Response-Guided Omission of Anthracycline in Patients with HER2-Positive Early Breast Cancer Treated with Neoadjuvant Taxane and Trastuzumab: 5-Year Follow-Up of Prognostic Study Using Propensity Score Matching.

BACKGROUND: De-escalation therapy omitting anthracycline has been generally adopted for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in the adjuvant setting, but not in the neoadjuvant chemotherapy (NAC) setting. We investigated whether anthracycline can be omitted in HER2-positive early breast cancer patients receiving neoadjuvant taxane plus trastuzumab with clinical response. METHODS: HER2-positive primary breast cancer patients treated using NAC containing trastuzumab were enrolled between September 2006 and July 2018 at Osaka Breast Clinic. The primary outcome was disease-free survival (DFS). The secondary outcome was overall survival (OS). We investigated survival with or without fluorouracil, epirubicin, and cyclophosphamide (FEC) using the log-rank test and propensity score matching (PSM). RESULTS: In total, 142 patients were retrospectively included and median follow-up was 61 months. There was no significant difference in DFS (p = 0.93) and OS (p = 0.46) between the FEC-omitted group and the FEC-added group. The 5-year DFS was 91% and 88% and OS was 100% and 100%, respectively. After PSM, the FEC-omitted group and the FEC-added group had no significant differences in DFS (p = 0.459) and there were no death events in either group. The 5-year DFS was 90% and 88% and OS was 100% and 100%, respectively. CONCLUSIONS: Using PSM, the 5-year DFS of HER2-positive early breast cancer was not different with or without anthracycline. Response-guided omission of anthracycline may be an option for HER2-positive early breast cancer patients receiving neoadjuvant taxane and trastuzumab with good response in order to avoid overtreatment.

Prognostic Factors in HER2-Positive Primary Breast Cancer Patients Treated Using Neoadjuvant Chemotherapy Plus Trastuzumab.

BACKGROUND: It is unclear for whom new anti-human epidermal growth factor receptor 2 (anti-HER2) agents, such as pertuzumab and T-DM1, should be considered. We investigated prognostic factors before neoadjuvant chemotherapy (NAC) among HER2-positive invasive breast cancer patients and those after NAC among patients who did not achieve pathological complete response (pCR) using conventional adjuvant trastuzumab. METHODS: HER2-positive primary breast cancer patients treated using NAC containing trastuzumab were enrolled between September 2006 and June 2017 at the Osaka Breast Clinic. Patients with distant metastasis or using NAC containing pertuzumab were excluded. The main outcome was disease-free survival (DFS). We investigated pre- and post-NAC prognostic factors using the log-rank test and Cox proportional hazards model. RESULTS: In total, 157 patients were included. Among the pre-NAC prognostic factors, younger age (under 40 years old) and positive clinical nodal status were significantly poorer prognostic factors (hazard ratio [HR] 3.47, 95% CI 1.06-10.12, p = 0.041 and HR 3.32, 95% CI 1.03-14.78, p = 0.045) by multivariate analysis. Among the post-NAC prognostic factors, patients with non-pCR (3-year DFS; 85 vs. 96%, p = 0.022) had a poorer DFS than patients with pCR. DFS was assessed for non-pCR patients (n = 64). High post-NAC Ki-67 status (≥20%; HR 6.73, 95% CI 1.82-31.93, p = 0.004) was a significant and large post-NAC tumor size (≥2 cm; HR 3.65, 95% CI 0.97-14.71, p = 0.056) was a marginally significant prognostic factor by multivariate analysis. After having combined them, high post-NAC Ki-67 status or large post-NAC tumor size was also a significant prognostic factor (HR 5.75, 95% CI 1.32-16.12, p = 0.017). CONCLUSIONS: Positive clinical nodal status and young age were found to be prognostic factors before NAC in HER2-postive invasive breast cancer patients. A high post-NAC Ki-67 status and large post-NAC tumor size were significant and marginally significant prognostic factors, respectively, after NAC in patients who did not achieve pCR. New anti-HER2 agents, such as pertuzumab and T-DM1, should be considered for the patients with those prognostic factors.

