Relationship between endocrine resistance and the periods of adjuvant endocrine treatment for hormone receptor-positive, HER2-negative breast cancer.

BACKGROUND: Current guidelines define primary and secondary endocrine resistance according to the periods of adjuvant endocrine therapy (adj-ET); however, the relationship between adj-ET period and endocrine resistance remains unclear. OBJECTIVE: We examined progression-free survival (PFS) after primary ET for recurrent hormone receptor-positive/HER2-negative breast cancer, and evaluated the relationship between endocrine resistance and the periods of adj-ET. METHODS: We assessed PFS among 183 patients who received ET as primary treatment for the first recurrence, according to the period of adj-ET (adj-ET < 1 year, 1-2 years, ≥2 years, and completion). RESULTS: Patients who relapsed during the first year of adj-ET had the significantly shortest PFS. PFS did not significantly differ between patients who relapsed at 1-2 years of adj-ET and patients who relapsed while on adj-ET but after the first 2 years. CONCLUSIONS: Relapse at 1-2 years after adj-ET initiation might be better classified as secondary endocrine resistance rather than primary endocrine resistance.

New insights into patterns of first metastatic sites influencing survival of patients with hormone receptor-positive, HER2-negative breast cancer: a multicenter study of 271 patients.

BACKGROUND: The initial therapeutic strategy for hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer is based on the first metastatic site; however, little evidence is available regarding the influence of metastatic distribution patterns of first metastatic sites on prognosis. In this study, we aimed to identify the metastatic distribution patterns of first metastatic sites that significantly correlate with survival after recurrence. METHODS: We performed a retrospective review of records from 271 patients with recurrent metastatic HR+/HER2- breast cancer diagnosed between January 2000 and December 2015. We assessed survival after recurrence according to the metastatic distribution patterns of the first metastatic sites and identified significant prognostic factors among patients with single and multiple metastases. RESULTS: Prognosis was significantly better in patients with a single metastasis than in those with multiple metastases (median overall survival after recurrence: 5.86 years vs. 2.50 years, respectively, p < 0.001). No metastatic organ site with single metastasis was significantly associated with prognostic outcome, although single metastasis with diffuse lesions was an independent risk factor for worse prognosis (HR: 3.641; 95% CI: 1.856-7.141) and more easily progressing to multiple metastases (p = 0.002). Multiple metastases, including liver metastasis (HR: 3.145; 95% CI: 1.802-5.495) or brain metastasis (HR: 3.289; 95% CI: 1.355-7.937), were regarded as significant independent poor prognostic factors; however, multiple metastases not involving liver or brain metastasis were not significantly related to prognosis after recurrence. CONCLUSIONS: Single metastases with diffuse lesions could more easily disseminate systemically and progress to multiple metastases, leading to a poor prognosis similar to multiple metastases. Our findings indicate that the reconsideration of the determinant factors of therapeutic strategies for first recurrence in HR+/HER2- breast cancer may be needed.

Differential Involvement of Autophagy and Apoptosis in Response to Chemoendocrine and Endocrine Therapy in Breast Cancer: JBCRG-07TR.

Endocrine therapy is an essential component in the curative treatment of hormone receptor (HR)-positive breast cancer. To improve treatment efficacy, the addition of metronomic chemotherapy has been tested and shown to improve therapeutic effects. To better understand cellular reactions to metronomic chemoendocrine therapy, we studied autophagy-related markers, beclin 1 and LC3, and apoptosis-related markers, TUNEL and M30, in pre- and post-treatment cancer tissues from a multicenter neoadjuvant trial, JBCRG-07, in which oral cyclophosphamide plus letrozole were administered to postmenopausal patients with HR-positive breast cancer. Changes in the levels of markers were compared with those following neoadjuvant endocrine therapy according to clinical response. Apoptosis, in addition to autophagy-related markers, increased following metronomic chemoendocrine therapy and such increases were associated with clinical response. By contrast, following endocrine therapy, the levels of apoptosis-related markers did not increase regardless of clinical response, whereas the levels of autophagy-related markers increased. Furthermore, levels of the apoptosis-related marker, M30, decreased in responders of endocrine therapy, suggesting that the induction of apoptosis by metronomic chemoendocrine therapy was involved in the improved clinical outcome compared with endocrine therapy. In conclusion, metronomic chemoendocrine therapy induced a different cellular reaction from that of endocrine therapy, including the induction of apoptosis, which is likely to contribute to improved efficacy compared with endocrine therapy alone.

