Association of oral mucositis induced by anthracycline-cyclophosphamide and subsequent docetaxel treatment for perioperative breast cancer.

PURPOSE: Anthracycline-cyclophosphamide followed by docetaxel-containing chemotherapy is effective for perioperative breast cancer treatment. However, these treatments frequently induce oral mucositis (OM), with an incidence ranging from 20 to 50%. The association of OM development between different chemotherapeutic treatments remains unclear. Consequently, this study aimed to compare OM development during docetaxel-containing chemotherapy between patients with and without OM experience during previous anthracycline-cyclophosphamide treatments to assess the association between OM development and treatment regimens. METHODS: Seventy-two patients with breast cancer receiving anthracycline-cyclophosphamide followed by docetaxel-containing chemotherapy as a perioperative treatment were categorized into the control (no prior OM experience with anthracycline-cyclophosphamide) and OM-experience (OM development during previous treatment) groups and retrospectively evaluated. The primary endpoint was the incidence of all-grade OM in the first docetaxel-containing chemotherapy cycle. Additionally, the incidences of OM and dysgeusia during all treatment cycles and factors associated with the incidence of OM were evaluated. RESULTS: The incidence of all-grade OM in the first cycle was significantly higher in the OM-experience group (54.2%) than in the control group (10.4%; P < 0.0001). Furthermore, its incidence in all treatment cycles was higher in the OM-experience group (66.7%) than in the control group (12.5%, P < 0.0001). However, the incidence of dysgeusia did not differ between the groups. Multivariate logistic regression analysis revealed OM experience during previous anthracycline-cyclophosphamide treatment and concomitant pertuzumab use as independent risk factors for OM development in subsequent docetaxel-containing chemotherapy. CONCLUSION: Our study suggests that patients experiencing OM with anthracycline-cyclophosphamide during perioperative breast cancer treatment exhibit symptoms following subsequent docetaxel-containing chemotherapy.

Tumor-derived interleukin-34 creates an immunosuppressive and chemoresistant tumor microenvironment by modulating myeloid-derived suppressor cells in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by a lack of therapeutic targets. The paucity of effective treatment options motivated a number of studies to tackle this problem. Immunosuppressive cells infiltrated into the tumor microenvironment (TME) of TNBC are currently considered as candidates for new therapeutic targets. Myeloid-derived suppressor cells (MDSCs) have been reported to populate in the TME of TNBC, but their roles in the clinical and biological features of TNBC have not been clarified. This study identified that interleukin-34 (IL-34) released by TNBC cells is a crucial immunomodulator to regulate MDSCs accumulation in the TME. We provide evidence that IL-34 induces a differentiation of myeloid stem cells into monocytic MDSCs (M-MDSCs) that recruits regulatory T (Treg) cells, while suppressing a differentiation into polymorphonuclear MDSCs (PMN-MDSCs). As a result, the increase in M-MDSCs contributes to the creation of an immunosuppressive TME, and the decrease in PMN-MDSCs suppresses angiogenesis, leading to an acquisition of resistance to chemotherapy. Accordingly, blockade of M-MDSC differentiation with an estrogen receptor inhibitor or anti-IL-34 monoclonal antibody suppressed M-MDSCs accumulation causing retardation of tumor growth and restores chemosensitivity of the tumor by promoting PMN-MDSCs accumulation. This study demonstrates previously poorly understood mechanisms of MDSCs-mediated chemoresistance in the TME of TNBC, which is originated from the existence of IL-34, suggesting a new rationale for TNBC treatment.

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.

[A Case of Male Recurrent Breast Cancer Successfully Treated with Bevacizumab plus Paclitaxel Therapy for Carcinomatous Pericarditis].

We report the case of a 44-year-old male who underwent mastectomy plus axillary lymph node dissection after neoadjuvant chemotherapy for left breast cancer. During adjuvant therapy, multiple bone metastases and pericardial effusion were detected. Pericardial drainage was mandated for the patient, although no malignant cells were found. Despite the change in treatment, pericardial effusion worsened. Based on clinical findings, the patient was diagnosed with carcinomatous pericarditis and was switched to bevacizumab plus paclitaxel therapy. CT at 5 months showed improved pericardial effusion; treatment is ongoing.