Gemcitabine and Vinorelbine Combination Chemotherapy in Taxane-Pretreated Patients with Metastatic Breast Cancer: A Phase II Study of the Kinki Multidisciplinary Breast Oncology Group (KMBOG) 1015.

BACKGROUND: This phase II study was conducted to evaluate the efficacy and safety of the chemotherapy combination of gemcitabine and vinorelbine in taxane-pretreated Japanese metastatic breast cancer patients. METHODS: In this multicenter, phase II, single-arm study, patients with recurrent or metastatic HER2-negative breast cancer were administered gemcitabine (1,200 mg/m2) and vinorelbine (25 mg/m2) intravenously on days 1 and 8 every 3 weeks. The primary endpoint was the objective response rate, and other endpoints included progression-free survival, overall survival, and safety. RESULTS: A total of 42 patients were enrolled in this study. The objective response rate and clinical benefit rate were 24 and 43%, respectively. The median progression-free survival was 4.0 months. The median overall survival was 11.1 months. Grade 3/4 neutropenia was the most common hematologic toxicity, occurring in 22 patients (54%). Nonhematologic toxicity was moderate and transient, with fatigue (48%) being the most common condition and no severe adverse event reported. CONCLUSION: The combination of gemcitabine and vinorelbine is an effective and tolerable regimen for HER2-negative, taxane-pretreated, metastatic breast cancer patients in Japan.

[Efficacy of capecitabine/cisplatin chemotherapy after failure of all conventional therapies in patients with advanced gastric cancer].

There is no standard therapy for advanced gastric cancer patients who had already failed treatment with major anti-cancer drugs including fluoropyrimidine, cisplatin, taxans, and irinotecan. We report the results of treatment with capecitabine and cisplatin(XP)after the failure of all other conventional therapies. A total of five advanced gastric cancer patients were treated. The median age was 59 years(range, 46-76); there were 3male and 2 female patients; performance status was 0/1/2: 2/2/ 1 patients, respectively. The median duration from start of first-line chemotherapy to XP was 653 days(range, 372-1,107). Three patients were treated after fourth-line therapy and two patients after fifth-line therapy. All of the patients had received S-1, cisplatin, irinotecan, paclitaxel, and docetaxel previously. Patients received 80mg/m2 of cisplatin intravenously on day 1, and 1,000mg/m2 of capecitabine orally twice a day from day 1 to day 14 followed by a 7-day rest period. Treatment courses were between 2 to 5. Median time to progression was 107 days. Median overall survival was 245 days. One PR and one SD were reported. All reported adverse events were manageable. XP is considered one of the effective regimens for advanced gastric cancer after all conventional therapies have failed.

[A case of HER2-positive advanced gastric cancer successfully treated with a combination of capecitabine, cisplatin, and trastuzumab as first-line chemotherapy].

We report a case of human epidermal growth factor receptor(HER)2-positive advanced gastric cancer successfully treated with a combination of capecitabine, cisplatin(CDDP), and trastuzumab as first-line chemotherapy. A 66-year-old woman diagnosed as having advanced gastric cancer underwent chemotherapy after abdominal computed tomography (CT)revealed multiple metastases to the liver, lung, lymph nodes, and peritoneum. Histopathological examination indicated a type 3, tub1, cT3(SS), N3, H1, P1, M1(LYM, PUL), cStage IV gastric tumor. Because overexpression of HER2 protein was observed in primary tumor immunostaining, combination therapy of capecitabine+CDDP+trastuzumab was administered as first-line chemotherapy. After 4 courses, CT scans revealed decreased primary tumor size, liver lesion, lymph nodes, and elimination of the lung lesion, thereby suggesting a partial response(PR). The grade 3 adverse events were neutropenia, anemia, and anorexia. After discontinuation of CDDP because of elevation of serum creatinine levels, combination therapy with capecitabine and trastuzumab was continued.

[A case of advanced gastric cancer with para-aortic lymph node metastasis successfully treated with preoperative S-1/Lentinan chemotherapy followed by curative gastrectomy].

