Stage I Breast Cancer in the Modern Era: A Retrospective Cohort Study of 328 Patients Diagnosed from 2002 to 2006 with a 14- year Median Follow-Up.

INTRODUCTION: This study aimed to evaluate the long-term outcomes of stage I breast cancer (BC) patients diagnosed during the current era of screening mammography, immunohistochemistry receptor testing, and systemic adjuvant therapy. METHODS: A retrospective cohort study was conducted on 328 stage I BC patients treated consecutively in a single referral center with a follow-up period of at least 12 years. The primary endpoints were invasive disease-free survival (IDFS) and overall survival (OS). The influence of tumor size, grade, and subtype on the outcomes was analyzed. RESULTS: Most patients were treated by lumpectomy, sentinel node biopsy and adjuvant endocrine therapy and most (82%) were of subtype luminal-A. Adjuvant chemotherapy was administered to 25.6 % of our cohort. Only 24 patients underwent gene expression testing, which was introduced toward the end of the study period. Mean IDFS was 14.64 years, with a 15-year IDFS of 75.6%. Mean OS was 15.28 years with a 15-year OS of 74.9%. In a Cox multivariate analysis, no clinical or pathologic variable impacted on OS and only tumor size (< 1 centimeter (cm) vs 1-2 cm), impacted significantly on IDFS. During follow-up, 20.1% of the cohort developed second primary cancers, including BC. The median time to diagnosis of a second BC was 6.49 years. CONCLUSION: The study results emphasize the importance of long-term follow-up and screening for subsequent malignancies of patients with stage I BC and support the need for using prognostic and predictive indicators beyond the routine clinicopathological characteristics in luminal-A patients.

Neoadjuvant therapy with doxorubicin-cyclophosphamide followed by weekly paclitaxel in early breast cancer: a retrospective analysis of 200 consecutive patients treated in a single center with a median follow-up of 9.5 years.

PURPOSE: We analyzed outcomes of doxorubicin-cyclophosphamide (AC) followed by weekly paclitaxel as neoadjuvant chemotherapy (NAC) for breast cancer (BC), in an everyday practice with long-term follow-up of patients. METHODS: All patients (n = 200) who received the AC-paclitaxel combination as NAC for BC at the Soroka University Medical Center from 2003 to 2012 were included in this retrospective cohort study. AC was administered on an every 3-week schedule (standard dose) until May, 2007 (n = 99); and subsequently every 2-week dose dense (dd) (n = 101). Clinical pathologic features, treatment course, and outcome information were recorded. Complete pathologic response (pCR) was analyzed according to BC subtype, dose regimen, and stage. RESULTS: Median age was 49 years; 55.5% and 44.5% of patients were clinically stage 2 and 3, respectively. Standard dose patients had more T3 tumors. Subtypes were human epidermal growth factor receptor-2 (HER2)-positive 32.5% (of whom 82% received trastuzumab), hormone receptor-positive/HER2-negative 53%, and triple negative 14.5%. Breast-conserving surgery (BCS) was performed in 48.5% of patients; only 9.5% were deemed suitable for BCS prior to NAC. Toxicity was acceptable. The overall pCR rate was 26.0% and was significantly higher in the dd group and HER2-positive patients. With a median follow-up of 9.51 years median event-free survival (EFS) and overall survival (OS) are 10.85 years and 12.61 years, respectively. Patients achieving pCR had significantly longer EFS and OS. CONCLUSION: NAC for BC with AC-paclitaxel can be safely administered in the "real-world' setting with high efficacy. Current efforts are aimed at increasing rates of pCR and identifying patients who may benefit from additional therapy or conversely, de-escalated treatment.

The 21-gene recurrence score assay (Oncotype DX™) in estrogen receptor-positive male breast cancer: experience in an Israeli cohort.

