and its appropriate management can significantly contribute to less onerous chemotherapy provision, further studies are required.

Fulvestrant plus palbociclib in advanced or metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer after fulvestrant monotherapy: Japan Breast Cancer Research Group-M07 (FUTURE trial).

PURPOSE: The combination of cyclin-dependent kinase 4/6 inhibitors and endocrine therapy is a standard treatment for hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC); however, their toxicities and financial burden are major issues, especially for prolonged treatment. We investigated fulvestrant plus palbociclib in patients with HR-positive MBC resistant to fulvestrant monotherapy. METHODS: Patients who initially received fulvestrant as their first- or second-line endocrine therapy were assigned to group A. Patients with disease progression during fulvestrant monotherapy who subsequently received fulvestrant plus palbociclib were assigned to group B. The primary endpoint was progression-free survival (PFS1) in group B. We set the threshold median PFS of 5 months (null hypothesis). RESULTS: Between January 2018 and February 2020 we enrolled 167 patients in group A (January 2018-February 2020) from 55 institutions, of whom 72 subsequently received fulvestrant plus palbociclib and were enrolled in group B. The median follow-up was 23.8 and 8.9 months in groups A and B, respectively. The median PFS in group B (combination therapy) was 9.4 (90% confidence interval [CI]: 6.9-11.2) months (p < 0.001). This was 25.7 (90% CI: 21.2-30.3) months in group A (fulvestrant monotherapy). The TTF in group B was 7.2 (90% CI: 5.5-10.4) months. In the post-hoc analysis, the median PFS1 in group B among patients with longer-duration fulvestrant monotherapy (> 1 year) was longer than that of patients with shorter-duration monotherapy (≤ 1 year) (11.3 vs. 7.6 months). No new toxicities were observed. CONCLUSION: Our findings suggest that palbociclib plus fulvestrant after disease progression despite fulvestrant monotherapy is potentially safe and effective in patients with HR-positive/HER2-negative advanced MBC.

Risk Factor Analysis for the Occurrence of Severe Adverse Effects in Eribulin Treatment.

BACKGROUND/AIM: Eribulin is an effective chemotherapeutic agent for the treatment of metastatic breast cancer and advanced or metastatic soft-tissue sarcomas. However, severe adverse effects (SAEs) occur in 30-40% of the patients, and significantly reduce the patients' quality of life and disturb the recommended treatment schedules. Neutropenia is the main cause of treatment suspension, delay, and/or dose reductions, also leading to relative dose intensity reduction. This study aimed to examine the risk factors for SAE occurrence after eribulin treatment. PATIENTS AND METHODS: Eighty patients with metastatic breast cancer or advanced or metastatic soft tissue sarcoma who received eribulin were retrospectively evaluated. Risk factors for SAE occurrence in the first cycle were primarily assessed. In addition, factors associated with SAE occurrence during all treatment cycles were evaluated. RESULTS: SAEs in the first cycle occurred in 45% of patients. The primary SAE was neutropenia (91.7%). The incidence of SAEs during all treatment cycles was 61.3%. Multivariate analyses suggested that lower baseline neutrophil and hemoglobin levels were risk factors for SAE occurrence and severe neutropenia incidence in the first cycle. An independent factor associated with SAE occurrence during all cycles was age ≥65 years and a tendency was confirmed for baseline anemia. CONCLUSION: Baseline neutropenia and anemia were risk factors for SAE occurrence during the first eribulin treatment cycle. Age ≥65 years was also associated with SAE occurrence during all treatment cycles. Patients with these risk factors should be carefully monitored for assessment and prophylaxis.

Influence of Dose Reduction of Prophylactic Dexamethasone on Chemotherapy-induced Nausea and Anorexia in Patients Under 55 Years Old Treated With Anthracycline-containing Regimens.