We report a case of advanced gastric cancer successfully treated with preoperative S-1/Lentinan (LTN)chemotherapy followed by curative gastrectomy. The patient was a 75-year-old man with right hypochondralgia. Endoscopic examination revealed a huge type 2 gastric cancer in the middle body of the stomach. Abdominal computed tomography (CT) revealed multiple perigastric lymph node metastases and bulky para-aortic lymph node metastases. The clinical diagnosis was cT 4N3M1( LYM) with cStage IV. We thought a complete resection would be difficult, so he was treated with S-1( 80 mg/m2 day 1-28/q6w) and LTN (2 mg weekly) in May 2010. After 3 courses, the primary lesion was markedly reduced, and gastric endoscopic biopsy showed no malignant lesion. After 4 courses, abdominal CT showed no lymph node swelling at the perigastric and para-aortic areas. After 5 courses, distal gastrectomy with D2 lymphadenectomy was performed. The histological diagnosis was ypT2( MP) N0M0, Stage IB. Histological features of the primary tumor and lymph nodes were judged to be Grade 2 and Grade 3, respectively. After surgery, S-1/LTN treatment was continued for 1 year. During this period, there were no serious adverse events. The patient has been in good health without recurrence for 28 months after surgery.

[A case of paclitaxel-resistant recurrent gastric cancer responsive to S-1 plus docetaxel].

We report the case of a patient with paclitaxel (PTX) -resistant recurrent gastric cancer who was effectively treated with S-1 plus docetaxel( DOC). A 62-year-old woman underwent total gastrectomy for Stage IV advanced gastric cancer (type 4, por 2>sig, pT4a (SE), pN3a, pP1, CY1) in 2009. Although S-1 was administered as first-line chemotherapy, recurrent peritoneal metastasis was diagnosed 22 months after surgery. S-1 plus irinotecan (CPT-11) was administered as second-line chemotherapy, and this was followed by weekly PTX (80 mg/m2) as third-line chemotherapy. However, computed tomography (CT) showed increased ascites and peritoneal wall thickening in the pelvis. As the tumor proved resistant to PTX, making the treatment ineffective, S-1( 80 mg/m2, day 1-14, q3w) plus DOC( 40 mg/m2, day 1, q3w) was initiated. Two months later, the ascites and peritoneal wall thickening in the pelvis disappeared. Twelve months after initiation of S-1 plus DOC chemotherapy, no sign of recurrence has been noted.

[Two cases of HER2-positive advanced or metastatic breast cancer, responding to lapatinib and capecitabine].

The first patient was a 59-year-old woman who was diagnosed with invasive scirrhous carcinoma. The tumor was estrogen receptor (ER)-positive, progesterone receptor (PgR)-positive, and human epidermal growth factor receptor 2 (HER2)-positive. The patient was treated with adjuvant chemotherapy and endocrine therapy after surgery. Liver metastases developed 5 years after surgery. She was treated with trastuzumab combined with vinorelbine, paclitaxel, or docetaxel. The liver metastases increased in size, 9 years after surgery, and she was treated with lapatinib and capecitabine. The efficacy of chemotherapy was judged as a partial response. The second patient was a 74-year-old woman who was diagnosed with invasive ductal carcinoma in 2005. The tumor was ER-negative, PgR-positive, and HER2-positive; she was treated with trastuzumab and paclitaxel. She developed dyspnea in January 2010. Chest radiograph showed increased lung metastases and left pleural effusion; she was treated with lapatinib and capecitabine. Lung metastases decreased and left pleural effusion disappeared after the first cycle of chemotherapy. The efficacy of chemotherapy was judged as a partial response.

Carcinosarcoma of the gallbladder producing alpha-fetoprotein and manifesting as leukocytosis with elevated serum granulocyte colony-stimulating factor: report of a case.

A 69-year-old man was referred to our hospital for investigation of leukocytosis and a persistent fever of 38 degrees C, but we could find no evidence of a specific infection. The leukocyte count was 18,000/mm(3), and the serum granulocyte colony-stimulating factor (G-CSF) and alpha-fetoprotein (AFP) levels were both elevated, at 66.3 pg/ml and 1,495 ng/ml, respectively. Computed tomography (CT) showed a gallbladder tumor and we performed extended cholecystectomy. Postoperatively, the fever subsided and the leukocyte count, serum G-CSF and AFP level normalized. Histologically, the tumor was a carcinosarcoma of the gallbladder. Immunohistochemical staining of the tumor cells was positive for AFP, but negative for G-CSF. This is the first report of a carcinosarcoma of the gallbladder producing AFP. The laboratory findings and clinical course strongly suggested that the tumor produced not only AFP, but also G-CSF.

