Seamus O'Reilly

Safety of trastuzumab (Herceptin ® ) during pregnancy: two case reports

We report on two cases of women on trastuzumab therapy for breast cancer who became pregnant and delivered healthy live infants. At the time of reporting the children are growing and developing normally (ages 3 and 2).

Are Dose-Dense and Triplet Chemotherapy Regimens Optimal Adjuvant Therapy in the Majority of Women With Node-Positive Early Breast Cancer?

ful. The US Food and Drug Administration has similarly proposed expansion of access to data submitted in regulatory applications. Mello et al recently proposed a framework for broad sharing of participant-level data from clinical trials and related documents. Four possible data-sharing models are proposed, varying in who the decision maker would be for releasing these data. As of October 25, 2013, over 154,000 studies have been listed on clinicaltrials.gov. This represents millions of clinical trial participants whose impact on health care is only magnified by the opportunity for additional gains from their efforts. We wholeheartedly agree with the sentiments of Read, although, as the US Food and Drug Administration and EMA outline, these databases will undoubtedly include privately and publicly funded clinical trial data. The devil is in the details.

Cost Effectiveness and Cancer Drugs

patient populations may place greater relevance on different aspects with younger, fitter patients placing more importance on extending OS and older, frailer patients placing more importance on QOL. Composite end points may better reflect what matters to the elderly patients such as QOL-adjusted survival, which is used by payers to assess the benefit of a treatment for society. We disagree that composite end points predispose to type II error if competing risks were appropriately incorporated in the trial design and power determination. We agree with Mell et al, that coprimary end points are good alternatives to composite end points and believe they will be useful for elderly trials as they reflect the multidimensionality of treatment outcome.

Subcutaneous herceptin therapy.

In a recent issue of the Journal of Clinical Pharmacology, we noted with interest the paper by Wynne et al which compared subcutaneous and intravenous administration of trastuzumab in a Phase l/lb trial in healthy male volunteers and patients with HER‐2 positive breast cancer. As discussed in the paper, the potential benefits of such a formulation of traztuzumab include significantly reduced administration time, reducing time commitments for patients and health care workers and improved convenience. It may also be associated with improved compliance and a reduction in the frequency and/or intensity of infusion‐related reactions. While the use of a novel formulation of traztuzumab is certainly welcome, we are concerned about potential under dosing and as such under treating of overweight and obese patients with this formulation which uses standard dose for all patients in contrast to mg/kg individualised intravenous dosing used heretofore. Obesity is an established risk factor for the development of breast cancer and is also independently associated with poorer breast cancer outcomes overall in both pre‐ and post‐menopausal women. Ogden et al in the National Health and Nutrition Examination Survey assessed the prevalence of obesity in the US and reported that more than one‐third of adults were obese in 2009– 2010. Similar figures exist in Ireland, with at least a third of Irish adults being overweight and a quarter obese. Mean body mass index (BMI) for patients included in the Wynne et al study was 17.3–48.3 kg/m, with the majority falling into the normal weight (18.5–24.9 kg/m) and overweight (25–29.9 kg/m) categories. Analysis of all patients (n1⁄4 1,041) receiving adjuvant breast cancer chemotherapy at one of our centers from 2001 to 2010 showed the overweight and obese (BMI> 30) categories to be representative of more than 60% of the total; more than 20% of patients weighed more than 80 kg (Figure 1). Cancer‐specific outcomes tend to be worse in obese patient groups. The American Society of Clinical Oncology believe that less than full weight‐based dosing and unnecessary dose reductions may explain, to some extent, the significantly higher cancer mortality rates seen in the overweight and obese patient groups. This would be of particular concern in patients with chemoresponsive and potentially curable disease. Such observations highlight the need for additional evaluations for dosing of subcutaneous herceptin in obese and overweight patients.

Translocation Renal Cell Carcinomas: An Evolving Entity and a Member of the Microphthalmia Transcription Factor-Associated Family of Tumors

Introduction Translocation renal cell carcinomas are a novel, rare, and distinct clinicopathologic entity first described in 2001. We report 3 cases of this rare subtype of renal cell carcinoma from an Irish regional cancer center and provide an up to date literature review of the topic. Translocation renal cell carcinomas are caused by genetic translocations which fuse a transcription factor gene (TFE3 or TFEB) with a fusion partner containing an active promoter region lead-

BRCA1|[sol]|2 germline testing in non-mucinous epithelial ovarian carcinoma: changing international practice and implications for service provision

Ovarian carcinoma is the fourth most common cancer for women in Republic of Ireland, with an average of 361 cases per year.1 The association with germline mutations in BRCA1/2 genes in non-mucinous ovarian cancer risk is well established.2 Determining the BRCA status of ovarian cancer patients has important prognostic and therapeutic implications for individual patients.3 The frequency of BRCA1/2 germline mutations in non-mucinous ovarian carcinoma is estimated at 14–15%,2 with previous studies finding a higher rate of 16.6% in serous ovarian carcinoma and 17.1% in high-grade serous carcinoma.3 Family history has been shown not to be sufficiently accurate to predict mutation status.2, 3 In Ireland, as in most European countries, and the United States, the current recommendation is that patients with a family history of breast/ovarian cancer should be offered full mutation screening of the BRCA1/2 genes as appropriate following the assessment by a clinical genetics service.4

