TP53 signature predicts pathological complete response after neoadjuvant chemotherapy for breast cancer: Observational and confirmational study using prospective study cohorts.

The TP53 signature is considered a predictor of neoadjuvant chemotherapy (NAC) response and prognostic factor in breast cancer. The objective of this study was to confirm TP53 signature can predict pathological complete response (pCR) and prognosis in cohorts of breast cancer patients who received NAC in prospective studies. Development cohorts (retrospective [n = 37] and prospective [n = 216] cohorts) and validation cohorts (NAC administered prospective study cohorts [n = 407] and retrospective perioperative chemotherapy (PC)-naïve, hormone receptor (HrR)-positive cohort [PC-naïve_HrR+ cohort] [n = 322]) were used. TP53 signature diagnosis kit was developed using the development cohorts. TP53 signature predictability for pCR and the relationship between recurrence-free survival (RFS), overall survival (OS), and the TP53 signature were analyzed. The pCR rate of the mutant (mt) signature group was significantly higher than that of the wild-type (wt) signature group (odds ratio, 5.599; 95 % confidence interval = 1.876-16.705; P = 0.0008). The comparison of the RFS and OS between the HrR+ and HER2- subgroup of the NAC cohort and of the PC-naïve_HrR+ cohort indicated that the RFS and OS benefit of NAC was greater in the mt signature group than in the wt signature group. From post hoc analyses, the RFS and OS benefit from adding capecitabine to FEC+T as NAC might be observed only in the mt signature group. The TP53 signature can predict the pCR after NAC, and the RFS and OS benefit from NAC may be greater in the mt signature group than in the wt signature group.

[A Case of De Novo Stage â £ Breast Cancer with Umbilical Metastasis and Peritoneal Dissemination].

The patient was a 48-year-old woman. At the time of consultation, a hard mass of 30 mm in size was palpated in area A of the right breast, and a firm mass of about 10 mm was seen in the umbilical region. Histological diagnosis of the breast mass was invasive ductal carcinoma. PET-CT scan showed accumulation in the right breast, as well as suspicion of umbilical metastasis and peritoneal dissemination, uterine mass, and left ovarian cancer. Since this is an atypical metastatic site for invasive ductal carcinoma of the breast, and the possibility of peritoneal dissemination due to gynecological cancer complications cannot be ruled out, resection of the umbilical mass and laparoscopy was performed. The review laparoscopy revealed no evidence of primary cancer in the uterine body or left ovary, and a white nodular lesion of suspected seeding in the peritoneum around the left ovary. The histology and immunostaining results of the umbilical mass and left peri-ovarian nodule both showed glandular luminal structures similar to those of the primary breast cancer, and the left peri-ovarian nodule was ER positive, GATA3 positive, and PAX8 negative, leading to the diagnosis of umbilical metastasis and peritoneal seeding derived from breast cancer. Umbilical metastasis is often referred to as Sister Mary Joseph's nodule in the case of visceral malignancies and is often associated with peritoneal dissemination and is often caused by invasive metastasis of peritoneal dissemination lesions on the dorsal side of the umbilical region. In this case, histological examination of the umbilical specimen showed no disseminated lesion on the peritoneal side, so it was not considered to be an invasive metastasis due to peritoneal dissemination.

[The Six Cases of Recurrence of Lung Metastasis after Radical Resection of Pancreatic Cancer Performed at Our Hospital].

Prognosis of pancreatic cancer is extremely poor due to recurrence in the early postoperative period. However, there are some reports that the prognosis for lung recurrence alone is relatively better than that of others. In this study, we report the cases of lung recurrence alone after radical resection of pancreatic cancer performed at our hospital. Among 255 cases of radical resection of pancreatic cancer performed at our hospital between July 2010 and August 2021, 6 cases in which the initial recurrence site of recurrence was lung alone were included in the study. The median age of the patients was 72 years (62-82), and there were 5 males and 1 female. Four patients had undergone pancreaticoduodenectomy and 2 patients underwent distal pancreatectomy. Four patients received adjuvant chemotherapy, 3 with S-1 and 1 with GEM. No patients underwent surgical resection for recurrence of lung metastasis, and all patients were treated with chemotherapy. The median time to recurrence was 351 days. As initial therapy after recurrence, 3 patients received GEM plus nab-PTX combination therapy and 3 patients received S-1. The median overall survival after recurrence was 1,979 days, and the 1-year and 3-year overall survival rates after recurrence were 100% and 100%, respectively. The prognosis of patients with recurrence of lung metastasis after surgery for pancreatic cancer at our hospital was similarly good as the previous reports.