A case of advanced mucinous cystadenocarcinoma of the pancreas with peritoneal dissemination responding to gemcitabine.

Mucinous cystic neoplasm(MCN)of the pancreas is a rare disease. A 34-year-old female was referred to our hospital for a giant cystic tumor in the left epigastrium, suspected of being a pancreatic MCN. The surgical findings revealed that the tumor originated in the pancreatic tail with the presence of peritoneal dissemination. A distal pancreatectomy and a splenectomy were performed, and the resected specimen histologically revealed an invasive mucinous cystadenocarcinoma of the pancreas. The postoperative computed tomography(CT)scan showed metastatic tumors of the Douglas pouch and the left ovary. Gemcitabine(GEM)was thereafter systemically administered for palliative chemotherapy with a regimen of 1,000 mg/m / 2week for 3 weeks, followed by a week of rest. When assessed by a CT scan after 4 courses of chemotherapy, marked shrinkage of the tumors was identified, and we could not detect the tumors clearly. Moreover, the serum CA19-9 level fell from 341 U/mL to almost normal and there were no severe adverse events. Therefore, systemic chemotherapy with GEM is considered to possibly be an effective treatment against MCN. We describe herein the first case of advanced mucinous cystadenocarcinoma of the pancreas with peritoneal dissemination responding to GEM and a brief review of the literature.

[Feasibility of peripheral vein during FOLFOX/FOLFIRI chemotherapy through peripheral venous system].

FOLFOX/FOLFIRI chemotherapy is usually applied through central venous catheters because of possible occurrence of phlebitis during application of these regimen via peripheral vein. However, the exact frequency and degree of the problems at peripheral venous access site during FOLFOX/FOLFIRI chemotherapy via peripheral vein in the clinical setting has not been reported previously. We investigated the frequency of infusion failure and phlebitis in 43 patients with advanced or recurrent colorectal cancer who received FOLFOX4, mFOLFOX6 or FOLFIRI chemotherapy in our institution. After informed consent, FOLFOX/FOLFIRI chemotherapy was applied via peripheral vein in 29 cases; all courses (13.1+/-8.1 (Mean+/-SD)courses, 5-FU: 3,510+/-743 mg/body/course) were completed via peripheral vein in the 20 cases (70%). In the other 9 cases, the access site was converted to the central vein because of the problems of access site following completion of 5.9+/-2.0 courses via peripheral vein. Fifty eight times of phlebitis were recognized during total of 301 courses; severe phlebitis requiring medical treatment was not recognized in any case. Seventy seven times of the change of venous access site were required during total of 301 courses. These data would be essential for the exact informed consent for choosing the access site for FOLFOX/FOLFIRI chemotherapy.

Randomized phase II study of anastrozole plus tegafur-uracil as neoadjuvant therapy for ER-positive breast cancer in postmenopausal Japanese women (Neo-ACET BC).

PURPOSE: This phase II study evaluated the efficacy and safety of anastrozole concurrent with tegafur/uracil (UFT) as neoadjuvant therapy for ER-positive postmenopausal breast cancer. METHODS: Postmenopausal Japanese women with ER-positive, HER2-negative, T2,N0-1,M0 breast cancer seen at tertiary hospitals were eligible for this open-label, randomized, multicenter study. Patients were randomized 1:1 by minimization to orally receive either anastrozole (1 mg once daily) plus UFT (tegafur/uracil combination in 1:4 molar ratio; 270 mg/m2/day in two divided doses) or anastrozole (as above) alone for 24 weeks. Tumor response was assessed by investigator and central review as per RECIST v1.1. The primary endpoint was the proportion of patients with best overall response of CR or PR [clinical response rate (RR)] determined by central radiologic review. RESULTS: The study was prematurely terminated due to Grade ≥ 3 liver dysfunction reported in 3 patients receiving anastrozole/UFT. Of 57 patients randomized before termination (29 anastrozole/UFT, 28 anastrozole), all were analyzed for safety and 56 (28 each group) for tumor response. Compared with anastrozole alone, anastrozole/UFT did not achieve significantly higher RR [39.3% (90% CI 23.8-56.5%) vs 14.3% (90% CI 5.0-29.8%); p = 0.0683, Fisher's exact test], but produced significantly greater tumor shrinkage (mean tumor reduction rate 31.0 vs. 14.2%; p = 0.0181, unpaired t-test). Grade ≥ 3 adverse events were more common with anastrozole/UFT than with anastrozole (17.2 vs. 0%). CONCLUSION: Although the study was terminated owing to the altered liver function, it showed that there was a trend to greater shrinkage of tumor in the combination group for ER-positive, HER2-negative postmenopausal breast cancer.