Response to First-line Recurrence Treatment Influences Survival in Hormone Receptor-positive, HER2-negative Breast Cancer: A Multicenter Study.

BACKGROUND/AIM: Little evidence is currently available on significant determinants of post-recurrence survival for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer. The objective of this study was to evaluate factors influencing post-recurrence survival in HR+/HER2-breast cancer. PATIENTS AND METHODS: A cohort of 236 patients with recurrent HR+/HER2- breast cancer was retrospectively analyzed to identify significant factors correlating with prognosis after recurrence. RESULTS: Multivariate analysis revealed independent prognostic factors of poor survival as follows: short intervals between recurrence and the end of adjuvant endocrine therapy (ET; p=0.046); short disease-free intervals (p=0.019); liver metastasis (p=0.007) or multiple metastases (p<0.001) at recurrence; and a poor response to first-line treatment (p<0.001). A poor first-line treatment response was significantly associated with a shorter response to a subsequent treatment line (p=0.007). Logistic regression analysis indicated that liver metastasis significantly increased the risk of a poor first-line-ET response (p=0.009). CONCLUSION: The first-line treatment response was the key to post-recurrence survival in patients with HR+/HER2- breast cancer. Particularly poor responses led to subsequent unfavorable prognostic outcomes.

A multicenter phase II trial of neoadjuvant letrozole plus low-dose cyclophosphamide in postmenopausal patients with estrogen receptor-positive breast cancer (JBCRG-07): therapeutic efficacy and clinical implications of circulating endothelial cells.

Neoadjuvant endocrine therapy has been reported to decrease tumor size, which leads to increased breast conservation rates. To improve the clinical response, metronomic chemotherapy with endocrine therapy is a promising strategy. A multicenter phase II single-arm neoadjuvant trial with letrozole and cyclophosphamide was conducted. Eligibility criteria included postmenopausal status, T2-4 N0-1, and estrogen receptor-positive breast carcinoma. Letrozole (2.5 mg) plus cyclophosphamide (50 mg) was given orally once a day for 24 weeks. The primary endpoint was the clinical response rate (CRR). To investigate anti-angiogenic effects, circulating endothelial cells (CECs) were quantified using the CellSearch system. From October 2007 to March 2010, 41 patients were enrolled. The CRR was 67.5% (52.0-80.0%), which was above the prespecified threshold (65%). The conversion rate from total mastectomy to breast-conserving surgery was 64% (18/28). Grade 3 or greater nonhematological toxicity was not reported. Clinical response was associated with improved disease-free survival (DFS) (P = 0.020). The increase in CEC counts at 8 weeks was observed in nonresponders (P = 0.004) but not in responders. Patients with higher CEC counts at baseline or post-treatment showed worse DFS than those with lower counts (P < 0.001 at baseline and = 0.014 post-treatment). Multivariate analysis showed that post-treatment CEC counts but not pretreatment counts were independently correlated with DFS (P = 0.046). In conclusion, neoadjuvant letrozole plus cyclophosphamide showed a good clinical response for postmenopausal patients with estrogen receptor-positive breast cancer. CEC quantification is a promising tool for treatment monitoring and prognostic stratification for metronomic therapy following validation of our results in larger studies. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000001331 Phase II study of neoadjuvant letrozole combined with low-dose metronomic cyclophosphamide for postmenopausal women with endocrine-responsive breast cancer (JBCRG-07).

The Difference in Prognostic Outcomes Between De Novo Stage IV and Recurrent Metastatic Patients with Hormone Receptor-positive, HER2-negative Breast Cancer.