[Robot Assisted Para-Aortic Lymphadenectomy in Gastric Cancer Surgery].

Para-aortic lymphadenectomy in gastric cancer surgery is a highly difficult surgical technique. In our hospital, we introduced robotic surgery in anticipation of the minimal invasiveness and advanced operability. We use a tunneling approach that progresses from the Treitz ligament to the peri-aorta. The transverse mesocolon is expanded with a tissue grasping clip, and the retroperitoneum is incised from the side of the Treitz ligament to approach the abdominal aorta and inferior vena cava. The No.16b1 and No.16a2 latero lymph nodes can be dissected with a good visual field. When it is judged that the visual field development of the No.16a2 inter-lymph nodes is poor, Kocher's operation is added. Since 2016, 18 patients have undergone para-aortic lymphadenectomy, 3 of whom underwent robotic surgery in our hospital. R0 resection was performed in all the cases, and 22.5 lymph nodes were dissected as No.16 lymph nodes(20.0 in all the cases included laparotomy). Although only a small number of patients were examined, robot-assisted para-aortic lymphadenectomy was considered safe.

[A Case of Combined Use of Mohs Paste and Radiation Therapy for Advanced Breast Cancer with Bleeding].

A 75-year-old female, at her initial presentation, the tumor occupied her entire right breast, with a foul-smelling exudate. A biopsy revealed ER-positive, HER2-negative breast cancer, and CT revealed multiple lung metastases. Paclitaxel and fulvestrant were administered sequentially, the bleeding from the right breast mass stopped and the mass flattened. But, as the tumor progressed, the right breast mass re-enlarged and began to re-bleed. Therefore, hemostatic treatment with Mohs paste was performed in parallel with tamoxifen. Hemostatic effect was observed for a while, but she gradually became refractory to Mohs paste, necessitating frequent blood transfusions. It was decided to discontinue systemic drug therapy and consider palliative treatment, and to perform radiation therapy in parallel with Mohs paste treatment for the purpose of local control. After radiation therapy, the bleeding has completely stopped and blood transfusion has not to be required for 6 months. Although systemic drug therapy has been discontinued at the patient's request, she is still alive. While systemic drug therapy was discontinued, we were able to confirm the pure local control effect of combination of radiation therapy and Mohs paste.

[Clinicopathological Characteristics of Early-Onset Colorectal Cancer(EOCRC)Cases in Our Hospital].

BACKGROUND: In recent years, the number of colorectal cancer in Europe and the U. S. has been decreasing, but there are increasing reports on the trend of early-onset colorectal cancer(EOCRC), which is a rare population with no established knowledge on its characteristics. SUBJECTS AND METHODS: Of 3,501 colorectal cancer cases treated at our hospital between April 2011 and December 2021, those aged 39 years and younger were included. RESULTS: There were 32 EOCRC cases, 11 males/21 females. The histological type was tub in 31 cases and por in 1 case. Postoperative adjuvant chemotherapy was administered in 14 patients, and 12 completed the scheduled course. Twenty nine patients underwent R0 resection, of which 6 patients had recurrence and 5 patients died of primary disease. In summary, although EOCRC patients were in good general condition and had a high completion rate of adjuvant chemotherapy, the relapse rate was high, suggesting the need for aggressive adjuvant chemotherapy and careful postoperative surveillance.

[A Case of Recurrent Breast Cancer Detected with Diplopia Caused by Sphenoid Bone Metastasis].

