Baseline gut microbiota as a predictive marker for the efficacy of neoadjuvant chemotherapy in patients with early breast cancer: a multicenter prospective cohort study in the Setouchi Breast Project-14.

PURPOSE: Various studies have demonstrated the causal relationship between gut microbiota and efficacy of chemotherapy; however, the impact of gut microbiota on breast cancer has not been fully elucidated. This study aimed to evaluate the associations between the gut microbiota before neoadjuvant chemotherapy and its consequent efficacy in breast cancer. METHODS: This prospective observational study included patients who received neoadjuvant chemotherapy for primary early breast cancer at eight institutions between October 1, 2019, and March 31, 2022. We performed 16S rRNA analysis of fecal samples and α and ß diversity analyses of the gut microbiota. The primary endpoint was the association between the gut microbiota and pathological complete response (pCR) to neoadjuvant chemotherapy. RESULTS: Among the 183 patients, the pCR rate after neoadjuvant chemotherapy was 36.1% in all patients and 12.9% (9/70), 69.5% (41/59), and 29.6% (16/54) in those with the luminal, human epidermal growth factor receptor 2, and triple-negative types, respectively. The α diversity of the gut microbiota did not significantly differ between patients with pCR and those without pCR. Among the gut microbiota, two species (Victivallales, P = 0.001 and Anaerolineales, P = 0.001) were associated with pCR, and one (Gemellales, P = 0.002) was associated with non-pCR. CONCLUSION: Three species in the gut microbiota had potential associations with neoadjuvant chemotherapy efficacy, but the diversity of the gut microbiota was not associated with response to chemotherapy. Further research is needed to validate our findings.

Lung Oligometastasis of Breast Cancer: Prospective Cohort Study of Treatment Strategies (SBP-06).

While local treatment of metastases is considered to be unrelated to prognosis, previous studies have suggested that local treatment of isolated lung metastases may have positive prognostic impact. We designed this prospective cohort study to investigate the clinical situation and its outcomes. We enrolled patients with fewer than 3 lung nodules suspected of being oligometastases after curative breast cancer surgery. Treatments, including local and systemic therapy, were selected by the physician and patient in consultation. The primary outcome was overall survival (OS); secondary outcomes were the efficacy and the safety of the surgery for lung oligometastases. Between May 2015 and May 2019, 14 patients were enrolled. Resection of lung nodules (metastasectomy) was performed in 11 (78.6%) of 14 patients, and one of these cases was diagnosed as primary lung cancer. Metastasectomies were all performed employing video-assisted thoracic surgery (VATS) without perioperative complications. Systemic therapies were administered to all patients except one. The respective 3-year and 5-year OS rates of patients with lung oligometastases were 91.6% and 81.5%, respectively. Progression occurred in 6 patients: 3 of the 10 with metastasectomy and all 3 without this surgical procedure. Lung metastasectomy was worthwhile as a diagnostic evaluation and may provide long-term benefit in some patients.

Pilot trial of an electronic patient-reported outcome monitoring system in patients with metastatic breast cancer undergoing chemotherapy.

BACKGROUND: Electronic patient-reported outcomes monitoring (ePROM) is a useful communication tool for patients and healthcare providers in cancer chemotherapy. In this study, we examined the feasibility of our newly developed ePROM system, which we refer to as "Hibilog". METHODS: An ePROM app was developed by extracting 18 items from the Patient-Reported Outcome-Common Terminology Criteria for Adverse Events (PRO-CTCAE). Symptom monitoring was conducted every two weeks for patients with metastatic breast cancer undergoing chemotherapy. The primary outcome was the response rate to the ePROM system. The secondary outcomes were response time, item missing rate, and distribution of responses for each symptom. RESULTS: A total of 71 cases (mean age 52.6 years) were analyzed. Performance status was 0 in 76% of the cases and 1 or higher in 24%. First-line treatment was being administered in 30% of cases, second-line treatment in 17%, and third-line or higher treatment in 53%. The response rate to the ePROM system from registration to week 40 remained high at around 80%, indicating good compliance. The average response time was 5.5 min and the missing rate for each item was below 0.4%. Among 1,093 responses, the top 3 symptoms causing interference with daily life were Fatigue (63%), Numbness and tingling (48%), and General pain (46%). CONCLUSION: Our developed ePROM system was able to capture symptoms accurately in patients with metastatic breast cancer undergoing chemotherapy while maintaining a high response compliance.

