High concordance of 70-gene recurrence risk signature and 80-gene molecular subtyping signature between core needle biopsy and surgical resection specimens in early-stage breast cancer.

BACKGROUND AND OBJECTIVES: With increased neoadjuvant therapy recommendations for early-stage breast cancer patients due to the COVID-19 pandemic, it is imperative that molecular diagnostic assays provide reliable results from preoperative core needle biopsies (CNB). The study objective was to determine the concordance of MammaPrint and BluePrint results between matched CNB and surgical resection (SR) specimens. METHODS: Matched tumor specimens (n = 121) were prospectively collected from women enrolled in the FLEX trial (NCT03053193). Concordance is reported using overall percentage agreement and Cohen's kappa coefficient. Correlation is reported using Pearson correlation coefficient. RESULTS: We found good concordance for MammaPrint results between matched tumor samples (90.9%, κ = 0.817), and a very strong correlation of MammaPrint indices (r = 0.94). The concordance of BluePrint subtyping in matched samples was also excellent (98.3%). CONCLUSIONS: CNB samples demonstrated high concordance with paired SR samples for MammaPrint risk classification and BluePrint molecular subtyping, suggesting that physicians are provided with accurate prognostic information that can be used to guide therapy decisions.

Addition of chemotherapy to local therapy in women aged 70 years or older with triple-negative breast cancer: a propensity-matched analysis.

BACKGROUND: There is a scarcity of data exploring the benefits of adjuvant or neoadjuvant chemotherapy in the treatment of breast cancer in older women. We aimed to explore the effect of adding chemotherapy to local therapy on overall survival in older women with triple-negative breast cancer. METHODS: For this propensity-matched analysis, we used data from the National Cancer Database, a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. We included data from women aged 70 years or older with surgically treated, American Joint Committee on Cancer (AJCC) Stage I-III invasive triple-negative breast cancer diagnosed from 2004 to 2014. Patients with T1aN0M0 disease and those with incomplete data on oestrogen receptor status, progesterone receptor status, or HER2 status were excluded. To reduce bias, patients were subdivided into three groups: those who were recommended chemotherapy but did not receive it; those who received chemotherapy; and those for whom chemotherapy was not recommended and not given. The primary outcome was overall survival. Multivariate Cox regression analysis and propensity score matching were done to minimise bias. FINDINGS: Between Jan 1, 2004, and Dec, 31, 2014, 16 062 women with triple-negative breast cancer in the database met the inclusion criteria for this analysis. Median follow-up was 38·3 months (IQR 20·7-46·1, range 0-138·0; 95% CI 37·8-38·7). Collectively, the 5-year overall survival estimate of the 16 062 patients in the study cohort was 62·3% (95% CI 59·7-64·4). 5-year estimated overall survival was 68·5% (95% CI 66·4-70·6) for patients receiving chemotherapy, 61·1% (59·0-63·2) for patients recommended but not given chemotherapy, and 53·7% (51·8-55·8) for patients not recommended chemotherapy and not given chemotherapy (pooled log rank p<0·0001). Multivariate Cox regression analysis of a propensity score-matched sample comparing those who received chemotherapy with those who were recommended but not given chemotherapy (n=1884 matched pairs) identified improved overall survival with chemotherapy (hazard ratio [HR] 0·69 [95% CI 0·60-0·80]; p<0·0001). After stratifying the propensity score matching sample, this benefit persisted for node-negative women (HR 0·80 [95% CI 0·66-0·97]; p=0·007), node-positive women (0·76 [0·64-0·91]; p=0·006), and those with a comorbidity score greater than 0 (HR 0·74 [95% CI 0·59-0·94]; p=0·013). INTERPRETATION: These data support consideration of chemotherapy in the treatment of women aged 70 years or older with triple-negative breast cancer. FUNDING: None.

Mammary-like Carcinoma of the vulva: A diagnostic challenge.