BACKGROUND/AIM: The incidence of acute nausea in patients treated with anthracycline-containing regimens for breast cancer, was significantly increased by dose reduction of prophylactic antiemetic dexamethasone on day 1, whilst reducing it on days 2-4 did not affect delayed nausea. We also found that patients <55 years old were at higher risk of developing nausea. In this retrospective study, we evaluated the influence of dexamethasone dosage on gastrointestinal symptoms in patients <55 years old. PATIENTS AND METHODS: Patients (20-54 years old) who had received anthracycline-containing regimens for breast cancer were divided into reduced dose (6.6 mg dexamethasone on day 1, and 4 mg on days 2-4) and control (9.9 mg and 8 mg, respectively) groups and retrospectively evaluated. The incidence and severity of nausea, vomiting and anorexia were compared. Risk factors associated with nausea were also assessed. RESULTS: The incidence of acute nausea was significantly higher in the reduced dosage group than in the control group (75.0% and 45.2%, respectively; p=0.02). In contrast, the rate of delayed nausea was not different (p=0.41); the incidence of vomiting and anorexia, and the severity of nausea and anorexia were also not statistically different. Multivariate logistic analysis suggested that patients with no-to-low alcohol consumption and those administered 6.6 mg dexamethasone on day 1 were at a higher risk of acute nausea. CONCLUSION: Our study suggests that dexamethasone dose reduction on day 1 in patients treated with anthracycline-containing regimens is not suitable for acute nausea management, and that the dosage can be reduced to at least 4 mg on days 2-4, even in patients under 55 years of age.

Impact of systemic dexamethasone administration on oral mucositis induced by anthracycline-containing regimens in breast cancer treatment.

Oral mucositis (OM) is one of the most common complications associated with chemotherapy. Here, we evaluated whether systemic dexamethasone (DEX) dosage in prophylactic antiemetics affected the incidence of OM in anthracycline-containing regimens. Patients receiving anthracycline-containing regimens for breast cancer were divided into high- and low-DEX dose groups and retrospectively evaluated. The incidence of all-grade OM in the first cycle in the high- and low-dose groups was 27.3% and 53.5%, respectively, and was significantly lowered by increasing the DEX dose (P < 0.01); thus, the study met its primary endpoint. The result in all treatment cycles was also significant (P = 0.02). In contrast, the incidence of dysgeusia was similar between the high- and low-dose groups in the first and all cycles (13.6% and 16.3% in the first cycle [P = 0.79] and 27.3% and 34.9% in all cycles [P = 0.42], respectively). Multivariate analysis revealed that low DEX dosage was an independent risk factor for all-grade OM development. In conclusion, our study suggests that DEX attenuates OM in anthracycline-containing regimens for breast cancer treatment in a dose-dependent manner. Further evaluation of OM prophylaxis, including DEX administration, is required for better control.

Clinical Relevance of Estrogen Reactivity in the Breast Cancer Microenvironment.

Purpose: Estrogen signals play an important role in the phenotype of estrogen receptor-positive breast cancer. However, comprehensive analyses of the effect of responsiveness to estrogen signals on the tumor microenvironment and survival in large cohorts of primary breast cancer patients have been lacking. We aimed to test the hypothesis that estrogen reactivity affects gene expression and immune cell infiltration profiles in the tumor microenvironment and survival. Methods: A total of 3,098 breast cancer cases were analyzed: 1,904 from the Molecular Taxonomy of Breast Cancer (METABRIC) cohort, 1,082 from The Cancer Genome Atlas (TCGA) cohort, and 112 from the Hokkaido University Hospital cohort. We divided the group into estrogen reactivity-high and estrogen reactivity-low groups utilizing the scores of ESTROGEN_RESPONSE_EARLY and ESTROGEN_RESPONSE_LATE in Gene Set Variation Analysis. Results: Breast cancer with high estrogen reactivity was related to Myc targets, metabolism-related signaling, cell stress response, TGF-beta signaling, androgen response, and MTORC1 signaling gene sets in the tumor microenvironment. Low estrogen reactivity was related to immune-related proteins, IL2-STAT5 signaling, IL6-JAK-STAT3 signaling, KRAS signaling, cell cycle-related gene sets, and EMT. In addition, breast cancer with high levels of estrogen reactivity had low immune cytolytic activity and low levels of immunostimulatory cells. It also had low levels of stimulatory and inhibitory factors of the cancer immunity cycle. Patients with high estrogen reactivity were also associated with a better prognosis. Conclusion: We demonstrated the relationship between estrogen reactivity and the profiles of immune cells and gene expression, as well as survival.