BACKGROUND/AIM: Patients with de novo stage IV and recurrent metastatic breast cancer are often treated with the same strategies, although the difference in prognostic outcomes remains unclear. The objective of this retrospective chart review study was to compare the prognostic outcomes between two types of patients with hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer. PATIENTS AND METHODS: We estimated overall survival of the two groups and evaluated the progressive course of the disease using disease-free interval (DFI) and interval from the end of adjuvant treatment to the first recurrence (AFI). RESULTS: We studied 172 patients with HR+/HER2- breast cancer, of which 65 were de novo and 107 were recurrent. Median OS between de novo and recurrent BC was 4.85 and 3.45 years, respectively (p=0.046). Recurrent patients with a DFI<2 years were found to have a significantly poorer prognosis than recurrent patients with a DFI≥2 years (p=0.016) and de novo patients (p=0.002). Similarly, recurrent patients with an AFI<1 year had a significantly poorer prognosis compared to de novo patients (p=0.026). CONCLUSION: De novo patients had better prognoses than recurrent patients with DFI<2 years or AFI<1 year, likely due to their therapy-naïve status or lower resistance to systemic treatment.

[Clinical Experience of Ramucirumab for Treating Advanced Gastric Cancer].

BACKGROUND: The REGARD and RAINBOW trials showed that ramucirumab(RAM)alone and RAM plus paclitaxel(PTX) were effective therapies for advanced gastric cancer patients previously treated with chemotherapy. In this retrospective study, we evaluated the safety and efficacy of RAM alone and PTX plus RAM in such patients. METHODS: Patients who were received RAM at 8mg/kg or RAM plus PTX at 80mg/m2(on days 1, 8, and 15 of a 28-day cycle)between June 2015 and March 2016 were enrolled in this study. We compared the clinical outcome of RAM alone(RAM group, n=10)with that of RAM plus PTX(PTX+RAM group, n=13). RESULTS: The RAM group contained many more patients with poor performance status or prior chemotherapy of 2 or more regimens than the PTX+RAM group. All patients in both groups received chemotherapy on an outpatient basis. One case of grade 3 or 4 hematological adverse events was found in the RAM group and 6 cases were found in the PTX+RAM group. The overall response rate was 10% in the RAM group and 30% in the PTX+RAM group. Progression-free survival was 54 days in the RAM group and 187 days in the PTX+RAM group(p=0.0374). Overall survival was 158 days in the RAM group and was not reached in the PTX+RAM group(p=0.1091). CONCLUSIONS: RAM alone and RAM plus PTX can be administered safely on an outpatient basis and are beneficial for advanced gastric cancer patients previously treated with chemotherapy.

[A Case of an Elderly Patient with Unresectable Gastric Cancer Treated by Paclitaxel and Ramucirumab].

An 80-year-old man was admitted to our hospital with appetite loss in December 2014. Gastroduodenal scope, abdominal computed tomography(CT), and laparoscopy revealed type 4 advanced gastric cancer(poorly differentiated adenocarcinoma) with multiple lymph node(LN)involvement and multiple peritoneal metastasis. S-1(80mg/body)was administrated between January 2015 and September 2015 in the outpatient clinic. A partial response was obtained, but a gastric tumor, ascites, and LN re-growth were observed. Since October 2015, paclitaxel(PTX)(70mg/m2; day 1, 8, and 15)and ramucir- umab(RAM)(8mg/kg; day 1 and 15)have been administered. After 2 courses, bi-weekly PTX plus RAM were continued for grade 3 neutropenia and grade 2 anorexia. The tumor and LNs partially responded, and the ascites disappeared. With this dosage and administration schedule, the partial response(PR)was maintained for approximately 8 months without any severe adverse reactions. This successful case might indicate that it is important for elderly patients with gastric cancer that progressed with prior chemotherapy regimens to consider appropriate reduction of the PTX dosage, schedule, and continuation of RAM.

[Three Cases of Bleeding from Advanced Gastric Cancer during Chemotherapy Treated with Transcatheter Arterial Embolization(TAE)].

