Janice Maria Walshe

Amenorrhea in Premenopausal Women After Adjuvant Chemotherapy for Breast Cancer

Chemotherapy and ovarian ablation both independently improve survival in premenopausal women with hormone-sensitive breast cancer. Amenorrhea is a well-recognized occurrence after chemotherapy. The rate of chemotherapy-induced amenorrhea varies with patient age and chemotherapy regimens administered. However, the impact of chemotherapy-induced amenorrhea on prognosis is still being defined. Older studies in premenopausal women argue that the benefit with chemotherapy is a result of direct cytotoxicity alone. However, studies that restrict outcome analysis to hormone receptor-positive tumors suggest that chemotherapy has a dual mechanism in women with hormone-responsive tumors; indirect endocrine manipulation secondary to chemotherapy-induced ovarian suppression and direct cytotoxicity. The significant health ramifications involved with the induction of premature menopause as well as potential benefits necessitate a comprehensive evaluation of chemotherapy-induced amenorrhea. This review will discuss the incidence of amenorrhea with commonly-used adjuvant chemotherapeutic regimens, the possible benefits of chemotherapy-induced amenorrhea, and the challenges of interpreting the existing data in breast cancer trials.

Phase II Trial of Ixabepilone, an Epothilone B Analog, in Patients With Metastatic Breast Cancer Previously Untreated With Taxanes

PURPOSE Ixabepilone is an epothilone B analog that binds to microtubules and results in microtubule stabilization and mitotic arrest. Ixabepilone was evaluated for efficacy and safety in a phase II clinical trial for women with metastatic breast cancer. PATIENTS AND METHODS Patients were eligible if they had not previously received treatment with a taxane and had measurable metastatic breast cancer. Ixabepilone was administered at 6 mg/m(2)/d intravenously days 1 through 5 every 3 weeks until unacceptable toxicity or disease progression. Patients underwent pretreatment and post-treatment tumor biopsies, and tissues were analyzed for acetylated alpha-tubulin, tau-1, and p53 expression when possible. RESULTS Twenty-three patients received 210 cycles with a median of eight cycles (range, two to 22 cycles) per patient. Thirteen patients (57%; exact 95% CI, 34.5% to 76.8%) had partial responses, six patients (26%) had stable disease, and four patients (17%) had progressive disease. Median time to progression and duration of response were 5.5 and 5.6 months, respectively. Four patients required dose reductions for neutropenia, neuropathy, or fatigue. Grade 3 or 4 toxicities included neutropenia (22%), fatigue (13%), anorexia (9%), and motor neuropathy (4%). Thirty-nine percent of patients experienced grade 1, 13% experienced grade 2, and none experienced grade 3/4 sensory neuropathy. The six patients with paired biopsies all had increases in tumor alpha-tubulin acetylation after treatment. Baseline or cycle 2 acetylated alpha-tubulin, tau-1, or p53 expression did not correlate with clinical response. CONCLUSION Women with metastatic breast cancer previously untreated with taxanes have a meaningful durable response to single-agent ixabepilone therapy. Minimal hematologic toxicity and no grade 3 sensory neuropathy were noted.

Cardiac Toxicity and Efficacy of Trastuzumab Combined with Pertuzumab in Patients with Trastuzumab-Insensitive Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

Purpose: To evaluate safety and efficacy of trastuzumab with pertuzumab in patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer who had progressive disease on trastuzumab-based therapy. Experimental Design: Patients with measurable HER2+ metastatic breast cancer, ≤3 trastuzumab-based regimens, and left ventricular ejection fraction (LVEF) ≥55% received 8 or 6 mg/kg trastuzumab and 840 mg pertuzumab i.v. followed by 6 mg/kg trastuzumab and 420 mg pertuzumab every 3 weeks. Cardiac evaluation and tumor response were assessed every 3 and 6 weeks, respectively. Results: Eleven patients received 64 cycles of trastuzumab plus pertuzumab. A total of 92 echocardiograms and 8 cardiac magnetic resonance imaging studies were done. With the lower limit of normal LVEF 55%, left ventricular systolic dysfunction was observed in six patients, three grade 1, two grade 2, and one grade 3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The objective response rate was 18%. Two patients had partial responses, three had stable disease, and six had progressive disease. The median time to progression was 6 weeks. In baseline tumors from formalin-fixed paraffin-embedded primary and/or metastatic tumor biopsies, pHER2-Y1248 trended toward an increase in patients with partial response compared with those with stable disease/progressive disease (P = 0.095). Conclusion: Trastuzumab plus pertuzumab may have clinical benefit in selected patients who have previously been treated with trastuzumab. Cardiac toxicity, although asymptomatic in most cases, was associated with this treatment. Further evaluation of efficacy of this combination is required to define the overall risks and benefits.

Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with [corrected] human epidermal growth factor receptor 2-positive metastatic breast cancer.

Purpose: To evaluate safety and efficacy of trastuzumab with pertuzumab in patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer who had progressive disease on trastuzumab-based therapy. Experimental Design: Patients with measurable HER2+ metastatic breast cancer, ≤3 trastuzumab-based regimens, and left ventricular ejection fraction (LVEF) ≥55% received 8 or 6 mg/kg trastuzumab and 840 mg pertuzumab i.v. followed by 6 mg/kg trastuzumab and 420 mg pertuzumab every 3 weeks. Cardiac evaluation and tumor response were assessed every 3 and 6 weeks, respectively. Results: Eleven patients received 64 cycles of trastuzumab plus pertuzumab. A total of 92 echocardiograms and 8 cardiac magnetic resonance imaging studies were done. With the lower limit of normal LVEF 55%, left ventricular systolic dysfunction was observed in six patients, three grade 1, two grade 2, and one grade 3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The objective response rate was 18%. Two patients had partial responses, three had stable disease, and six had progressive disease. The median time to progression was 6 weeks. In baseline tumors from formalin-fixed paraffin-embedded primary and/or metastatic tumor biopsies, pHER2-Y1248 trended toward an increase in patients with partial response compared with those with stable disease/progressive disease (P = 0.095). Conclusion: Trastuzumab plus pertuzumab may have clinical benefit in selected patients who have previously been treated with trastuzumab. Cardiac toxicity, although asymptomatic in most cases, was associated with this treatment. Further evaluation of efficacy of this combination is required to define the overall risks and benefits.

Influence of Garlic (Allium sativum) on the Pharmacokinetics of Docetaxel

Purpose: The herbal supplement garlic (Allium sativum) is commonly used by cancer patients. Preclinical studies have shown that allicin, a major component of garlic, may affect cytochrome P450 3A4 (CYP3A4) activity. This study examines the influence of garlic supplementation on the pharmacokinetics of docetaxel, a CYP3A4 substrate. Experimental Design: Women with metastatic breast cancer were treated with docetaxel (30 mg/m2) given weekly for 3 of 4 weeks. Three days after the initial dose of docetaxel, patients received 600 mg of garlic twice daily for 12 consecutive days. Docetaxel pharmacokinetics were assessed during the first three administrations. Results: In 10 evaluable patients, the mean baseline clearance of docetaxel was 30.8 L/h/m2 [95% confidence intervals (95% CI), 16.7-44.9]. Coadministration of garlic reduced mean clearance of docetaxel to 23.7 L/h/m2 (95% CI, 15.5-31.8) and 20.0 L/h/m2 (95% CI, 13.3-26.7) on days 8 and 15, respectively (P = 0.17). Additional pharmacokinetic variables of docetaxel, including peak concentration (P = 0.79), area under the curve (P = 0.36), volume of distribution (P = 0.84), and half-life (P = 0.36), were also not statistically significantly different. The mean area under the curve ratio between day 15 and day 1 was 3.74 in three individuals with the CYP3A5*1A/*1A genotype (all African American) compared with 1.02 in six individuals with the CYP3A5*3C/*3C genotype (all Caucasian). Conclusions: This study indicates that garlic does not significantly affect the disposition of docetaxel. However, it cannot be excluded that garlic decreases the clearance of docetaxel in patients carrying a CYP3A5*1A allele.