OBJECTIVE: The 21-gene recurrence score (RS) assay has been widely adopted for use in early estrogen receptor (ER)-positive breast cancer to assess the risk for distant recurrence and the potential benefit of adjuvant chemotherapy. The primary aim of this study was to assess RS distribution in Israeli male breast cancer (MBC) patients. METHODS: The study population included 65 newly diagnosed Israeli MBC patients. Clinical and pathologic data were collected at the time of referral. Pathologic examinations were conducted at the pathology departments of the referring centers. The RS assay (Oncotype DX™) was performed on paraffin-embedded tumor samples at Genomic Health laboratories. RESULTS: The mean age of the patients was 65.1 years (range 38-88 years). Low-risk (RS<18), intermediate-risk (RS 18-30) and high-risk (RS≥31) scores were noted in 29 patients (44.6%), 27 patients (41.5%) and 9 patients (13.9%), respectively. The distribution of RS in male patients was similar to the distribution in 2,455 female patients from Israel referred during the same time period. CONCLUSION: Our data suggest that the distribution of Oncotype DX RS in ER-positive MBC patients is similar to that of female breast cancer patients.

Safety and rapid response of dabrafenib and trametinib therapy during hyperbilirubinemia in metastatic melanoma.

This case report describes the occurrence of hyperbilirubinemia as a complication of metastatic melanoma. A 72-year-old male patient was diagnosed with BRAF V600E-mutated melanoma with metastases in the liver, lymph nodes, lungs, pancreas, and stomach. Due to a lack of clinical data and specific guidelines for the treatment of mutated metastatic melanoma patients with hyperbilirubinemia, a conference of specialists debated between initiating treatment or providing supportive care. Ultimately, the patient was started on the combination therapy of dabrafenib and trametinib. This treatment resulted in a significant therapeutic response via normalization of bilirubin levels and an impressive radiological response of metastases just one month post-treatment initiation.

Clinical outcomes in estrogen receptor-positive early-stage breast cancer patients with Recurrence Score 26-30: observational real-world cohort study.

Data on adjuvant chemotherapy (CT) benefit in ER + HER2‒ early-stage breast cancer (EBC) patients with Recurrence Score (RS) 26-30 are limited. This real-world study evaluated the relationships between the RS, adjuvant treatments, and outcomes in 534 RS 26-30 patients tested through Clalit Health Services (N0: n = 394, 49% CT-treated; N1mi/N1: n = 140, 62% CT-treated). The CT-treated and untreated groups were imbalanced (more high-risk clinicopathologic characteristics in CT-treated patients). With median follow-up of 8 years, Kaplan-Meier estimates for overall survival (OS), distant recurrence-free survival (DRFS), and BC-specific mortality (BCSM) were not significantly different between CT-treated and untreated N0 patients. Seven-year rates (95% CI) in CT-treated vs untreated: OS, 97.9% (94.4-99.2%) vs 97.9% (94.6-99.2%); DRFS, 91.5% (86.6-94.7%) vs 91.2% (86.0-94.6%); BCSM, 0.5% (0.1-3.7%) vs 1.6% (0.5-4.7%). For N1mi/N1 patients, OS/DRFS did not differ significantly between treatment groups; whereas BCSM did (1.3% [0.2-8.6%] vs 6.2% [2.0-17.7%] for CT-treated and untreated patients, respectively, p = 0.024).

Second breast cancer: recurrence score results, clinicopathologic characteristics, adjuvant treatments, and outcomes-exploratory analysis of the Clalit registry.

Data on using the 21-gene Recurrence Score (RS) testing on second breast cancer (BC; second primary or local recurrence) are lacking. This cohort study examined patients with first and second BC, who underwent 21-gene testing both times. It included a 'study-cohort' (60 N0/N1mi/N1 ER + HER2‒ BC patients with ≥2 RS results >1 year apart) and a 'general 21-gene-tested BC-cohort' (2044 previously described N0/N1mi/N1 patients). The median time between the first and second BC was 5.2 (IQR, 3.1-7.1) years; the second BC was ipsilateral in 68%. Patient/tumor characteristics of the first- and second-BC in the 'study-cohort' were similar, except for the RS which was higher in the second BC (median [IQR]: 23 [17-30] vs 17 [14-22], p < 0.001). Overall, 56 patients had follow-up data, of whom 5 experienced distant recurrence (2 RS 11-25 patients and 3 RS 26-100 patients). Studies exploring the prognostic utility of the RS in this setting are warranted.

Prospective phase II study of neoadjuvant therapy with cisplatin, 5-fluorouracil, and bevacizumab for locally advanced resectable esophageal cancer.