Systemic immunity markers are associated with clinical outcomes of atezolizumab treatment in patients with triple-negative advanced breast cancer: a retrospective multicenter observational study.

Immune checkpoint inhibitors (ICI) are reportedly efficacious against triple-negative breast cancer (TNBC) and are now recommended as first-line therapy. Systemic immunity markers, the absolute lymphocyte count (ALC) and the neutrophil-to-lymphocyte ratio (NLR), have been identified as predict ICI efficacy in patients with various cancers. We retrospectively enrolled 36 TNBC patients who received atezolizumab treatment between September 2019 and May 2021 at eight Japanese medical institutions. We evaluated systemic immunity markers, including dynamic changes in these markers, as predictors of survival benefit derived from atezolizumab treatment. Median time-to-treatment failure (TTF) and overall survival (OS) were 116 days and "not reached", respectively. Patients with low NLR at baseline and decreased NLR at the start of the second cycle (SO2nd) had significantly longer OS than those with high NLR at baseline and increased NLR (SO2nd) (log-rank P < 0.001 and log-rank P = 0.049, respectively). Multivariate analyses identified high ALC at baseline and decreased NLR (SO2nd) as independent predictive markers for longer TTF (P = 0.043 and P = 0.002, respectively), and low NLR at baseline and decreased NLR (SO2nd) as independent predictive markers for longer OS (P < 0.001 and P = 0.013, respectively). The safety profile was consistent with those of previous trials. This retrospective multicenter observational study showed the clinical efficacy and safety of atezolizumab treatment. Furthermore, systemic immunity markers, including their dynamic changes, were found to be associated with clinical outcomes of atezolizumab treatment in patients with advanced or metastatic TNBC.

[A Case of Breast Cancer Complicated by Fibrous Dysplasia That Was Difficult to Differentiate from Bone Metastasis].

A 58-year-old woman with HER2-negative hormone-sensitive postmenopausal breast cancer underwent preoperative bone scintigraphy and CT to search for distant metastasis. Bone metastasis was suspected in the spinous process of the seventh cervical vertebra. MRI revealed a mass that was hypointense on T1- and T2-weighted images and hyperintense on diffusion- weighted images, with intense contrast enhancement, indicating bone metastasis at cT1N0M1, Stage Ⅳ(M: OSS). The patient underwent partial mastectomy and sentinel lymph node biopsy. The postoperative diagnosis was pT2N0cM1, Stage Ⅳ, with the status of bone metastasis being key to staging. PET-CT showed uptake in the spinous process of the seventh cervical vertebra but no other metastatic findings. However, solitary bone metastasis to the cervical spinous process is atypical. CT-guided needle biopsy confirmed benign fibrous dysplasia, and the final diagnosis was breast cancer at pT2N0M0, Stage ⅡA. Fibrous dysplasia is characterized by impaired osteogenesis leading to fibroplasia and commonly occurs in the skull, jaw bones, ribs, and limbs. Solitary fibrous dysplasia in the cervical spinous process is rare. The lesion was asymptomatic and pathologically benign, requiring no treatment. The patient underwent postoperative radiation therapy for the conserved breast and is followed up with endocrine therapy.

[A Case of Breast Cancer Brain Metastases Successfully Treated with Pembrolizumab Therapy after Disease Progression with Atezolizumab Therapy].