NUT Midline Carcinoma in a Young Woman

Case Report A 22-year-old Latvian woman presented to the accident and emergency department with a 3-week history of nonproductive cough and right-sided pleuritic chest pain. Her medical, surgical, and family histories were unremarkable. Socially, she smoked approximately 20 cigarettes per day and drank alcohol infrequently. Examination of her chest was significant for right basal crepitations, reduced breath sound on auscultation, and stoney dullness on percussion, clinically consistent with a right-sided pleural effusion. Laboratory investigations were significant for elevated WBC of 14.5 10mm/L (normal range [NR], 4.0 to 11.0 10mm/L) consisting predominantly of neutrophils (11.3 10mm/L; NR, 2.0 to 7.5 10mm/L), raised C-reactive protein (155 mg/L; NR, 0 to 5 mg/L), and lactate dehydrogenase (LDH; 762 u/L; NR, 100 to 350 u/L). Chest radiograph demonstrated a right-sided pleural effusion and widening of the mediastinum, suggestive of a hilar mass (Fig 1). Computed tomography (CT) of the thorax confirmed a large 13 11 cm right anterior upper mediastinal mass with extension into the right lower lobe and a pleural effusion (Figs 2A, cross-sectional CT of thorax at diagnosis; 2B, coronal view of right anterior medistinal mass at diagnosis). The differential diagnosis was extensive, but because the clinical picture was suggestive of lymphoma, a positron emission tomography/CT scan was performed. There were multiple focal abnormal areas of fluorodeoxyglucose accumulation in the visualized axial and appendicular skeleton, suggestive of bone marrow involvement. Pleurocentesis confirmed an exudate but demonstrated nonmalignant cytology. Endoscopic ultrasound–guided core biopsy of the mediastinal mass revealed a neoplastic process consisting of small to moderately sized neoplastic cells with focal areas of necrosis. Immunohistochemistry staining ruled out lymphoma. The tumor demonstrated a high proliferative index with focal cytokeratin staining of uncertain significance. The differential diagnosis now included Ewing’s sarcoma, synovial sarcoma, or another rare variant of poorly differentiated carcinoma. Because more tissue was required, bone marrow samples were obtained. Hematoxylin and eosin (HE) staining showed hypercellular marrow with approximately 50% replacement by malignant cells of intermediate size with high nuclear to cytoplasmic ratio (Fig 3A, low-power HE staining of bone marrow biopsy demonstrating replacement of marrow space by tumor cells on left). A majority of the cells were dyshesive, with some focal cohesive growth pattern and no clear pattern of differentiation (Fig 3B, high-power HE staining of bone marrow biopsy demonstrating medium to large tumor cells with dyshesive growth pattern). Immunohistochemistry showed focal positivity for pan-cytokeratin AE1/AE3, CK7, and CK19; diffuse expression of EMA and CD99; and scanty vimentin positivity, with no evidence of melanocytic, germ cell, or mesothelial differentiation (Fig 3C, immunohistochemical staining for AE1/3). Molecular testing for the transcripts associated with synovial sarcoma was negative. Given the patient’s age and presence of disseminated disease in the context of a mediastinal mass, a diagnosis of NUT carcinoma was considered. Sections sent for immunohistochemical staining at the Brigham and Women’s Hospital (Boston, MA) were positive for expression of nuclear protein in testis (NUT), confirming this diagnosis (Fig 3D). At confirmation of diagnosis, the patient had worsening chest pain and elevated LDH of 13,525 U/L. Intensive chemotherapy (doxorubicin 60 mg/m day 1 and ifosfamide 1,750 mg/m continuous infusion days 1 to 3, every 3 weeks) was urgently administered. Within 10 days of chemotherapy administration, the patient had clinically improved, and LDH had fallen to 2,000 U/L. She was discharged from the hospital and received two additional treatment cycles without complications. Despite this initial improvement, she was readmitted to the hospital before her fourth treatment cycle with worsening chest pain and dyspnea. CT scan confirmed marked disease progression, with compromise of the superior vena cava and obliteration of the right main bronchus (Figs 4A, crosssectional CT of thorax at 3 months postdiagnosis; 4B, coronal view of CT of thorax at 3 months postdiagnosis). She deteriorated rapidly over 3 days and died.

The American Joint Commission Cancer 8th Edition Prognostic Stage Including Oncotype DX® Recurrence Score: Impact on Staging of Early Breast Cancer

Background: The American Joint Commission Cancer (AJCC) Cancer Staging Manual 8th edition introduced a breast cancer (BC) Prognostic Stage (PS) that combines tumour grade, oestrogen (ER), progesterone (PgR), and human epidermal growth factor-2 (HER2) receptor status with Anatomic TNM Stage (AS). In a further modification, patients with early BC and an Oncotype DX® Recurrence Score (RS) < 11 are assigned to PS 1A irrespective of grade and size up to 5 cm. This study profiles the impact of these changes on staging in patients with early BC and RS < 11. Methods: A total of 127 patients, with primary BC and RS < 11, were identified from a consecutive series of 729 patients with ER-positive, HER2-negative, lymph node-negative, primary BC whose tumours were tested using the Oncotype DX® 21 multigene assay. Each patient was assigned AS, PS, and RS-modified PS, and staging categories were compared. Results: Applying AS, 100 patients were stage IA and 27 IIA. Applying PS, 89 were stage IA, 33 IB, 4 IIA, and 1 IIB. All patients were IA according to RS-modified PS. Comparing PS to AS, 26.7% of patients (n = 34) changed stage, 9.4% (n = 12) to a higher and 17.3% (n = 22) to a lower stage. RS-modified PS versus AS resulted in downstaging in 21.3% (n = 27). Comparing PS modified by RS to PS alone, 29.9% (n = 38) were downstaged. Conclusion: Application of PS and RS-modified PS results in tumour downstaging in approximately 20% of patients with early BC. Upstaging was observed in 9% of patients when staged according to PS and was primarily due to the impact of high histological grade.