BACKGROUND: We investigated the efficacy and tolerability of cisplatin and 5-fluorouracil (5-FU) plus bevacizumab as neoadjuvant therapy for patients with locally advanced resectable esophageal cancer. PATIENTS AND METHODS: In this prospective phase II study, 22 patients with adenocarcinoma and 6 with squamous cell carcinoma received 2 4-day cycles of bevacizumab 7.5 mg/kg followed by cisplatin 80 mg/m(2) infusion on day 1 followed by 5-FU 1,000 mg/m(2) as a 96-h continuous infusion on days 1-4, separated by a 3-week interval. RESULTS: The response rate was 39%, the R0 resection rate was 43%, and the median overall survival (OS) was 17 months. The regimen was well tolerated, with the most common severe toxicities being venous thromboembolism (10%), nausea, and gastrointestinal bleeding (7% each). In 37 patients previously treated with cisplatin and 5-FU alone at our institution and thus serving as historical controls, the response rate was 30%, the R0 resection rate was 44%, and the median OS was 23 months. There was no statistically significant difference between the 2 groups of patients. CONCLUSION: Adding bevacizumab to cisplatin and 5-FU neoadjuvant chemotherapy was active and well tolerated but did not seem to improve the resection rate or OS compared with prior regimens, including the historical controls at our institution.

Management Strategies for Hyperglycemia Associated with the α-Selective PI3K Inhibitor Alpelisib for the Treatment of Breast Cancer.

Alpelisib is an α-selective phosphatidylinositol 3-kinase inhibitor used for treating hormone receptor-positive (HR+), human epidermal growth receptor 2-negative (HER2-), PIK3CA-mutated locally advanced or metastatic breast cancer following disease progression on or after endocrine therapy. Hyperglycemia is an on-target effect of alpelisib affecting approximately 60% of treated patients, and sometimes necessitating dose reductions, treatment interruptions, or discontinuation of alpelisib. Early detection of hyperglycemia and timely intervention have a key role in achieving optimal glycemic control and maintaining alpelisib dose intensity to optimize the benefit of this drug. A glycemic support program implemented by an endocrinology-oncology collaborative team may be very useful in this regard. Lifestyle modifications, mainly comprising a reduced-carbohydrate diet, and a designated stepwise, personalized antihyperglycemic regimen, based on metformin, sodium-glucose co-transporter 2 inhibitors, and pioglitazone, are the main tools required to address the insulin-resistant hyperglycemia induced by alpelisib. In this report, based on the consensus of 14 oncologists and seven endocrinologists, we provide guidance for hyperglycemia management strategies before, during, and after alpelisib therapy for HR+, HER2-, PIK3CA-mutated breast cancer, with a focus on a proactive, multidisciplinary approach.

Ten-year clinical outcomes in N0 ER+ breast cancer patients with Recurrence Score-guided therapy.

The 21-gene Recurrence Score (RS) assay is a validated prognosticator/predictor of chemotherapy (CT) benefit in early-stage estrogen receptor (ER)-positive breast cancer (BC). Long-term data from real-life clinical practice where treatment was guided by the RS result are lacking. We performed exploratory analysis of the Clalit Health Services (CHS) registry, which included all CHS patients with node-negative ER+ HER2-negative BC who underwent RS testing between 1/2006 and 12/2009 to determine 10-year Kaplan-Meier estimates for distant recurrence/BC-specific mortality (BCSM) in this cohort. The analysis included 1365 patients. Distribution of RS results: RS 0-10, 17.8%; RS 11-25, 62.5%; RS 26-100, 19.7%. Corresponding CT use: 0, 9.4, and 69.9%. Ten-year distant recurrence rates in patients with RS 0-10, 11-25, and 26-100: 2.6% (95% confidence interval [CI], 1.1-6.2%), 6.1% (95% CI, 4.4-8.6%), and 13.1% (95% CI, 9.4-18.3%), respectively (P < 0.001); corresponding BCSM rates: 0.7% (95% CI 0.1-5.1%), 2.2% (95% CI, 1.3-3.7%), and 9.5% (95% CI, 6.0-14.9%) (P < 0.001). When the analysis included patients treated with endocrine therapy alone (95.5/87.5% of patients with RS 0-10/11-25), 10-year distant recurrence and BCSM rates for RS 0-10 patients were 2.7% (95% CI, 1.1-6.5%) and 0.8% (95% CI, 0.1-5.3%), respectively, and for RS 11-25 patients, 5.7% (95% CI, 3.9-8.3%) and 2.0% (95% CI, 1.1-3.7%), respectively. For RS 11-25 patients, no statistically significant differences were observed in 10-year distant recurrence/BCSM rates between CT-treated and untreated patients; however, this should be interpreted cautiously since the number of events was low and patients were not randomized. In conclusion, in node-negative ER+ HER2-negative BC patients, where treatment decisions in real-life clinical practice incorporated the RS, patients with RS 0-25 (~80% of patients, <10% CT use) had excellent outcomes at 10 years. Patients with RS 26-100 had high distant recurrence risk despite CT use and are candidates for new treatment approaches.