Mammary-like carcinoma of the vulva is incredibly rare with less than 30 cases published since 1935, and the similarities of such pathology between breast cancer metastases, squamous adenocarcinoma, Bartholin gland carcinomas, etc, make an accurate diagnosis challenging. A diagnosis can be made utilizing immunohistochemical staining and patient history to rule out more likely causes such as metastases to ensure a correct diagnosis.

Adjuvant chemotherapy and survival in women aged 70 years and older with triple-negative breast cancer: a Swedish population-based propensity score-matched analysis.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer associated with poor survival, in which adjuvant systemic treatments are limited to chemotherapy. Due to competing mortality risks and comorbidities, older patients with TNBC are often undertreated with adjuvant chemotherapy, and clinical trials on this problem are scarce, despite a growing patient population. This study aimed to assess outcomes for patients aged 70 years and older with TNBC with or without chemotherapy in a national population-based registry, to provide information that can assist in treatment decisions for these patients. METHODS: In this population-based registry study, data on all patients aged 70 years and older diagnosed with primary early TNBC (larger than 5 mm in diameter and without distant metastasis) and surgically treated between Jan 1, 2009, and Dec 31, 2016, were retrieved from the Swedish National Breast Cancer Register, the Swedish Patient Register, and the Swedish Cause of Death Register. Patients with incomplete data (on oestrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 status, surgical procedure in the breast, or information about chemotherapy) were excluded. A propensity score-matched (PSM) model was used to examine the outcomes of adjuvant chemotherapy on 5-year breast cancer-specific survival (BCSS) and 5-year overall survival (OS), adjusted for age, tumour size, tumour grade, nodal status, and comorbidities. FINDINGS: Of 1130 women eligible for analysis, 368 (32·6%) received adjuvant chemotherapy, 45 (4·0%) received neoadjuvant treatment, and 717 (63·5%) did not receive chemotherapy. 5-year BCSS was significantly improved in patients who received adjuvant chemotherapy (85% [95% CI 81-89]) compared with patients who did not receive chemotherapy (68% [64-72]; p<0·0001). A similar benefit was observed in 5-year OS (79% [95% CI 75-84] vs 49% [45-53]; p<0·0001). In our PSM analysis, 5-year BCSS in patients treated with adjuvant chemotherapy was 83% (95% CI 78-89), versus 73% (67-80; p=0·014) in patients not treated with chemotherapy. 5-year OS in patients treated with adjuvant chemotherapy was 75% (95% CI 69-82), versus 63% (57-71; p=0·029) in patients who did not receive chemotherapy. INTERPRETATION: In this PSM registry analysis of surgically treated female patients aged 70 years and older with TNBC without distant metastasis, we identified a significant benefit both in 5-year BCSS and 5-year OS with adjuvant chemotherapy versus no chemotherapy, which persisted when adjusting for age and comorbidities. These results underline the importance of considering adjuvant chemotherapy in older patients. FUNDING: Knut and Alice Wallenberg Foundation, Assar Gabrielsson Foundation.

Breast cancer brain metastases: Molecular subtype, treatment and survival.

BACKGROUND: No clear guidelines exist for management of breast cancer brain metastases (BCBM). OBJECTIVE: We assessed the relationship between patient and tumor characteristics, treatment, and overall survival (OS). METHODS: We conducted a retrospective review of 196 patients who received brain radiation for BCBM between 2009-2013 at Mayo Clinic. Primary tumor characteristics were collected, including simplified molecular subtype. Other characteristics included patient's ECOG, number of brain lesions at BCBM diagnosis, and treatment received, including neurosurgery, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). The primary endpoint was OS from time of BCBM diagnosis. RESULTS: Single-variable analysis revealed patients with HER2+ breast cancer had improved OS (HR = 0.6, p = 0.008). Compared to patients with 1-3 brain lesions, the risk of death in patients with leptomeningeal disease was 2.5-fold higher (p = 0.003). Worsening ECOG status was associated with worsening OS. Patients who received SRS and WBRT had improved OS (HR = 0.37, p < 0.001) compared to patients receiving WBRT alone. CONCLUSIONS: Patients with the best OS had an ECOG of 0, HER2+ disease, and 1-3 brain lesions. The best OS was associated with the combination of neurosurgery and radiation therapy. A comprehensive treatment plan including neurosurgical evaluation and radiation therapy should be considered for patients with BCBM.