Incidence of long-term hair loss (LHL) following docetaxel (D)-containing non-anthracycline (A) adjuvant chemotherapy (Adj) of early stage breast cancer (ESB).

e12522Background: Taxane-containing Adj is an accepted life-prolonging component of modern multi-modal ESB therapy. One of the most distressing complications of Adj is alopecia. While patients (pts) are usually reassured that this is temporary, there have been troubling reports of LHL, generally with regimens that include D and A. We attempted to define the incidence of LHL in a large cohort of patients who received Adj which contained D without A. Methods: Pts who received Adj/neo-Adj which contained D but not A for ESB in clinical trials, or as standard of care in our single academic institution were identified. Pts had completed Adj more than one year. Trials pts were contacted directly, non-trials pts assessed during clinic visits. LHL was graded as 0,1 or 2 (CTCAE). Results: We identified 368 pts, with a median follow-up of >5 years. Pts received DC4 or DC6 (D/cyclophosphamide 75/600 mg/2 iv 3-weekly 4 or 6 times); or DPH (D 75 mg/m2, carboplatin AUC 6 and trastuzumab given 3-weekly iv). LHL occurred...

Impact of timing of trastuzumab initiation on long-term outcome of patients with early-stage HER2-positive breast cancer: the “one thousand HER2 patients” project

BackgroundThe optimal timing of (neo)adjuvant trastuzumab initiation with respect to chemotherapy and surgery remains undefined.MethodsRetrospective analysis of a large institutional database of HER2-positive patients who received anti-HER2 therapy. We included all Stage I to III patients treated with trastuzumab with a minimum follow up of 3 years. The date of first breast biopsy was recorded as initial diagnosis.ResultsA total of 506 patients [adjuvant: 386 (76%)-neo-adjuvant: 120 (24%)] were included. The median time-to-first-trastuzumab (TFT) from diagnosis was 12 weeks (range 1.9–122.3). Median follow-up is 73.3 months (range 1.4–176.3). TFT was significantly shorter in the neo-adjuvant than in the adjuvant cohort (median: 4.4 vs. 14 weeks, p < 0.00001). Despite the neo-adjuvant cohort having significantly more node-positive patients (75 vs. 53%, p < 0.0001), DFS rate (neo-adjuvant: 12.5 vs. adjuvant: 18%, p = 0.094) was numerically superior in neo-adjuvant patients. A TFT ≤ 12 weeks was associated with significantly superior DFS and OS over TFT > 12 weeks. Early concomitant regimens were associated with superior DFS over delayed-concomitant and sequential regimens.ConclusionsInitiating trastuzumab more than 12 weeks from diagnosis has a negative impact on clinical outcome. Neo-adjuvant anti-HER2 therapy could be the optimal strategy to treat early stage HER2-positive breast cancer.

A review of therapy-related myelodysplastic syndromes and acute myeloid leukaemia (t-MDS/AML) in Irish patients: a single centre experience

ABSTRACT Objectives: To demonstrate the incidence, characteristics, treatment and outcomes of patients with therapy-related myelodysplastic syndromes and therapy-related acute myeloid leukaemia (t-MDS/AML) in a tertiary referral centre. Methods: Patients meeting the diagnostic criteria for t-MDS/AML from 2003 to 2014 were reviewed to analyse their diagnostic features, details of antecedent disorder and treatment, approach to management and survival. Results: 39 patients who developed t-MDS/AML were identified with incidence of 8.7%. Median age and gender distribution were similar to de novo MDS but t-MDS/AML patients had greater degree of cytopenia and adverse karyotypes. Time to development of t-MDS/AML was shortest for patients with antecedent haematological malignancy compared to solid tumours and autoimmune disorders (46, 85 and 109 months). Patients with prior acute leukaemia had the shortest latency and poor overall survival. Treatment options included best supportive care (56%), Azacitidine (31%) or intensive chemotherapy/allogeneic transplant (13%). Median OS of all patients was 14 months. Survival declined markedly after two years and 5-year OS was 13.8%. Longer survival was associated with blast count <5% at diagnosis, previous haematological disorder, lower risk IPSS-R and a normal karyotype. Four out of five patients who received intensive therapy/transplant remain alive with median OS of 14 months. Median OS of Azacitidine-treated group was 11 months. Discussion: t-MDS/AML patients showed unique characteristics which influenced their treatment and outcomes. IPSS-R may be useful in risk-adapted treatment approaches and can predict outcomes. Survival remains poor but improved outcomes were seen with allogeneic transplantation. Azacitidine may be effective in patients unfit for intensive therapies.