Disseminated intravascular coagulation at presentation of advanced gastric cancer.

BACKGROUND: Disseminated intravascular coagulation associated with malignant bone marrow involvement has been described as a rare complication of gastric carcinoma and most patients die within 1-4 weeks. Effective chemotherapy of the underlying malignancy may be the only way to control acute DIC. OBJECTIVES: To assess the benefit of infusional 5-fluorouracil as the primary treatment of metastatic gastric carcinoma and DIC at diagnosis. METHODS: From February 2001 to January 2005, six women (median age 48 years) with gastric carcinoma who presented with diffuse bone metastases and acute DIC were treated in our department. Diagnosis was based on primary gastric and bone marrow biopsies. DIC was confirmed by laboratory findings. Initial treatment consisted of infusional 5FU 200 mg/m2/day. When the bleeding tendency stopped, cisplatin 60 mg/m2 and epirubicin 50 mg/m2 every 3 weeks were added. RESULTS: Within one week of starting the treatment, the clinical and laboratory signs of acute DIC were resolved in five of six patients. Upon clinical improvement, five patients subsequently received epirubicin and cisplatin. Survival, however, was short (mean 15 weeks). All patients died with symptoms of bleeding, showing clinical and laboratory signs of DIC. CONCLUSIONS: Based on our experience, infusional 5FU is an effective regimen with negligible myelosuppression; thus, it may be a good choice as initial therapy for this group of patients. The response induced by protracted 5FU was usually short and lasted for only a few weeks. Therefore, once DIC symptoms are controlled, the addition of newer cytotoxic drugs may be necessary to consolidate the remission.

Adjuvant brachytherapy for Stage IB Grade 2 endometrial carcinoma: Multivariate analysis of a single institution experience.

OBJECTIVE: The aim was to investigate the value of postoperative brachytherapy for patients with Stage IB, Grade 2 endometrial carcinoma. PATIENTS AND METHODS: Forty-six patients with Stage IB, Grade 2 endometrial carcinoma, were treated with simple hysterectomy and bilateral oophorectomy in our institution. The mean age was 63 (range, 42-81). Surgical staging, defined as peritoneal washing and pelvic lymph node sampling was performed in 73% of patients. Twenty-two patients (47%) received a postoperative intravaginal brachytherapy (IVRT), and 24 patients (53%) were followed-up without additional treatment. RESULTS: The median follow-up was 60 months. The 5-year overall survival for irradiated and nonirradiated patients, was 83.5 and 94.7%, respectively. Four patients (8.7%) developed relapse, two in the group of postoperative IVRT and 2 in the follow-up only group. Multivariate analysis demonstrated a borderline association (P = 0.06) between lower uterine segment involvement and poor pelvic-vaginal control. The presence of GOG #99 high-risk features did not affect the pelvic control rate. CONCLUSION: According to our experience and previously published data, most patients with FIGO Stage IB, Grade 2 endometrial carcinoma may be cured with surgery alone.

Rituximab in a patient with acute renal failure due to B-cell lymphomatous infiltration of the kidneys.

Renal failure is known to occur in lymphoproliferative disorders because of ureteral obstruction or parenchymal infiltration by disease. Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B-lymphocytes. The pharmacokinetics and metabolism of rituximab is not well established. The extent of renal clearance is not fully known, with little experience reported on the use of rituximab in patients with renal failure. We present a case where rituximab was administered to a patient with acute renal failure due to bilateral kidney infiltration by non-Hodgkin's lymphoma (NHL). The patients renal function improved on therapy, with no need for hemodialysis and there were no significant toxicities. Rituximab may be used as a treatment option for NHL patients with impaired renal function.