A 39-year-old woman was diagnosed with right breast cancer(cT3N1M0, cStage ⅢA, triple negative type). After preoperative chemotherapy using dose-dense doxorubicin and cyclophosphamide, followed by dose-dense paclitaxel every 2 weeks, the patient underwent right modified radical mastectomy. Postmastectomy radiotherapy to the right chest wall and right supraclavicular area and oral capecitabine therapy were administered. Computed tomography 1 year after surgery showed multiple lung metastases. The patient received atezolizumab and nab-paclitaxel therapy. Six months after the first chemotherapy, metastatic brain tumor in right frontal lobe, 12 mm in size, was observed along with enlargement of lung metastases. Because the brain tumor showed rapid growth after CyberKnife therapy, emergency tumorectomy was performed. One month after cranial surgery, new 3 brain metastases were appeared. Gamma knife therapy to brain metastases and pembrolizumab, carboplatin, gemcitabine therapy was started. Although insufficient doses of carboplatin and gemcitabine were administered due to bone marrow suppression, no progression was observed for about 1 year after initiation of pembrolizumab therapy. Pembrolizumab therapy may show anti-tumor effect to breast cancer brain metastases, even after a failure of atezolizumab therapy.

Optimizing the timing of 3.6 mg Pegfilgrastim Administration for Dose-Dense Chemotherapy in Japanese Patients with Breast Cancer.

Perioperative dose-dense chemotherapy (DDCT) with pegfilgrastim (Peg) prophylaxis is a standard treatment for high-risk breast cancer. We explored the optimal timing of administration of 3.6 mg Peg, the dose approved in Japan. In the phase II feasibility study of DDCT (adriamycin+cyclophosphamide or epirubicin+cyclophosphamide followed by paclitaxel) for breast cancer, we investigated the feasibility, safety, neutrophil transition, and optimal timing of Peg treatment by administering Peg at days 2, 3, and 4 post-chemotherapy (P2, P3, and P4 groups, respectively). Among the 52 women enrolled, 13 were aged > 60 years. The anthracycline sequence was administered to P2 (n=33), P3 (n=5), and P4 (n=14) patients, and the taxane sequence to P2 (n=38) and P3 (n=6) patients. Both sequences showed no interaction between Peg administration timing and treatment discontinuation, treatment delay, or dose reduction. However, the relative dose intensity (RDI) was significantly different among the groups. The neutrophil count transition differed significantly among the groups receiving the anthracycline sequence. However, the neutrophil count remained in the appropriate range for both sequences in the P2 group. The timing of Peg administration did not substantially affect the feasibility or safety of DDCT. Postoperative day 2 might be the optimal timing for DDCT.

Fatal anaphylaxis due to alpha-gal syndrome after initial cetuximab administration: The first forensic case report.

Cetuximab is mainly used for the treatment of advanced and metastatic colorectal cancer. Owing to the oligosaccharide galactose-α-1,3-galactose (α-gal) in its heavy chain, cetuximab can induce severe IgE-dependent anaphylaxis. α-Gal is also the antigen responsible for α-gal syndrome, known as mammalian meat allergy. Patients with α-gal syndrome may suffer from cetuximab-induced anaphylaxis at the first administration because of developed α-gal-specific IgE antibodies. A male patient in his 50 s with metastatic colon cancer was receiving chemotherapy involving scheduled cetuximab administration. However, he died soon after the first administration. Forensic autopsy confirmed rectal cancer, metastatic rectal cancer in the liver, and renal cancer. Laboratory blood tests revealed the presence of cetuximab- and beef-specific IgE antibodies before cetuximab administration and an extremely high level of tryptase after administration. Thus, we determined that the death was caused by cetuximab-induced anaphylaxis due to the preexisting α-gal syndrome. To the best of our knowledge, this is the first autopsy case report in forensic medicine of fatal anaphylaxis after initial cetuximab administration.

[A Case of Intraductal Papilloma of the Male Breast].