[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.

Evaluation of the impact of systemic dexamethasone dosage on docetaxel-induced hand-foot syndrome in patients with breast cancer.

Hand-foot syndrome (HFS) is a frequently occurring and treatment-requiring adverse effect of docetaxel. We previously reported that systemic dexamethasone (DEX) prevents the other docetaxel-induced adverse inflammatory effects in a dose-dependent manner. This study aimed to evaluate the dose-dependent efficacy of systemic DEX in attenuating HFS in patients with breast cancer receiving docetaxel. Patients with breast cancer receiving docetaxel (75 mg/m2)-containing regimens (n = 111) were divided into 4 and 8 mg/day DEX groups, with each DEX dose administered on days 2-4, and analyzed retrospectively. Development of all-grade HFS in all treatment cycles was significantly lower in the 8 mg group (50.0%) than in the 4 mg group (73.0%, P = 0.03), with primary endpoint accomplishment. Moreover, its development in the first cycle was also lower in the 8 mg group than in the 4 mg group. These results were confirmed in a propensity score-matched population. Logistic regression analysis suggested higher DEX dosage as an independent preventive factor (adjusted odds ratio 0.35; 95% confidence interval 0.14-0.86, P = 0.02 for all cycles; 0.26, 0.11-0.63, P = 0.003 for the first cycle). Our study suggests that systemic DEX prevents the occurrence of docetaxel-induced HFS in patients with breast cancer in a dose-dependent manner in a real-world setting.

Significant improvement in paraneoplastic neurological syndromes without identifiable anti-neural antibodies in patients with breast cancer after breast surgery.

Paraneoplastic neurological syndromes (PNS) are neurological disorders that occur in close association with tumors without direct metastasis or invasion of the tumors and in which anti-neural antibodies may be present. Cerebellar ataxia is a common form of PNS in patients with breast cancer. However, reports of symptom improvement with breast cancer treatment are more common in patients with positive anti-neural antibodies and are rarely seen in those with negative anti-neural antibodies. In addition, there have been few quantitative evaluations of symptom improvement. We report a case in which neurological symptoms significantly improved after surgical treatment for breast cancer. The patient was a 78-years-old woman with subacute progressive cerebellar ataxia. A subsequent diagnosis of breast cancer led to the diagnosis of "PNS probable". A comprehensive search for anti-neural antibodies was negative in all cases. The quantitative index of the Scale for the Assessment and Rating of Ataxia (SARA) score, a standard evaluation method for ataxia in spinocerebellar degeneration, improved after breast cancer surgery. This case may provide a rationale for treating breast cancer patients negative for anti-neural antibodies, with the possibility of improving neurological symptoms.

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.

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.

A Case of Pneumothorax Required Surgical Treatment as a Complication of Paclitaxel with Bevacizumab Treatment.

A 63-year-old woman had a history of neoadjuvant chemotherapy, mastectomy, and adjuvant endocrine therapy for 5 years before being diagnosed with recurrent lesions involving the right anterior chest wall, multiple lymph nodes, and pulmonary metastases. The patient was subsequently initiated on a paclitaxel and bevacizumab regimen. During this treatment, the patient complained of palpitations and malaise. Chest radiography revealed a left pneumothorax. Despite attempts at conservative treatment, the pneumothorax did not improve and a thoracoscopic approach was required. One of the metastatic tumors in the left lower lobe appeared to rupture, and this area was estimated to be the cause of air leak. The tumor was covered with a tissue seal sheet, and the patient's condition improved with no recurrence of pneumothorax. This case highlights the importance of early conversion to surgical treatment when conservative treatment for pneumothorax is unresponsive due to the potential side effects of bevacizumab. The findings of this case report may be of interest to oncologists, pulmonologists, and other healthcare professionals involved in the care of patients with breast cancer and pulmonary metastases who are undergoing bevacizumab chemotherapy.