Post-Transplant Lymphoproliferative Disorder Presenting as CD20-Negative Plasmablastic Lymphoma in the Lung.

Post-transplant lymphoproliferative disorders (PTLD) are a serious complication of transplantation with a high mortality. Most PTLD present within the first year of transplantation and are associated with Epstein-Barr virus (EBV) infection. Plasmablastic lymphoma (PBL) is a rare but aggressive disease originally described in patients with HIV, presenting most commonly in the jaw and oral mucosa. To our knowledge, this is the first case of PBL presenting as PTLD of the lung in a HIV and EBV negative patient. Given the increasing number of transplants performed, we would like to share this uncommon presentation of PTLD as PBL.

Genomic profiling of high-grade large-cell neuroendocrine carcinoma of the colon.

High-grade neuroendocrine carcinoma (HGNEC) of the colon is a rare and aggressive cancer that has a poor prognosis. Currently no standard treatment exists, and published case series report an overall survival of approximately one year with treatment. Typically patients receive treatment similar to that recommended for small-cell lung cancer, extrapolating from the similarity in cancer biology. Here we report a case of HGNEC of the colon with genomic profiling that identified a KRAS G12D mutation and a PI3K mutation that has not yet been reported in the literature for this tumor type.

N0436 (Alliance): A Phase II Trial of Irinotecan With Cetuximab in Patients With Metastatic Breast Cancer Previously Exposed to Anthracycline and/or Taxane-Containing Therapy.

BACKGROUND: Irinotecan has a 20% to 25% response rate (RR) in patients with previously treated metastatic breast cancer (MBC). Epidermal growth factor receptor (EGFR) is overexpressed in some MBC, especially in triple-negative breast cancer (TNBC). Cetuximab is a monoclonal antibody against EGFR with additive preclinical activity with irinotecan. PATIENTS AND METHODS: We report a 1-stage phase II study on MBC, measurable disease, and previous anthracycline and/or taxane therapy. Patients received cetuximab 400 mg/m(2) on day 1 cycle 1 then 250 mg/m(2) weekly thereafter and irinotecan 80 mg/m(2) on days 1 and 8 of each 21-day cycle. The primary end point was overall RR (ORR) according to Response Evaluation Criteria in Solid Tumors criteria (version 1.1). RESULTS: Of 19 eligible patients enrolled from February to September 2006, 14 patients (74%) had visceral disease, seven patients (37%) were hormone receptor-positive, two patients (11%) HER2-positive, and 11 patients (58%) were triple-negative. Patients received a median of 2 cycles (range, 1-37). Confirmed ORR was 11% (95% confidence interval [CI], 1%-33%), with 1 partial response and 1 complete response. One patient had stable disease for 8 months. RR for TNBC versus non-TNBC was 18% versus 0% (P = .49). Median time to progression was 1.4 months (95% CI, 1.0-2.2) and median overall survival was 9.4 months (95% CI, 2.8-16.1). Twelve patients had disease progression within 2 cycles during therapy. Because of a low RR and rapid disease progression, the study leadership decided to close the trial early. CONCLUSION: The tolerability of the combination of cetuximab and irinotecan is acceptable but demonstrated low overall activity. Potentially promising results were noted in patients with TNBC and further studies of these patients might be considered.

Persistent Disparities Among Patients With T-Cell Non-Hodgkin Lymphomas and B-Cell Diffuse Large Cell Lymphomas Over 40 Years: A SEER Database Review.