We report a case of sphenoid bone metastasis from breast cancer detected with diplopia, as first site of recurrence. Forty- year-old woman with left breast cancer underwent breast-conserving surgery and sentinel lymph node biopsy. The diagnosis was papillotubular carcinoma, pT1pN0, ER(+), PgR(+), HER2(-). Tweleb years later, the examination of diplopia revealed left abducens nerve palsy for sphenoid bone metastasis from breast cancer. Radiation therapy(a total dose of 36 Gy with VMAT)was administrated as topical treatment, but diplopia did not improve. After that, systemic treatment was performed, and 2 years and 6 months have passed since the recurrence was found, she is still alive. We need to be careful of orbital metastasis as a symptom of metastasis from breast cancer.

[A Case of Breast Nodular Fasciitis Needed to Differentiate from Borderline Phyllodes Tumor].

A 28-year-old woman realized a left breast tumor. Mammography and ultrasonography revealed focal asymmetric density on the MI area(category 3)and a low-echoic 10 mm tumor with unclear boundaries. We performed an US-guided breast biopsy to confirm the diagnosis. The histopathological examination result suspected nodular fasciitis; however, borderline phyllodes tumor cannot be denied. Tumorectomy was performed under general anesthesia. The final histopathological examination revealed nodular fasciitis due to amplifying fibroblasts with irregular directions. Nodular fasciitis is a benign lesion and sometimes disappears spontaneously. Tumorectomy is often needed to confirm the diagnosis that cannot be identified by needle biopsy. We report a case of breast nodular fasciitis needed to differentiate from borderline phyllodes tumor.

[A Case of De Novo Stage â £ Her2-Positive Breast Cancer with Cardiac Tamponade Caused by Cancerous Pericarditis].

The patient was a 58-year-old woman. She was diagnosed with cT4b, cN3c, cM1, cStage Ⅳ, Her2 positive breast cancer with liver, lung and bone metastases. Seven days after the first visit, she came to our hospital for dyspnea. Chest X-ray, chest CT, and echocardiography showed a decrease in EF to 50.6% due to a large amount of pericardial effusion, and she was diagnosed with cardiac tamponade. On the same day, pericardial drainage was performed urgently. The cytopathology of pericardial fluid was malignant, that is to say, she was diagnosed with cancerous pericarditis. Pericardial drainage relieved respiratory distress, and echocardiography showed disappearance of pericardial fluid and improvement of EF up to 80.4%. Docetaxel plus trastuzumab plus pertuzumab therapy was started 10 days after pericardial drainage as first-line treatment. After starting chemotherapy, the response has continued for 6 months without re-accumulation of pericardial fluid.

[A Case of Drug-Induced Interstitial Pneumonia after Dose-Dense AC Therapy].

The patient is a 67-year-old female. She was diagnosed with left breast cancer cT2N1M0, Stage ⅡB, Luminal B-like, and was desided dose-dense AC therapy(ddAC)plus dose-dense paclitaxel therapy(ddPTX)as preoperative chemotherapy. After completing 4 courses of ddAC and visiting to start the first course of ddPTX, she presented with symptoms of fatigue and shortness of breath on exertion. Chest X-ray showed no abnormality and echocardiography showed decreased left ventricular wall motion, leading to a diagnosis of doxorubicin-induced cardiac dysfunction. Preoperative chemotherapy was discontinued and surgery was decided. Two weeks later, CT imaging was performed for preoperative evaluation, which showed the appearance of diffuse pale ground-glass opacity in the bilateral lung fields, and a diagnosis of drug-induced interstitial pneumonia was made. After 3 weeks of steroid treatment, the symptoms improved and the ground-glass opacity disappeared on CT imaging. We were keenly aware that interstitial pneumonia can develop with pale ground-glass opacity that is difficult to diagnose without CT imaging, and that the need for CT should always be considered.

[A Case of Locally Advanced Breast Cancer That Responded to Paclitaxel plus Bevacizumab and Underwent Radical Surgery].