Male breast cancer accounts for approximately 1% of the overall incidence of breast cancer. We report a rare case of intraductal papilloma(intracystic papilloma)in a 73-year-old man, which was suspected to be breast cancer as it presented as an approximately 6 cm mass below the left nipple in various imaging studies. The patient was aware of a mass measuring a few millimeters below the left nipple for 5 years, but had not sought treatment. He visited our department 3 months after redness and pain were noted around the nipple; the mass had enlarged. Palpation revealed a 6 cm smooth-surfaced mass as well as nipple retraction; diagnostic imaging showed a cystic tumor with a solid internal structure. Fine-needle aspiration cytology and core needle biopsy did not indicate a definitive diagnosis, and a left mastectomy and sentinel lymph node biopsy were performed based on a preoperative diagnosis of breast cancer. Pathological examination confirmed the diagnosis of intraductal papilloma, based on findings such as infarction-induced hemorrhagic necrosis, stromal and epithelial proliferation, apocrine metaplasia, and squamous epithelial metaplasia. Reports of a large-diameter intraductal papilloma(intracystic papilloma)suspicious for breast cancer in men are rare; therefore, surgical resection and detailed histopathological exploration of the whole tumor were required.

[A Case of Primary Acinic Cell Carcinoma of the Breast].

Acinic cell carcinoma(ACC)is an invasive malignancy primarily characterized by proliferation of tumor cells that resemble acinar cells of the salivary glands and pancreas. ACC of the mammary glands is rare. We report a case of primary ACC of the breast. Two masses were revealed in the left mammary gland of a 57-year-old woman who visited our hospital through screening mammography. The lesions were identified as synchronous multiple breast carcinoma of 2 different histological types; ACC and tubulolobular carcinoma. For treatment, left mastectomy and sentinel lymph node biopsy were performed, followed by postoperative chemotherapy and endocrine therapy. Hematoxylin-eosin staining of ACC revealed abundant acinar- like structures formed by tumor cells with prominent eosinophilic granules in the cytoplasm. Immunostaining was positive for S-100 protein, α1-antichymotrypsin, α1-antitrypsin, and lysozyme. The tumor cells were negative for estrogen, progesterone, and HER2 receptors, which indicated that they had a triple-negative phenotype. Although primary ACC of the breast is regarded as low-grade triple-negative breast carcinoma with a favorable prognosis, further accumulation of cases may be needed to elucidate the biological features of ACC and investigate appropriate therapeutic strategies.

[Importance of Local Therapy for Oligometastatic Breast Cancer-A Case Report].

A case of successful local treatment for metachronous oligometastases to the lung and mediastinal lymph nodes in a postmenopausal woman with breast cancer is presented. A 44-year-old woman underwent partial mastectomy and left axillary lymph node dissection for right breast cancer. Thirteen years and 3 months after the operation, she was referred to our hospital for a right lung mass detected by mass screening and diagnosed with a metastatic lung tumor from left breast cancer following CT-guided biopsy. She was simultaneously diagnosed with right breast cancer, and pulmonary metastasectomy, right partial mastectomy, and sentinel lymph node biopsy were performed. Two years after the second operation, follow-up CT showed a swollen lymph node at the pre-tracheal space, and endobronchial ultrasound-guided transbronchial needle aspiration confirmed the diagnosis of metastatic breast cancer. The mediastinal lymph node metastasis showed no change in size for 2 years and 7 months with fulvestrant therapy, and no other metastases were found. Proton beam therapy of 60 GyE in 30 fractions was administered to the metastatic lymph node. Substantial tumor shrinkage with no severe toxicity was observed, and to date, the patient has remained disease-free. More cases need to be studied to investigate the appropriate strategy for local therapy in patients with oligometastatic breast cancer.

Durable clinical benefit of letrozole in leptomeningeal metastasis of breast cancer.