BACKGROUND: As of 2013, more than 550,000 people are living with non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: We undertook a large Surveillance Epidemiology and End Results (SEER) based analysis to describe outcome disparities in different subgroups of aggressive T-cell and B-cell NHL patients, with a focus on various ethnicities. RESULTS: The final analysis included 7662 patients with T-cell and 84,910 with B-cell NHL. Survival analysis revealed that male sex and increasing age were independent predictors of worse overall survival (OS; P < .001). For aggressive T-cell NHL, there was no significant improvement in median OS between 1973 and 2011 (P = .081), and ethnic minorities (Asians, Hispanics, and African Americans) had significantly worse OS than whites (P < .001). There were similar trends for age, sex, and race for diffuse large B-cell NHL, but a significant improvement in median OS was seen over time (P < .001). CONCLUSION: These results are the first to elicit outcomes in a broad classification of ethnic minorities and underscore the urgency for development of novel therapeutics, especially in T-cell NHL. In addition, in-depth studies of disease biology and health care utilization are required for better triage of health care resources, especially for ethnic minorities.

Folate receptor-α (FOLR1) expression and function in triple negative tumors.

Folate receptor alpha (FOLR1) has been identified as a potential prognostic and therapeutic target in a number of cancers. A correlation has been shown between intense overexpression of FOLR1 in breast tumors and poor prognosis, yet there is limited examination of the distribution of FOLR1 across clinically relevant breast cancer subtypes. To explore this further, we used RNA-seq data from multiple patient cohorts to analyze the distribution of FOLR1 mRNA across breast cancer subtypes comprised of estrogen receptor positive (ER+), human epidermal growth factor receptor positive (HER2+), and triple negative (TNBC) tumors. FOLR1 expression varied within breast tumor subtypes; triple negative/basal tumors were significantly associated with increased expression of FOLR1 mRNA, compared to ER+ and HER2+ tumors. However, subsets of high level FOLR1 expressing tumors were observed in all clinical subtypes. These observations were supported by immunohistochemical analysis of tissue microarrays, with the largest number of 3+ positive tumors and highest H-scores of any subtype represented by triple negatives, and lowest by ER+ tumors. FOLR1 expression did not correlate to common clinicopathological parameters such as tumor stage and nodal status. To delineate the importance of FOLR1 overexpression in triple negative cancers, RNA-interference was used to deplete FOLR1 in overexpressing triple negative cell breast lines. Loss of FOLR1 resulted in growth inhibition, whereas FOLR1 overexpression promoted folate uptake and growth advantage in low folate conditions. Taken together, our data suggests patients with triple negative cancers expressing high FOLR1 expression represent an important population of patients that may benefit from targeted anti-FOLR1 therapy. This may prove particularly helpful for a large number of patients who would typically be classified as triple negative and who to this point have been left without any targeted treatment options.

HER2 testing and its predictive utility in anti-HER2 breast cancer therapy.

Breast cancer treatment is dependent on accurate pathologic diagnosis. HER2 testing is now universally recommended as part of evaluation of invasive breast cancer. HER2 testing is available via various slide and non-slide based assays, and interpretation of results continues to evolve. Herein we review these testing modalities and their incorporation into the 2013 ASCO/CAP guidelines. Once accurate HER2 status has been established the proper treatment based on recent clinical trials can be instituted.

Adjuvant chemotherapy in breast cancer: To use or not to use, the anthracyclines.

Breast cancer continues to be one of the leading causes of cancer mortality in the world. The treatment generally involves multiple modalities including surgery, radiation and/or chemotherapy. Anthracyclines, one of the first chemotherapeutic agents introduced in the 1960s, has been the backbone for the last 30 years and has been used extensively so far. However, the cardiac toxicity and the concern for secondary hematological malignancy has always been a challenge. A better understanding of the tumor biology, role of Her2 expression and the discovery of trastuzumab and other anti-Her 2 agents along with other effective novel therapeutic options, have revolutionized the treatment for breast cancer. The role of anthracyclines has come under close scrutiny, especially in the adjuvant setting for patients with early stage breast cancer and those with low or intermediate risk of disease recurrence. Recent studies have highlighted such a shift in the use of anthracyclines in both the academic and community clinical practice. However, in patients with a high risk of relapse, anthracyclines still hold promise. Ongoing clinical trials are underway to further define the role of anthracyclines in such a patient population. This review highlights the development, clinical utility, limitations and potential future use of anthracyclines in the adjuvant setting for patients with breast cancer. We consulted PubMed, Scopus, MEDLINE, ASCO annual symposium abstracts, and http://clinicaltrials.gov/ for the purpose of this review.