Identification of sentinel lymph nodes by contrast-enhanced ultrasonography with Sonazoid in patients with breast cancer: a feasibility study in three hospitals.

The aim of this prospective study was to evaluate the feasibility of periareolar injection of the contrast agent Sonazoid (SNZ) followed by ultrasonography (US) for the identification of sentinel lymph node (SLN) in breast cancer patients with clinically negative node. Patients (n = 100) with T1-2N0M0 breast cancer received a periareolar injection of SNZ followed by US to identify contrast-enhanced SLN. Each contrast-enhanced SLN underwent fine needle aspiration cytology (FNAC) followed by SLN biopsy with a conventional method using blue dye and/or radiocolloid (B/R). In almost all cases, contrast-enhanced lymphatic vessels were clearly visualized by US soon after the periareolar injection of SNZ and the SLNs were easily identified with an identification rate of 98% (98/100) for SNZ and 100% (100/100) for B/R. The number of SLNs identified by SNZ (SNZ-SLN) (mean per patient, 1.52) was significantly lower than that identified by B/R (B/R-SLN) (2.19) (P < 0.0001). Twenty-five patients with positive SLNs had at least one positive SNZ-SLN. On a node-by-node basis, sensitivity, specificity, and accuracy of FNAC for SNZ-SLNs (n = 149) were 33.3%, 99.2%, and 85.9%, respectively. Identification of SLN by periareolar injection of SNZ is a technically simple method with an identification rate as high as 98%. SNZ-SLN thus seems to be a good target for FNAC, but sensitivity of FNAC for SNZ-SLNs needs to be improved.

Weekly paclitaxel for a patient with advanced gastric cancer.

A 56-year-old woman diagnosed with gastric cancer was admitted to our hospital for operation on May 15, 2001. The operation was performed on May 23. The tumor formed a large mass from the antrum to the head of the pancreas, and cancer cells were detected in the ascitic fluid microscopically. During the operation, resection was impossible, and so 100 mg of cisplatin (CDDP) was infused into the abdominal cavity. After the operation, she experienced continuous nausea and there was a discharge of 1200-1600 ml of digestive fluid per day from her nasogastric tube. On July 17, a new regimen, of 4-week courses of chemotherapy, with weekly administrations of 65 mg/m2 of paclitaxel, along with premedication for 3 weeks, followed by 1 week of rest, was started. After the first of these 4-week courses, the discharge from her nasogastric tube decreased to 200-600 ml per day, and the tube was removed 78 days after insertion. Oral intake of food increased smoothly, and she was discharged on September 14. After another, short, hospitalization, she was discharged on October 20, and she has been coming to our outpatient clinic once a week. After paclitaxel was started, gastric fiberscopy and computed tomography (CT) scan showed reduction of the tumor. Of special note was the disappearance of a scitic fluid after two courses, rated as a "partial response" (Japanese classification). There was a decrease in hemoglobin, but neither leukocytopenia nor a decrease in platelets was found. Neuropathy was slight and no treatment was needed. Now, after 1 year, 11 courses of chemotherapy have been administered at the outpatient clinic. These results suggest weekly administration of paclitaxel to be a promising treatment for advanced gastric cancer with peritoneal dissemination. The therapeutic efficacy should be confirmed by further clinical trials.