Evaluation of a novel medical device for pegfilgrastim administration.

Pegfilgrastim, a pegylated form of granulocyte colony-stimulating factor, has reduced the risk of developing febrile neutropenia, which is associated with an increase in severe infection and prolonged hospitalization. However, pegfilgrastim administration requires that patients visit hospital following cancer chemotherapy, thus imposing a burden on patients and those around them. An on-body injector (OBI), which automatically administers pegfilgrastim about 27 hours after chemotherapy, was used in this study. The OBI, which consists of a main pump unit and infusion set, is a drug delivery device designed to be attached to the patient's body, with a timer-controlled dosing function. This study was conducted in breast cancer patients to evaluate the safety of pegfilgrastim administered subcutaneously via the OBI. The study period consisted of screening and treatment observation periods involving four cycles of neoadjuvant or adjuvant chemotherapy with docetaxel plus cyclophosphamide. One 3.6-mg pegfilgrastim dose was administered subcutaneously via OBI during each cycle of chemotherapy. The study enrolled 35 patients, and no serious adverse events or febrile neutropenia occurred. Administration of pegfilgrastim was successfully completed at all times when the OBI was attached to the patient, and no safety concerns associated with OBI function arose. For outpatients requiring pegfilgrastim following cancer chemotherapy, the use of an OBI was considered to be a safe option to reduce the need for outpatient visits that restrict their activities of daily living.

Impact of reducing day 1 dexamethasone dose in anthracycline-containing regimens on acute gastrointestinal symptoms associated with breast cancer treatment.

The potential of steroid sparing from day 2 onward is reported in anthracycline-containing regimens for breast cancer treatment. We evaluated whether the reduction of dexamethasone (DEX) dose from 9.9 to 6.6 mg on day 1 is possible in anthracycline-containing treatments. Patients receiving anthracycline-containing regimens were divided into control (9.9 mg DEX on day 1) and reduced (6.6 mg DEX on day 1) groups, and retrospectively evaluated. The complete response (CR) rate and the incidence and severity of nausea, vomiting, anorexia, and fatigue were evaluated. The CR rate in the acute phase (day 1) was 63.1% and 38.1% in the control and reduced groups, respectively, with significant difference (P = 0.01) between the groups. However, no difference was found in the delayed phase (days 2-7). The incidence of anorexia and vomiting during treatment was not statistically different. Severity of nausea tended to, but not statistically, worsen while anorexia significantly worsened in the reduced group. Multivariate analysis suggested that patients < 55 years, with non- or less-alcohol drinking habit (< 5 days/week), and administered reduced-DEX dosage on day 1, have a higher risk of acute nausea development. Thus, reducing day 1 DEX dose in anthracycline-containing regimens is not suitable for acute nausea management.

Severe Hypertriglyceridemia Induced by Docetaxel: A Novel Case Report.