Debulking surgery for patients with diffuse large B-cell non-Hodgkin's lymphoma.

Chemotherapy and radiotherapy have been the principal modalities of treatment for diffuse large B-cell non-Hodgkin's lymphoma (B-NHL) for over 30 years. Various treatment regimens have been designed over the years to try to increase response and cure rates. The role of surgery has been generally restricted to defined and limited situations including diagnostic tissue biopsies and treating abdominal emergencies such as organ rupture or perforation. We present two cases of refractory B-NHL, where surgery was used as a part of stepwise and multi-modal treatment with curative intent. In both cases, the treatment approach included standard dose chemotherapy, eradication of residual mass by surgery, high dose chemotherapy (HDC) with stem cell support and posttransplantant immunotherapy. Currently, 2 years after completing the therapy, both patients are well with no evidence of active disease. Based on our experience with 2 patients we believe that in specific cases of residual chemo-resistant lymphomatous mass, surgery should be considered as a part of a multimodal approach.

Ipsilateral breast carcinoma following treatment for primary breast lymphoma.

BACKGROUND: The breast is an unusual site for primary non-Hodgkin's lymphoma. Carcinoma in the same breast after treatment for lymphoma poses therapeutic challenges, but there is only 1 case report in Japanese, which describes this occurrence. PATIENT AND METHODS: A 59-year-old woman was diagnosed with infiltrating ductal carcinoma of the breast after receiving doxorubicinand vincristine-based chemotherapy for ipsilateral primary large cell breast lymphoma. The cancer was of high grade histology, with immunohistochemistry staining 3+ positive for HER2/neu. RESULTS: After lumpectomy and sentinel node biopsy, adjuvant paclitaxel without anthracyclines was given but had to be stopped early because of neurotoxicity. Radiotherapy to the breast was administered, and a 1-year course of trastuzumab was planned. CONCLUSION: Breast cancer can occur after breast lymphoma. For primary breast lymphoma, cumulative doses of cardiotoxic and neurotoxic drugs should be limited to 3-4 cycles of chemotherapy, using treatment protocols for stage I-II large cell lymphoma. Consolidation radiotherapy should be considered at a dose curative for microscopic breast cancer.

Combined multimodal approach to the treatment of metastatic anal carcinoma: report of a case and review of the literature.

BACKGROUND: We report on a patient with squamous cell anal carcinoma and liver metastases, who underwent multimodal treatment for cure, consisting of repeated partial hepatectomy in combination with chemoradiotherapy. PATIENTS AND METHODS: A 54-year-old woman presented with squamous cell anal carcinoma and liver metastases. She was treated with a combination of chemoradiotherapy for the primary tumor and then underwent surgery for liver metastases. 2 and 5 years after presentation, the patient underwent repeated partial hepatectomies for recurrent liver disease. At present, 5 months after completing therapy and 71 months after the initial diagnosis, she is in good health with no evidence of disease. RESULTS: Repeated partial hepatectomy led to prolonged survival in a patient with squamous cell anal carcinoma metastatic to the liver. CONCLUSIONS: This is the first report of aggressive partial hepatectomy for recurrent liver metastases resulting from anal cancer. Based on our experience, we suggest that in selected patients repeated hepatectomy should be part of an aggressive multimodal treatment program with curative intent.

Diabetes insipidus caused by isolated intracranial metatstases in patient with breast cancer.

We present a case of late recurrence of breast cancer manifested with diabetes insipidus caused by isolated intracranial metastases. A 57-year-old postmenopausal woman was diagnosed with breast cancer and underwent radical mastectomy, without any adjuvant therapy. Seventeen years later, she presented with polyuria, polydipsia, weight loss, weakness, diffuse bone pain, hoarseness and mild dyspnoea. Cranial CT revealed several dural masses in the frontal, parietal and occipital lobes and along the falx cerebri. The diagnosis of central diabetes insipidus without impairment of anterior pituitary function was based on the clinical symptoms, laboratory tests and imaging findings. The patient was successfully treated with desmopressin acetate and letrozole, and remained alive and ambulating 22 months after initial presentation with diabetes insipidus.