A case of a woman in her 60s with breast cancer, whose leptomeningeal metastasis (LM) of breast cancer improved remarkably with letrozole monotherapy, is reported. The patient complained of numbness of her left hand and hoarseness, followed by progressive asymmetric extremity weakness and a bladder and rectal disturbance. The patient had undergone surgery for left breast cancer 18 years earlier and was concerned about recurrence of breast cancer, but there were no typical findings with some imaging modalities. The third lumbar puncture showed the malignant cytology of breast cancer, and the patient was diagnosed with recurrent breast cancer. Her performance status was very poor, and it was difficult to administer systemic chemotherapy. Letrozole was started because immunohistochemistry was positive for estrogen and progesterone receptors. After 4 months of letrozole therapy, the symptoms improved gradually. LM has a poor prognosis, and there is little evidence on which to base treatment, but hormone therapy may be an option for LM when the tumor is hormone receptor-positive, slow growing, and has a small volume.

The efficacy and feasibility of dose-dense sequential chemotherapy for Japanese patients with breast cancer.

BACKGROUND: Perioperative dose-dense chemotherapy (DDCT) with granulocyte-colony stimulating factor (G-CSF) prophylaxis is a standard treatment for patients with high-risk breast cancer. The approval of this approach in Japan led to the widespread adoption of DDCT, despite limited efficacy and safety data among Japanese patients. We evaluated the efficacy and safety of neoadjuvant DDCT for Japanese patients with breast cancer. METHODS: This prospective, multicenter, phase II study evaluated 52 women with operable human epidermal growth factor receptor 2-negative breast cancer and axillary lymph node metastasis. Neoadjuvant DDCT (adriamycin plus cyclophosphamide or epirubicin plus cyclophosphamide followed by paclitaxel) was administrated every 2 weeks with G-CSF support. The study endpoints were the rates of pathological complete response (pCR), febrile neutropenia, treatment completion, toxicities, and the relative dose intensity (RDI). RESULTS: The pCR rate was 21.9% (9/41) and the triple-negative (TN) subtype was significantly associated with a high pCR rate (triple-negative: 53.3% vs. luminal A: 7.7% and luminal B: 0%; p = 0.003). The treatment completion rate was 80.8% (42/52) and the average RDI was 98.9%. Most adverse events were manageable and tolerable. Six patients (11.5%) developed febrile neutropenia. Grade 3-4 adverse events were slightly more common among older patients (57%) with a low protocol completion rate (≥ 65 years: 42.9% vs. <65 years: 86.7%, p = 0.0062). CONCLUSION: The pCR rate for DDCT was similar to that of standard chemotherapy, although it was remarkably effective for the TN subtype. DDCT may be feasible for Japanese patients with breast cancer although caution is needed for older patients.

Liver resection for HER2-enriched breast cancer metastasis: case report and review of the literature.

Liver metastasis from breast cancer usually results in the development of systemic metastasis. We report a breast cancer patient with an early isolated liver recurrence who survived more than 7 years with no recurrence. She was treated with aggressive HER2-directed chemotherapy and hepatic metastasectomy. Local hepatectomy with effective medical oncological therapy with curative intent is worth trying in patients with breast cancer liver metastasis.

[Safety management of intravenous cancer chemotherapy and oral premedication drugs].

The administration of oral premedication drugs (OPDs) is increased before intravenous cancer chemotherapy to prevent adverse events such as hypersensitivity or nausea and vomiting. As intravenous chemotherapy regimens and OPDs are ordered separately in the electronic medical record system, the prescription or administration of OPDs may be missed. To overcome this problem, we developed a combination regimen ordering (CRO) system, in which OPDs were included in the intravenous chemotherapy regimen enabling simultaneous ordering. This system used the electronic medical record system HAPPY ACTIS by TOSHIBA Medical Information Systems Co. in our hospital. OPDs were prepared in an envelope labeled with a bar code to identify the patient, which was then used by the nursing staff to administer the medication. Between August 2011 and January 2014, CRO systems were used in 66 regimens for the treatment of the following cancers: 21 lung cancers, 14 breast cancers, 9 hematologic malignancies, 7 genitourinary cancers, 6 gastrointestinal cancers, 5 gynecological cancers, 3 head and neck cancers, and 1 dermatological malignancy. The OPDs administered were diphenhydramine, loxoprofen, chlorpheniramine, aprepitant, and ramosetron. Although we were unable to check OPDs in the oral drug administration histories, no errors in the administration of OPDs have been reported after the adoption of the CRO system. Therefore, our CRO system improved the safety and quality of patient care for cancer chemotherapy.