The patient is a 69-year-old female. She was aware of a right breast mass about a year ago, but left it alone. In March 2021, she visited our hospital with a 11 cm mass occupying the right breast and self-destruction due to skin invasion. The diagnosis of invasive ductal carcinoma of the breast(ER-positive, PgR-positive, HER2-negative), cT4bN1M0, Stage ⅢB was made, and preoperative chemotherapy was decided. We expected a high response rate for bevacizumab(Bv)because it was predicted that the skin defect would increase at surgical resection if a response to chemotherapy was not achieved, and in April 2021, paclitaxel(PTX)plus Bv therapy was initiated. After 4 courses, the mass had shrunk to 5 cm and a marked response had been achieved. However, she was unable to continue the treatment due to peripheral neuropathy. Therefore, considering the period of delayed wound healing due to Bv, we decided on AC therapy followed by surgery. In December 2021, Bt plus Ax was performed and the wound could be closed without skin grafting. Since PTX plus Bv therapy is expected to have a high response rate, we considered it to be one of the effective treatment options for locally advanced breast cancer.

[Five Patients with Gastric Metastasis from Breast Cancer-A Case Report].

Five patients with gastric metastasis from breast cancer were treated in our hospital. About the histopathological types of primary breast cancer, 4 patients were invasive ductal carcinomas and 1 was invasive lobular carcinoma. One patient was found by gastrointestinal fiberscopy for a detailed examination of her high CEA, 2 for stenosis, 1 for bleeding and 1 for epigastralgia. After the diagnosis of gastric metastasis, 2 patients were treated with chemotherapies, 1 with hormone therapy and 2 with palliative treatments. One of them was treated with gastroduodenal stenting for pyloric stenosis, but she was died by bleeding from gastric lesion. Based on the results, constriction and bleeding with gastric metastasis is considered to be severe condition in the treatment of metastatic breast cancer.

[A Case of GIST That Recurred More Than 30 Years after Surgery and Could Be Resected].

The patient was a 77-year-old woman. She underwent a partial gastrectomy at the age of 40, and a partial colectomy at the age of 75 following a diagnosis of a carcinoid. In November 2019, a 1.5 cm mass with a clear boundary was found in the pancreatic tail, which was strongly stained uniformly. And furthermore, multiple masses between 2 cm and 3 cm with a clear boundary was found inside liver segment S1 and S6 and S7 and S8 on CT, which was strongly stained at the edge in the early phase and was seen as a low density area in the late phase. At a result of image examination, it was diagnosed as a pancreatic tail neuroendocrine tumor and its multiple liver metastases. The distal pancreatectomy, posterior segmentectomy, and partial S1 lt and S8 liver resection were performed. With postoperative pathological diagnosis, the pancreatic tumor was accessory spleen, and liver tumor were epithelioid type GIST which were positive for CD34 and PDGFRA and negative for c- kit. The pathology specimen of colectomy was re-examined, and the diagnosis from the previous surgery was changed to GIST from a carcinoid. Epithelioid type GIST was associated with a PDGFRA gene mutation and was known to have many gastric origins. Based on the clinical course, it was diagnosed as recurrence of gastric GIST at 40 years after 30 years or more.

[Occult Breast Cancer Presenting with a Swelling Axillary Lymph Node-A Case Report].

The patient was a 56-year-old woman. who was aware of a tumor in her left axilla and consulted a nearby doctor. She was referred to our hospital for a detailed examination. No abnormalities were found in the breast by visual inspection, mammography, or breast ultrasound examination. One 29 mm swollen lymph node was found in the axilla. Fine needle aspiration cytology revealed malignant lymphoma; thus, so axillary lymph node excision biopsy was performed, and a diagnosis of axillary lymph node metastasis of breast cancer was made. However, no abnormalities were found. Based on the information presented above, the patient was diagnosed with occult breast cancer cT0N1M0, Stage ⅡA, and breast preservation plus axillary lymph node dissection up to level Ⅱ was performed. No metastases were found in the dissected lymph nodes. The treatment policy for occult breast cancer has not yet been established. We report this case with a review of the literature.

[A Case of Late Recurrence of Breast Cancer with Chest Wall Recurrence 43 Years after Surgery].