Docetaxel (DOC) is one of the most effective agents for breast cancer treatment. Here, we report docetaxel-induced severe hypertriglyceridemia in a patient previously diagnosed with hyperlipidemia and corresponding therapeutic intervention. A postmenopausal woman, with previously controlled hyperlipidemia using rosuvastatin 5 mg daily, was diagnosed with stage IIB breast cancer with human epidermal growth factor receptor-2 overexpression; she received DOC (75 mg/m2), pertuzumab, and trastuzumab treatment as neoadjuvant chemotherapy. The serum triglyceride level was mildly higher than normal, and cholesterol level was normal at baseline. The serum triglyceride level was almost stable after chemotherapy initiation but suddenly increased to grade 3 (770 mg/dL) after the third cycle of the treatment without any symptoms. Sustained-release bezafibrate 400 mg was administered, resulting in a significant decrease to the baseline level; bezafibrate was discontinued on day 28 of the fourth chemotherapy as neoadjuvant chemotherapy was completed. The level was stable around the baseline level during adjuvant chemotherapy with pertuzumab and trastuzumab. Therefore, DOC-induced severe hypertriglyceridemia was strongly indicated in this case. The mechanism underlying the symptoms remains unclear; we speculate that it could be a resultant of a decrease in lipid metabolism as the patient had grade 2 diarrhea. Moreover, her backgrounds, such as mild hypertriglyceridemia, postmenopausal, diabetes, and obesity, in addition to DOC administration might have affected the outcome. Fibrate administration and cessation of treatment were as effective as in previous reports. DOC-induced hypertriglyceridemia presents with the possibility of severe complications. Elucidation of the exact mechanisms and epidemiological features is required for better management.

Impact of clinical targeted sequencing on endocrine responsiveness in estrogen receptor-positive, HER2-negative metastatic breast cancer.

Clinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients' prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.

Analysis of plasma HER2 copy number in cell-free DNA of breast cancer patients: a comparison with HER2 extracellular domain protein level in serum.

BACKGROUND: HER2 (human epidermal growth factor receptor 2) status has been evaluated in breast cancer (BC) tissues by immunohistochemistry or in situ hybridization. We evaluated HER2 copy number (CN) assay in plasma cell-free DNA (cfDNA) from blood samples and compared it with protein measurements of HER2 extracellular domain (ECD) in serum. METHODS: Serum HER2-ECD levels were measured by chemi-luminescence immunoassay using anti-HER2 monoclonal antibodies. Analyses were performed on 120 cases of primary BC, 30 cases of metastatic BC and 34 cases treated by neoadjuvant chemotherapy (NAC). This study was approved by Medical Research Review Advancement No. 1857 for Kumamoto University. RESULTS: There was a positive correlation between HER2-CN ratios and HER2-ECD levels, in primary (n = 54) and metastatic (n = 30) HER2-positive BC (P = 0.003 and P < 0.001, respectively). HER2-ECD levels were significantly higher in patients with a larger number of metastatic sites (P = 0.02). The usefulness of HER2 levels in discriminating primary and metastatic HER2-positive BC evaluated by ROC curve analysis was better in the HER2-ECD assay than in the HER2-CN assay. In 34 patients who received NAC, there was a small decrease in HER2-CN ratios between before and after NAC (P = 0.10), while there was an obvious decrease in HER2-ECD levels between before and after NAC (P < 0.001). CONCLUSION: Compared to HER2-ECD levels, the clinical usefulness of HER2-CN ratio was somewhat inferior. Improved measurement methods and further examination of the association with long-term prognosis and the response to anti-HER2 treatment analyzed by HER2-CN and HER2-ECD assay are required.

[Interstitial Pneumonia Caused by Olaparib during Treatment of Breast Cancer-A Case Report].

The characteristic adverse events of olaparib, a PARP inhibitor, are nausea, vomiting, and anemia, and interstitial pneumonia is rarely reported. We report a case of interstitial pneumonia following the treatment of a metastatic breast cancer with olaparib. The patient was a 34-year-old woman. In March 2018, she was diagnosed with stage Ⅳ breast cancer(multiple lung metastases). She was treated with epirubicin and cyclophosphamide followed by paclitaxel. In November 2018, brain and spinal cord metastases were detected, and she was treated with radiation. In December 2018, a BRCA1 deleterious mutation was confirmed, and treatment with olaparib was initiated. Six weeks later, olaparib was discontinued due to anemia; it also caused interstitial pneumonia. The interstitial pneumonia resolved following multidisciplinary treatment during hospitalization. Subsequently, she was treated with cyclophosphamide/methotrexate/fluorouracil. It is necessary to consider interstitial pneumonia as an adverse effect of olaparib.