Case 1: An 71-year-old man underwent chemotherapy with S-1 plus trastuzumab to treat type 3 gastric cancer that was diagnosed as Stage IV tubular adenocarcinoma(T4b[Panc], N3, H0, CY1, P0, M1). For anemia and active bleeding from the tumor, transcatheter arterial embolization(TAE)was performed with metallic coils on the splenic artery. Infarction of the spleen and left pleural effusion were observed. Second-line paclitaxel(PTX)chemotherapy was administered 4 weeks after TAE. Case 2: An 76-year-old man underwent chemotherapy with S-1 plus cisplatin to treat type 3 gastric cancer that was diagnosed as Stage IV tubular adenocarcinoma(T4a, N3, H0, P1, M1). For anemia and active bleeding from the tumor, TAE with gelatin sponge(Serescure®)was performed on the left and right gastric artery. Radiotherapy(31 Gy)with S-1 was performed because TAE was not effective for bleeding. After chemoradiotherapy, nab-PTX was administered. Case 3: An 74- year-old man underwent second-line chemotherapy with nab-PTX to treat type 4 advanced gastric cancer that was diagnosed as Stage IV tubular adenocarcinoma(T4a, N3, H1, P0, M1). For progression of anemia due to tumor bleeding, TAE with gelatin sponge(Serescure®)was performed on the left gastric artery. TAE was effective, and he was discharged from the hospital. In 2 of 3 cases, hemostasis was achieved by TAE. Therefore, TAE is effective to decrease bleeding from gastric cancer during chemotherapy.

[Eye Disorders Associated with S-1 Chemotherapy in Gastric Cancer Patients].

Eye disorders are one of the characteristic adverse events associated with S-1 chemotherapy. In this retrospective study, we investigated the frequency and outcome of eye disorders associated with S-1 chemotherapy in gastric cancer patients. This retrospective study included 75 advanced gastric cancer patients who received S-1 monotherapy between January 2014 and December 2015. We retrospectively evaluated the frequency, Grade, and treatment of eye disorders. Eye disorders were observed in 16 patients(21%). The median time of onset was 3(range, 1-8)months. Grade 2 watering eyes, eye discharge, and conjunctivitis were reported in 14, 8, and 4 patients, respectively. Artificial tears, fluorometholone eye-drops, and both of these treatments were used in 7, 1, and 8 patients, respectively. Ophthalmologic examination was performed for 3 patients. No delay or reduction of S-1 therapy was required for the eye disorders. Eye disorders associated with S-1 therapy in gastric cancer patients did not affect treatment if managed properly using eye drops.

[Efficacy and Safety of Pertuzumab for HER2-Positive Metastatic Breast Cancer].

The CLEOPATRA trial showed a significant improvement in the progression-free survival (PFS) and overall survival of patients with HER2-positive first-line metastatic breast cancer (MBC) who were treated with pertuzumab (PER), trastuzumab (TRA), and docetaxel (DTX), compared to those treated with placebo, TRA, and DTX. PER was approved in 2013 for treating HER2-positive MBC in Japan. Herein, we present the retrospective review of data from 10 HER2-positive MBC patients who received PER in our hospital between September 2013 and August 2014.T he median age was 52 years (range, 45-66 years), and 7 patients were positive for ER.Six patients had not received any previous chemotherapy for their metastatic disease, while the others had received comparatively heavy pretreatment doses of chemotherapy.Our patients received the PER, TRA, and DTX regimen, although 2 patients were treated without DTX. Four patients experienced a partial response, 6 patients experienced stable disease (SD), and 3 patients experienced SD for ≥6 months. The response rate was 40%, and the clinical benefit rate was 70%.The median PFS was 7.3 months (range, 2.5-11.5 months). Grade 3 neutropenia and allergic reactions were observed in 1 and 2 patients, respectively; no Grade 4 adverse events were observed, and thus, the regimen was well tolerated. Further clinical research seems to be warranted for developing new treatment strategies involving PER for HER2-positive MBC.

[Examination of the Usefulness of Palliative Self-Expanding Metallic Stents in Patients with Malignant Colorectal Obstruction].