The patient is an 85-year-old female who had previously undergone a mastectomy for right breast cancer at the age of 42 years. In September 2020, she visited our hospital with a chief complaint of a chest wall tumor. Physical examination revealed a 3×3 cm ulcerative lesion on the right side of the center chest wall. She underwent a skin biopsy of the tumor under local anesthesia and was diagnosed with a recurrence of right breast cancer(ER positive, PR positive, HER2 negative). PET-CT revealed localized skin thickening on the right side of the sternum and FDG accumulation in the same area, with no other findings suggestive of distant metastasis. Treatment was started with anastrozole and is still ongoing. In this article, we report a very rare case of recurrence 43 years after surgery.

[A Case of Stage â £ Breast Cancer Treated with Mastectomy after Spontaneous Removal of a Cosmetic Breast Implant].

A 51-year-oldwoman came to our hospital complaining of a skin ulcer in the left breast. She hadpreviously undergone cosmetic breast augmentation by placement of a bag prosthesis under each mammary gland. She was diagnosed with Stage Ⅳ(T4bN1M1)breast cancer with multiple bone metastases. Following the diagnosis, 3 regimens of hormonal therapy were sequentially administered. The treatment was then switched to chemotherapy following confirmation of tumor progression in the left breast tumor. After 3 cycles of paclitaxel andbevacizumab as the second-line of chemotherapy, the size of the left breast tumor was remarkably reduced. Mastectomy with axillary lymph node sampling and removal of the implant were scheduled for local control. However, due to gradual exposure of the implant under the left breast, it was spontaneously removedfrom the original position when the patient was waiting for the surgery. Therefore, only mastectomy with axillary lymph node sampling was performed, followed by 45 Gy/25 times of postmastectomy and locoregional lymph node irradiation. Six months after the surgery, the patient is alive with no signs of local recurrence.

Baseline neutrophil-to-lymphocyte ratio and c-reactive protein predict efficacy of treatment with bevacizumab plus paclitaxel for locally advanced or metastatic breast cancer.

The effect of bevacizumab plus paclitaxel therapy on progression-free survival (PFS) is prominent; however, no overall survival (OS) benefit has been demonstrated. Our aim was to study the predictive efficacy of peripheral immune-related parameters, neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC), and c-reactive protein (CRP) in locally advanced and metastatic breast cancers. A total of 179 patients treated with bevacizumab plus paclitaxel were recruited from three institutes in the test cohort. The cut-off values of NLR, ALC, and CRP were set at 3, 1500/µL, and 1.0 mg/dL, respectively, and baseline values of these factors were measured. The PFS of patients with NLR-low was significantly longer than that of patients with -high (median, 12.6 vs. 7.2 months; hazard ratio (HR), 0.48, 95% confidence interval (95% CI), 0.31-0.73; p = 0.0004). OS of patients with NLR-low was significantly better than those with-high (22.2 vs. 13.5 months; HR, 0.57, 95% CI, 0.39-0.83; p = 0.0032). Similarly, improved PFS and OS were recognized in patients with CRP-low as compared with patients with -high (HR, 0.44, 95% CI, 0.28-0.68; p = 0.0001 and HR, 0.39, 95% CI, 0.26-0.61, p < 0.0001, respectively). In the validation cohort from two institutes (n = 57), similar significant improvements in PFS and OS were confirmed for patients with NLR-low (p = 0.0344 and p = 0.0233, respectively) and CRP-low groups (p < 0.0001 and p = 0.0001, respectively). Low levels of NLR and CRP at baseline were significantly associated with improved prognosis in patients treated with bevacizumab plus paclitaxel.

[A Case of Liver Metastases of Ampullary Carcinoma with Clinical Complete Response Treated with Gemcitabine plus Cisplatin].

We report a case of liver metastases of ampullary carcinoma that achieved clinical complete response after gemcitabine plus cisplatin(GC)combination chemotherapy. A 69-year-old man with obstructive jaundice was diagnosed with ampullary carcinoma and underwent laparoscopic pancreaticoduodenectomy. Postoperative histopathological examination revealed pT3aN0M0, Stage ⅡA adenocarcinoma of the papilla of Vater. Five months after surgery, multiple liver metastases were identified by CT and MRI. The patient received GC chemotherapy intravenously at doses of 1,000 and 25mg/m2 on days 1 and 8, respectively, every 3 weeks. After 3 courses of GC chemotherapy, a CT scan revealed that the liver metastases reduced in size, and PR was achieved based on the RECIST standard. However, Grade 3 neutropenia appeared. After 7 courses, the liver metastases disappeared, and the patient had achieved CR. After 9 courses, the clinical CR continued. Approximately 14 months have passed since the recurrence, and the patient is currently alive.