Transcriptomic and functional pathway features were associated with survival after pathological complete response to neoadjuvant chemotherapy in breast cancer.

Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) has been proposed as a surrogate endpoint for the prediction of long-term survival in breast cancer (BC); however, an increased pCR rate has not clearly correlated with improved survival. We hypothesized that some transcriptomic and functional pathway features correlate with survival after pCR in BC. We utilized 2 published NAC cohorts, 105 women with gene expression data before, "Baseline", and that changed during NAC, "Delta", and TCGA database with 1068 BC patients to investigate the relationship between the efficacy of NAC and survival utilizing differentially expressed-mRNAs, construction and analysis of the mRNA-hub gene network, and functional pathway analysis. In mRNA expression profiling, S100A8 was a gene involved in survival after pCR in Baseline and NDP was a gene involved in recurrence after pCR in Delta. In functional pathway analysis, we found multiple pathways involved in survival after pCR. In mRNA-hub gene analysis, HSP90AA1, EEF1A1, APP, and HSPA4 were related to recurrence in BC patients with pCR due to NAC. TP53, EGFR, CTNNB1, ERBB2, and HSPB1 may play a significant role in survival for patients with pCR. Interestingly, high HSP90AA1, HSPA4, S100A8, and TP53, and low EEF1A1, EGFR, and CTNNB1 expressing tumors have significantly worse overall survival in TCGA BC cohort. We demonstrated the genes and functional pathway features associated with pCR and survival utilizing the bioinformatics approach to public BC cohorts. Some genes involved in recurrence after pCR due to NAC also served as prognostic factors in primary BC.

HER2 Gene Amplification in ER-positive HER2 Immunohistochemistry 0 or 1+ Breast Cancer With Early Recurrence.

BACKGROUND/AIM: In estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, standard chemotherapies as well as adjuvant endocrine therapy might not be enough for prevention of early relapse. MATERIALS AND METHODS: We focused on ER-positive, HER2 immunohistochemistry (IHC) 0 or 1+ breast cancer, and retrospectively examined HER2 gene amplification and TP53 mutation in breast cancer tissues in patients with or without early recurrence. Post-relapse survival in patients with early recurrence was also analyzed by mutation status of HER2 and TP53. RESULTS: Surprisingly, amplification of the HER2 gene was found in 15% of patients with early recurrence. None of the patients without relapse had HER2-amplified tumors. Post-relapse survival in patients with HER2 gene amplification and/or TP53 mutation in primary tumors was shorter than that in patients without these mutations, especially among postmenopausal women. CONCLUSION: HER2 gene amplification exists in ER-positive, HER2 IHC 0 or 1+ breast cancer in patients who developed early distant metastasis.

The Impact of Immunofunctional Phenotyping on the Malfunction of the Cancer Immunity Cycle in Breast Cancer.

The cancer-immunity cycle (CIC) is a series of self-sustaining stepwise events to fight cancer growth by the immune system. We hypothesized that immunofunctional phenotyping that represent the malfunction of the CIC is clinically relevant in breast cancer (BC). Total of 2979 BC cases; 1075 from TCGA cohort, 1904 from METABRIC cohort were analyzed. The immunofunctional phenotype was classified as follows: hot T-cell infiltrated (HTI), high immune cytolytic activity (CYT), Cold T-cell infiltrated (CTI), high frequency of CD8+ T cells and low CYT, and non-inflamed, low frequency of CD8+ T cells and low CYT. The analysis of tumor immune microenvironment in the immunofunctional phenotype revealed that not only immunostimulatory factors, but also immunosuppressive factors were significantly elevated and immunosuppressive cells were significantly decreased in HTI. Patients in HTI were significantly associated with better survival in whole cohort and patients in CTI were significantly associated with worse survival in triple negative. Furthers, HTI was inversely related to estrogen responsive signaling. We demonstrated that immunofunctional phenotype not only indicated the degree of anti-cancer immune dysfunction, but also served as a prognostic biomarker and HTI was inversely related to estrogen response.