Self-expanding metallic stents (SEMS) are a useful palliative option in malignant colorectal obstruction. The aim of this study was to evaluate the clinical outcomes of SEMS used for palliation. Patients with malignant colorectal obstruction who underwent SEMS insertion in our hospital from April 2014 to March 2015 were enrolled in the study. Clinical outcomes and complications of palliative SEMS insertion were retrospectively analyzed. Nine patients were enrolled in the palliative SEMS group. The success rate was 100%, while the complication rate was 11%. Successful SEMS insertion may enable oral intake in a few days, but 3 patients required up to several weeks to resume oral intake. Palliative SEMS are effective and beneficial for malignant colorectal obstruction.

[A Case of Bone Metastasis from Early Gastric Cancer after a Five-Year Disease-Free Interval Following Gastrectomy].

A woman in her 50s underwent distal gastrectomy and D1+b dissection in December 2005 for early gastric cancer that was diagnosed as a signet-ring-cell carcinoma, fStage Ⅱ (T1a, N2, H0, P0, CY0, M0) with 12 lymph node metastases in the second field. Multiple bone metastases were diagnosed on the basis of CT and bone scintigraphy findings and serum ALP elevation (2,743 IU/L) I n December 2010. Fourteen courses of S-1 plus CDDP and 4 mg of zoledronate were administered from January to September in 2011. Pancytopenia, D-dimmer elevation, myelocytes, and metamyelocytes were observed in October 2012, indicating she had bone marrow metastasis. She was treated with a transfusion, anti-DIC therapy, and paclitaxel. She died from gastric cancer in December 2012. We report a rare case of recurrence with bone metastasis from early gastric cancer. S-1 plus CDDP chemotherapy and zoledronate therapy is an effective treatments for multiple bone metastases from gastric cancer.

[Two Cases of Bleeding Advanced Gastric Cancer Treated with Palliative Radiation Therapy].

Case 1: A man in his 70's was being treated with chemotherapy for unresectable advanced gastric cancer. Blood transfusion, endoscopic intervention including argon plasma coagulation, and transcatheter arterial embolization (TAE) were all used to treat repeated tumor bleeding causing anemia, but controlling the bleeding was difficult. In order to control the hemorrhage, radiation therapy of 31 Gy/10 Fr to the cancer was administered. After receiving radiation therapy, the anemia stopped. Case 2: A man in his 70's considered an operation for advanced gastric cancer, but his cardiac performance was poor and it was impossible to perform an operation. We conducted radiation therapy of 39 Gy/13 Fr for the purpose of preventing bleeding from gastric cancer. After receiving radiation therapy, the anemia stopped. We believe that radiation therapy is effective to stop bleeding from gastric cancer.

[Three Cases of Bleeding from Advanced Gastric Cancer Treated by Transcatheter Arterial Embolization(TAE)and Continued Chemotherapy].

Case 1: A man in his 70s was underwent transcatheter arterial embolization (TAE) because of progressive anemia, and the gastroduodenal artery and left gastric artery were embolized. Two weeks later, he started chemotherapy (S-1, Tmab). Case 2: A man in his 60s was underwent TAE because of anemia. The left gastric artery and right gastroepiploic artery were embolized. Bleeding was controlled and he continued chemotherapy. Case 3: A man in his 70s was who vomited blood during the course of chemotherapy underwent TAE, during which contrast dye extravasated from the anterior gastric artery. The splenic artery was embolized. After TAE, abdominal pain and splenic infarction appeared, but could be treated by conservative therapy. Chemotherapy was started 4 weeks later. TAE is an effective method for controlling bleeding from advanced gastric cancer.

[A Case of Invasive Ductal Carcinoma in the Fat Replacement of the Pancreatic Body and Tail].

A 56 year-old woman with obesity (BMI3 2) and diabetes mellitus was diagnosed with right renal cell carcinoma. She underwent right nephrectomy 1 year ago. Seven months after surgery, CT revealed a rapidly growing mass near the spleen. The mass showed slight accumulation of FDG (SUVmax=2.4) on PET-CT. Since the lesion grew rapidly and was not enhanced in the early phase of enhanced CT, we diagnosed pancreatic cancer. Distal pancreatectomy and splenectomy were performed. The final pathological diagnosis was invasive ductal carcinoma in the fat replacement of the pancreatic body and tail. Postoperatively, the patient had no complications such as pancreatic fistula or aggravation of glucose intolerance. She received postoperative chemotherapy with gemcitabine. Since she developed pulmonary artery thrombosis, postoperative chemotherapy was interrupted after 8 courses. Thirty-two months after the surgery, she was still living without any recurrence. Acinar cells were absent in the fat replacement of the pancreas, but the pancreatic duct cells were still present. There was carcinoma in situ in the main pancreatic duct surrounding chronic inflammation. Fat replacement itself could be potentially precursor of the pancreatic cancer.