[A case of recurrent breast cancer with brain metastases successfully treated with vinorelbine and anastrozole after multiple chemo-endocrine therapies].

We report a case of recurrent hormone receptor-positive breast cancer with brain metastases that showed good response to vinorelbine(VNR)and anastrozole(ANA). A 49-year-old woman with a history of left breast cancer had initially undergone modified radical mastectomy, but was diagnosed with lung metastases 8 years postoperatively. Despite treatment with docetaxel and tamoxifen, multiple brain metastases were detected 10 years postoperatively. To achieve prompt improvement of neurological symptoms, surgical resection was performed for two large brain foci. Stereotactic radiosurgery using a gamma- knife was applied for the remaining multiple brain metastases. Histological examination identified the brain tumors as estrogen receptor-positive, HER2-negative metastatic breast cancer. Despite the use of cyclophosphamide, adriamycin and 5- fluorouracil(CAF therapy)and capecitabine, brain metastases recurred twice along with pleuritis carcinomatosis and bone metastasis. In addition to gamma-knife re-treatment, therapy was started with VNR and ANA. All metastatic sites including brain showed a good response to therapy with few adverse reactions, and no recurrence has been observed over 3 years.

[A case of organizing pneumonia with a reversed halo sign following postoperative irradiation for breast cancer].

A 69-year-old woman received radiation therapy of 50 Gy following surgery for left breast cancer. Eleven months later, chest computed tomography revealed infiltrative shadows with air bronchograms in both lower lung fields and a reversed halo sign in the right lower lobe. Transbronchial lung biopsy revealed polypoid granulation tissue in the terminal air spaces, which was consistent with organizing pneumonia (OP). Prednisolone therapy resolved the radiographic abnormalities. The reversed halo sign was believed to be specific to cryptogenic organizing pneumonia. We reported a case of OP with a reversed halo sign following postoperative irradiation for breast cancer.

Benign myoepithelioma of the breast: origin and development.

A case of benign myoepithelioma of the breast in a 55-year-old woman is described. The tumor was a well-circumscribed solid mass, measuring 13 x 12 mm. Histopathology indicated that the tumor was composed of entirely myoepithelial cells, which was confirmed by immunoreactivity to calponin and S-100. There was no ductal differentiation in the tumor, and staining for pan-cytokeratin and epithelial membrane antigen was weak and negative, respectively. Although the biological behavior of the tumor remains to be ascertained, the tumor was considered to be myoepithelioma with benign features due to mild nuclear pleomorphism, sparse mitotic figures, low Ki-67 labeling index and low S-phase fraction. Diagnostic confusion between benign myoepithelioma and other myoepithelial-rich cell tumors is possible. Considering the classification of myoepithelial tumor in the salivary glands, benign myoepithelioma of the breast may possess a different development process from adenomyoepithelioma.

Intracystic adenomyoepithelioma of the breast--case report and review.

A case of an intracystic adenomyoepithelioma of the breast mimicking intracystic carcinoma is described. Preoperative examination with mammography, sonography, computed tomography, and magnetic resonance imaging showed an intracystic tumor with an indistinct margin and several swollen lymph nodes in the ipsilateral axilla. Because the results of fine-needle aspiration cytology of the tumor were interpreted as carcinoma, partial mastectomy with dissection of the axillary nodes was performed. Histopathologic and immunohistochemical examination revealed an intracystic adenomyoepithelioma without nodal involvement. The imaging features of this rare tumor may vary widely, which may result in an incorrect diagnosis of breast carcinoma. Indeed, adenomyoepithelioma has metastatic potential; however, lymphatic spread is rare and axillary intervention may be over-treatment for most cases. While the imaging descriptions of intracystic adenomyoepitheliomas are very limited, this tumor should be considered in the differential diagnosis to avoid unnecessarily aggressive treatment.