Combination of Mirogabalin and Duloxetine Attenuates Peripheral Neuropathy by Eribulin: A Novel Case Report.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most severe complications associated with chemotherapy for breast cancer. We encountered a case in which mirogabalin initially ameliorated, and additional duloxetine further attenuated eribulin-induced CIPN. Herein, we report its management. A 53-year-old woman received eribulin treatment as third-line chemotherapy for recurrent breast cancer. She experienced grade 2 CIPN with adjuvant docetaxel and cyclophosphamide treatment (worst numeric rating scale (NRS) 6/10 for numbness and 6/10 for pain) and had baseline grade 1 symptoms only in the hands (NRS 1/10 for each). CIPN in the hands and feet worsened to NRS 3/10 on day 1 of cycle 4. Mirogabalin (5 mg twice daily) was initiated, resulting in stable symptoms for approximately 6 weeks with grade 1 somnolence and heaviness of the head. The dosage was increased with careful attention to adverse effects to 22.5 mg per day, and the NRS was reduced from 5/10 to 3/10 for numbness and from 8/10 to 5/10 for pain. We administered duloxetine 20 mg with domperidone (10 mg three times a day) for further pain attenuation on day 1 of cycle 15, decreasing the NRS to 1/10 for numbness and 3/10 for pain. Duloxetine was increased due to CIPN degradation (NRS 3/10 and 5/10), resulting in a significant pain attenuation to 1/10. As the CIPN-attenuating mechanisms of mirogabalin and duloxetine are different, we consider that the additive and synergetic effects of this combination affected the results. Combination therapy with these drugs may be a promising strategy.

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.

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.

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.

Reversible Cancer Therapeutics-related Cardiac Dysfunction Complicating Intra-cardiac Thrombi.

Epirubicin-based chemotherapy carries a risk of inducing heart failure, although the frequency is rare. Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, has recently been widely used in patients with recurrent breast cancer as a first-line chemotherapeutic agent. Heart failure or arterial thromboembolism has been reported as a rare cardiovascular complication of bevacizumab. We herein report a breast cancer patient with reversible cancer therapeutics-related cardiac dysfunction associated with bevacizumab and epirubicin complicating intracardiac thrombi in the left atrium and left ventricle. This case underscores the importance of tailored medical planning according to the individual status in patients receiving anti-cancer therapies.

Tamoxifen withdrawal in women with progressive metastatic breast cancer: a case series of six patients.

Estrogen receptor (ER)-positive metastatic breast cancers after a period of response to tamoxifen develop resistance, and the disease progresses clinically. Domination of partial agonistic activity of tamoxifen over its antagonist activity has been implicated as one of the mechanisms for acquired tamoxifen resistance. Six patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who were treated with tamoxifen withdrawal were retrospectively reviewed. Three patients were premenopausal and three were postmenopausal at the beginning of this treatment. Three patients had stage IV disease and three had recurrent breast cancers with median disease-free intervals of 153 months. The treatment lines of tamoxifen therapy were first-line in two, second-line in two, and third-line in one patient. One patient had relapsed during adjuvant tamoxifen therapy. The median duration of tamoxifen therapy was 16 months. The metastatic disease sites at the time of tamoxifen withdrawal were lymph nodes in six, bone in three, chest wall in one, lung in two, pleura in one, and liver in one patient. The median duration of tamoxifen withdrawal was 6.5 months (range 5-> 23 months). Five of six patients had clinical benefits with tamoxifen withdrawal: partial response in one, long stable disease (SD) in four, and SD in one patient. Five patients were treated with aromatase inhibitors after tamoxifen withdrawal. Two patients had metastatic lymph nodes examined by multi-gene panel testing, and both of their tumors had the AKT1 E17K somatic mutation. One patient also had a BRCA1 germline mutation. Tamoxifen withdrawal at the time of tumor progression while on treatment might be an important treatment option, especially for women with highly endocrine-responsive disease.