Phase II study of S-1 in combination with trastuzumab for HER2-positive metastatic breast cancer.

AIM: We undertook a prospective phase II study to evaluate the efficacy of S-1 plus trastuzumab combination regimen for human epidermal-growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: HER2-positive MBC patients received oral administration of S-1 (80 mg/m2/day, days 1 to 28, every 6 weeks) and intravenous weekly trastuzumab (2 mg/kg), according to the results of a prior Phase I trial of our group. RESULTS: A total of 28 patients were enrolled and received a median of 3.5 (range 1-10) cycles of treatment. Overall response rate and clinical benefit rate were 53.6% and 75.0%, respectively. Progression-free survival was 30 weeks. With regard to grade 3 and 4 adverse effects, leucopenia, neutropenia, increase in serum alanine aminotransferase, and diarrhea were observed. CONCLUSION: Combination of S-1 and trastuzumab was tolerable and had excellent efficacy with good response and disease control in this trial.

[A case of metastatic colorectal cancer that reduced in size after re-challenging with an anti-EGFR monoclonal antibody].

A 58-year-old woman was confirmed as having multiple liver metastases after undergoing a high anterior resection for a sigmoid colon tumor. She was administered bevacizumab+FOLFOX as the first regimen and bevacizumab+FOLFIRI and S-1 and irinotecan (IRIS)therapy as the second regimen. During this treatment she also underwent hepatectomy 3 times and radiofrequency ablation once. She was administered panitumumab+irinotecan as the third regimen and, due to the presence of multiple pulmonary metastases, was subsequently considered to have had a partial response (PR). Because she subsequently developed progressive disease (PD), she received the fourth regimen as part of a clinical trial (TAS102) in another hospital. Cetuximab+irinotecan was administered as the fifth regimen after PD and the tumor was found to have reduced in size by 23%upon computed tomography (CT) 2 months later. Although stable disease (SD) was achieved, she was subsequently administered regorafenib for 8 months as a sixth regimen after the disease progressed a second time. In some cases of KRAS wild type metastatic colorectal cancer, re-challenging with an anti-epidermal growth factor receptor (EGFR) monoclonal antibody seems to be an effective strategy for reducing tumor mass.

[Long-term survival of a patient with esophageal metastasis from breast cancer treated with esophagectomy].

Esophageal metastasis from breast cancer is rarely observed. We encountered a case of long-term survival after esophageal metastasis from breast cancer that was treated with esophagectomy. A 79-year-old woman developed dysphagia 26 years after radical mastectomy. Endoscopic examination revealed stenosis at the mid-thoracic esophagus. An esophageal biopsy led to a diagnosis of undifferentiated cancer. A computed tomography (CT) scan revealed a massive tumor in the esophagus, but no distant metastases. Esophagectomy was performed with the suspicion of primary or metastatic esophageal cancer. Histopathologically, the excised tumor was an adenocarcinoma, which had histopathological features similar to that of the breast cancer. Accordingly, the adenocarcinoma was diagnosed as esophageal metastasis of the breast cancer. The patient is still alive 8 years after the esophagectomy.

[A case of brain abscess secondary to bisphosphonate-related osteonecrosis of the jaws in metastatic bone lesions from breast carcinoma].

Bisphosphonates have been used clinically as highly effective drugs in the treatment of hypercalcemia of malignancy, and bone metastasis of solid cancers. Despite these benefits, however, the emergence of bisphosphonate-related osteonecrosis of the jaws has become a growing and significant problem in a subset of patients receiving these drugs. We report a rare case of brain abscess secondary to BRONJ in metastatic bone lesions from breast carcinoma.