[Long-Term Survival in a Case of Breast Cancer with Brain Metastases and No Other Distant Metastases Treated by Surgical Removal and Gamma Knife Radiosurgery].

A 44-year-oldwoman was diagnosedwith right breast cancer andund erwent mastectomy andaxillary lymph node dissection in February 2006. She was pathologically diagnosed with invasive ductal carcinoma without lymph node metastasis. Immunohistochemical examination showedthat the tumor was estrogen receptor positive, progesterone receptor negative, andhada HER2 status score of 0. She received 4 cycles of AC, followedby leuprorelin andtamoxifen. Several metastases were identified in the right supraclavicular lymph nodes in August 2008 during the endocrine therapy. Then, she received S-1 as the first-line chemotherapy. Although metastases showed complete response, she developed an eye disorder caused by S-1 and thus the treatment agent was changedto leuprorelin andanastrozole. She complainedof headache andright homonymous hemianopsia in November 2013. MRI showeda 42mm diameter tumor in the left occipital lobe, suspectedto be brain metastasis from breast cancer. Craniotomy was performedto remove the brain tumor, which was pathologically diagnosedas metastasis from breast cancer. In the brain tumor, the estrogen receptor status hadchangedto negative, but the HER2 status remained unchanged, showing a score of 0. Vinorelbine was administered after the brain surgery. Unfortunately, brain metastasis was foundin the dura mater near the surgical cavity, andgamma knife radiosurgery was performedin January 2014. Thereafter, brain metastases were repeatedly found, and gamma knife radiosurgery was again performed in January 2015, September 2016, and February 2017. In addition, a large tumor appearedin the left occipital lobe andwas surgically removed in June 2016. No other distant metastases were found, andvinorelbine was continueduntil February 2018. Because the patient developed dyslexia caused by gamma knife-induced radiation necrosis, bevacizumab was administered between November 2018 and April 2019. MRI showed that the edema due to radiation necrosis reduced and dyslexia symptoms improved. As of now, she has survivedfor 5 years and 6 months after the diagnosis of brain metastases.

Detection of ESR1 mutations in plasma and tumors from metastatic breast cancer patients using next-generation sequencing.

PURPOSE: Liquid biopsy using digital PCR (dPCR) has been widely used for the screening of ESR1 mutations, since they are frequently identified in the hotspot. However, dPCR is limited to the known mutations. Therefore, we aimed to analyze the utility of next-generation sequencing (NGS) to discover novel ESR1 mutations. METHODS: Whole exon sequencing of the ESR1 gene using NGS was performed in 16 primary and 47 recurrent tumor samples and 38 plasma samples from hormone receptor-positive metastatic breast cancer patients. Functional analyses were then performed for the novel mutations we detected. RESULTS: We identified no mutations in primary tumors and six mutations in five recurrent tumors, including three types of known mutations (Y537C, Y537N, and D538G) and two novel mutations (E279V and G557R). We also identified seven mutations in five plasma samples, including three types of known mutations (S463P, Y537S, and D538G) and one mutation not reported in COSMIC database (L536H). All nine patients with ESR1 mutations were treated with aromatase inhibitors (AIs) prior to sampling, and the mutations were frequently detected in patients who received AI treatments in the metastatic setting. Among the three novel mutations (E279V, L536H, and G557R), L536H, but not E279V and G557R, showed ligand-independent activity. All three mutant proteins showed nuclear localization and had no relation with non-genomic ER pathways. CONCLUSIONS: Although the molecular mechanisms of the E279V and G557R mutations remain unclear, our data suggest the utility of NGS as a liquid biopsy for metastatic breast cancer patients and the potential to identify novel ESR1 mutations.