Vemurafenib: an evidence-based review of its clinical utility in the treatment of metastatic melanoma.

The discovery of BRAF mutations in the majority of patients with metastatic melanoma combined with the identification of highly selective BRAF inhibitors have revolutionized the treatment of patients with metastatic melanoma. The first highly specific BRAF inhibitor, vemurafenib, began clinical testing in 2008 and moved towards a rapid approval in 2011. Vemurafenib induced responses in ~50% of patients with metastatic BRAF-mutant melanoma and demonstrated improved overall survival in a randomized Phase III trial. Furthermore, vemurafenib is well-tolerated with a low toxicity profile and rapid onset of action. Finally, vemurafenib is active even in patients with widely metastatic disease. Despite the success of vemurafenib in treating patients with BRAF-mutant metastatic melanoma, most, if not all, patients ultimately develop resistance resulting in disease progression at a median time of ~6 months. Multiple mechanisms of resistance have been described and rationale strategies are underway to combat resistance. This review highlights the development, clinical utility, resistance mechanisms, and future use of vemurafenib both in melanoma and other malignancies. We consulted PubMed, Scopus, MEDLINE, ASCO annual symposium abstracts, and http://clinicaltrials.gov/ for the purpose of this review.

First report of Nocardia beijingensis infection in an immunocompetent host in the United States.

Here we describe the first reported case of Nocardia beijingensis infection in the United States, made rarer by its presence in an immunocompetent patient.

Mantle cell lymphoma and diffuse large B-cell lymphoma of the testis: a unique case of composite non-Hodgkin lymphoma.

Primary testicular non-Hodgkin lymphoma (NHL) is a rare entity with the most common histologic subtype consisting of diffuse large B-cell lymphoma (DLBCL). Patients with primary testicular lymphoma (PTL) have a poor prognosis and a higher propensity for relapse. Also rare are composite lymphomas (CL) defined as two or more morphologically and phenotypically distinct lymphomas coexisting in a single organ or tissue. Here we present the first reported case of primary testicular composite lymphoma consisting of DLBCL and mantle cell lymphoma (MCL).

Effect of body mass index on tumor characteristics and disease-free survival in patients from the HER2-positive adjuvant trastuzumab trial N9831.

BACKGROUND: Data suggest that weight, and specifically body mass index (BMI), plays a role in breast cancer development and outcome. The authors hypothesized that there would be a correlation between BMI and clinical outcome in patients with early stage, human epidermal receptor 2 (HER2)-positive breast cancer enrolled in the N9831 adjuvant trial. METHODS: Patients were grouped according to baseline BMI as follows: normal (BMI <25 kg/m(2)), overweight (BMI ≥25 kg/m(2) and <30 kg/m(2)), and obese (BMI ≥30 kg/m(2)). Disease-free survival (DFS) was estimated using the Kaplan-Meier method. Comparisons between treatment arms A, B, and C (chemotherapy with or without trastuzumab) were performed using a stratified Cox proportional hazards model. RESULTS: Analysis was completed on 3017 eligible patients. Obese patients were more likely to be older and postmenopausal (P < .0001 for both), to have larger tumors (P = .002), and to have positive lymph nodes (P = .004). In the pooled analysis cohort, differences in DFS among the BMI groups were statistically significant (5-year DFS rate: 82.5%, 78.6%, and 78.5% for normal weight, overweight, and obese women, respectively; log-rank P = .02). The adjusted hazard ratio comparing the DFS of overweight women with the DFS of normal women was 1.30 (95% confidence interval, 1.06-1.61); and, comparing the DFS of obese women with the DFS normal women, the adjusted hazard ratio was 1.31 (95% confidence interval, 1.07-1.59). There were no statistically significant differences in DFS by weight group for women within any trial arm. CONCLUSIONS: Patients with early stage, HER2-positive breast cancer and normal BMI had a better 5-year DFS compared with overweight and obese women. The current results indicated that adjuvant trastuzumab improves clinical outcome regardless of BMI.