Partner Diagnostics and the “Choosing Wisely” Campaign

TO THE EDITOR: The recent article by Schnipper et al 1 is a welcome contribution to the important discussion regarding optimum stewardship of precious health care resources. Their fifth recommendation regarding targeted therapy use only when the patient’s tumor has been tested with a validated test is prescient but would be enhanced, we believe, by highlighting the importance of quality assurance in testing. Past experience with the detection of biomarkers has been far from perfect. Erroneous estrogen receptor (ER) immunohistochemical assessment in breast cancer has come to the fore on a number of occasions; an estimated 40% of 2,000 retested specimens in the United States in 2006 has been incorrectly identified as ER negative. 2 Additional data from the United Kingdom National External Quality Assessment Scheme for Immunocytochemistry reveals significant interlaboratory discrepancies. 3 Points of weakness include the specimen preparation process, antigen retrieval, and antibody staining along with postanalytic failures. ER is not alone in this regard. Central testing for human epidermal growth factor receptor 2 (HER2) status in patients with breast cancer enrolled in the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation trial demonstrated that up to 6% of patients who were enrolled were not subsequently confirmed as being HER2 positive. 4 A similar story exists for other biomarkers. 5-7 Although guidelines such as those developed for HER2 testing in breast cancer 8 have reduced false-positive results, it is reasonable to assume that similar issues pertain to other targeted therapy–associated biomarkers, leading to costly inappropriate therapy for patients. Previous experience with targeted agents carries important lessons for more recently developed agents, which are increasingly used. The oncology community needs to place greater emphasis on an awareness

Rare imaging appearance of skeletal metastases in a 61-year-old breast cancer patient

A 56-year-old lady attended the breast clinic in 2011 with nipple retraction and a mass in her right breast. Breast imaging revealed a spiculated mass in the right breast measuring 40 mm in maximum transverse diameter. Biopsy of breast and axillary lymph nodes demonstrated a node-negative 35-mm grade 2 invasive lobular carcinoma. Biopsy showed an estrogen receptor-positive mass, progesterone receptor-positive mass, and HER-2-negative (score 1+) mass. Oncotype Dx testing of the tumor demonstrated a recurrence score of 21 with a 14% risk of distant recurrence over 10 years, provided adjuvant hormone therapy was administered. The patient underwent right mastectomy and SLNB, which was negative. The patient was initiated on tamoxifen in January 2012. In 2014, an attempt to rotate to anastrozole therapy was poorly tolerated and tamoxifen was re-initiated. In August 2016, the patient presented with a 6-month history of fluctuating lower back pain radiating to the right lower limb. This was initially managed conservatively with analgesia and physiotherapy. Symptoms progressed and an MRI of the lumbar spine was ordered. This demonstrated metastatic disease involving spine (Figures 1 and 2).

Evaluation of Discordance in Primary Tumor and Lymph Node Response After Neoadjuvant Therapy in Breast Cancer

Background: Neoadjuvant therapy (NAT) offers a unique opportunity to assess tumor response to systemic agents. However, a discrepancy may exist between the response of the primary tumor and involved nodes. We report on the frequency of response discordance after NAT in breast cancer. Patients and Methods: All consecutive node‐positive patients receiving NAT in our department from 2009 to 2014 were identified. Patient demographics, and radiologic and pathologic features were tabulated. Tumor response was estimated by magnetic resonance imaging of the breast. Lymph node (LN) response was estimated from pathologic treatment response measurements. Statistical analysis was performed. Results: A total of 108 node‐positive patients treated with NAT were eligible for inclusion. Median age was 51.73 years (range, 20‐87 years). All patients underwent axillary clearance, and 62% underwent mastectomy. A 40% mean reduction in tumor size was observed. Statistically, a positive correlation between tumor and LN response after NAT was observed (Spearman correlation coefficient, r = 0.46, P < .001). Complete pathologic response was observed in 17 patients (15.7%). However, 21 patients experienced complete LN response, with only 81% of these patients (n = 17) experiencing a complete response in tumor also. A complete response was observed in tumor in 20 patients, and this predicted complete nodal response in 85% of cases (n = 17). Fifteen percent of primary tumors with complete pathologic response had persistently positive LNs. Conclusion: A significant discordance exists between the primary tumor and LN response, representing a concern for the lack of response of occult regional or systemic metastases due to potential biologic heterogeneity.

Clinical Reasoning: Vanishing tumor A 7-year puzzle solved

In 2005, a 60-year-old man presented to the hospital complaining of a 2-month history of headaches and lethargy. His medical history included osteoarthritis and hypertension. From a social perspective, he was married with children, drove a truck for a living, and had never traveled abroad. His family history was unremarkable. Investigations included a brain CT, which highlighted an enhancing, space-occupying lesion in the left basal ganglia with associated edema and mass effect (figure, A). He was prescribed high-dose dexamethasone while awaiting a neurosurgical review. One week later, a prebiopsy, contrast-enhanced CT showed a reduction in the size of the caudate head mass (figure, B). MRI brain with gadolinium showed small white matter changes and no mass was evident. He did not proceed to biopsy and was subsequently observed. CSF analysis was abnormal, revealing mature, lymphoid cells and some larger immature cells, some of which appeared plasmacytoid (B cell). Although suspicious for lymphoma, this result was nondiagnostic. The CSF protein level was 331. CSF low-density lipoprotein, Epstein-Barr virus, and flow cytometry were not performed. The β2-microglobulin level and serum low-density lipoprotein were normal. Serology for cytomegalovirus and toxoplasma were negative, as were ELISA for Toxocara and HIV screen. Slit-lamp examination was unremarkable. He was discharged, but readmitted 2 weeks later with a deep vein thrombosis. Repeat CSF cytology was again nondiagnostic. CSF was not examined for oligoclonal bands or myelin basic protein. A bone marrow biopsy and staging CT had normal results. Whole body PET/CT was unavailable.