Oncolytic T-VEC virotherapy plus neoadjuvant chemotherapy in nonmetastatic triple-negative breast cancer: a phase 2 trial.

Talimogene laherparepvec (T-VEC) is an oncolytic virus hypothesized to enhance triple-negative breast cancer (TNBC) responses to neoadjuvant chemotherapy (NAC). This article describes the phase 2 trial of T-VEC plus NAC (ClinicalTrials.gov ID: NCT02779855 ). Patients with stage 2-3 TNBC received five intratumoral T-VEC injections with paclitaxel followed by doxorubicin and cyclophosphamide and surgery to assess residual cancer burden index (RCB). The primary end point was RCB0 rate. Secondary end points were RCB0-1 rate, recurrence rate, toxicity and immune correlates. Thirty-seven patients were evaluated. Common T-VEC toxicities were fevers, chills, headache, fatigue and injection site pain. NAC toxicities were as expected. Four thromboembolic events occurred. The primary end point was met with an estimated RCB0 rate = 45.9% and RCB0-1 descriptive rate = 65%. The 2-year disease-free rate is equal to 89% with no recurrences in RCB0-1 patients. Immune activation during treatment correlated with response. T-VEC plus NAC in TNBC may increase RCB0-1 rates. These results support continued investigation of T-VEC plus NAC for TNBC.

Preoperative ultrasound is not useful for identifying nodal metastasis in melanoma patients undergoing sentinel node biopsy: preoperative ultrasound in clinically node-negative melanoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is widely used in melanoma. Identifying nodal involvement preoperatively by high-resolution ultrasound may offer less invasive staging. This study assessed feasibility and staging results of clinically targeted ultrasound (before lymphoscintigraphy) compared to SLNB. METHODS: From 2005 to 2009, a total of 325 patients with melanoma underwent ultrasound before SLNB. We reviewed demographics and histopathologic characteristics, then compared ultrasound and SLNB results. Sensitivity, specificity, and positive and negative predictive value were determined. RESULTS: A total of 325 patients were included, 58% men and 42% women with a median age of 58 (range 18-86) years. A total of 471 basins were examined with ultrasound. Only six patients (1.8%) avoided SLNB by undergoing ultrasound-guided fine-needle aspiration of involved nodes, then therapeutic lymphadenectomy. Sixty-five patients (20.4%) had 69 SLNB positive nodal basins; 17 nodal basins from 15 patients with positive ultrasounds were considered truly positive. Forty-five SLNB positive basins had negative ultrasounds (falsely negative). Seven node-positive basins did not undergo ultrasound because of unpredicted drainage. A total of 253 patients with negative SLNBs had negative ultrasounds in 240 nodal basins (truly negative) but falsely positive ultrasounds occurred in 40 basins. Overall, sensitivity of ultrasound was 33.8%, specificity 85.7%, positive predictive value 36.5%, and negative predictive value 84.2%. Sensitivity and specificity improved somewhat with increasing Breslow depth. Sensitivity was highest for the neck, but specificity was highest for the groin. CONCLUSIONS: Routine preoperative ultrasound in clinically node-negative melanoma is impractical because of its low sensitivity. Selected patients with thick or ulcerated lesions may benefit. Because of variable lymphatic drainage patterns, preoperative ultrasound without lymphoscintigraphic localization will provide incomplete evaluation in many cases.

Axillary staging prior to neoadjuvant chemotherapy: the roles of sentinel lymph node biopsy and axillary ultrasonography.

BACKGROUND: Clinical evaluation of the axilla is an area of controversy in current breast cancer research and management. Evidence of axillary metastasis on biopsy affects all modalities of cancer therapeutics and is central to breast cancer staging. Neoadjuvant chemotherapy is standard therapy for patients with locally advanced breast cancer and considered for patients with early-stage breast cancer. METHODS: This article discusses axillary ultrasonography for axillary staging relative to neoadjuvant chemotherapy, reviews advances in sentinel lymph node (SLN) biopsy techniques, and explores an integrated approach to axillary staging. Techniques for staging the axilla after a breast cancer diagnosis relative to the use of neoadjuvant chemotherapy are also discussed. RESULTS: There is increasing support in the literature for routine axillary ultrasonography and percutaneous biopsy in the evaluation of regional nodal metastasis for breast cancer. SLN biopsy and axillary node dissection continue to be the standards for definitive staging. CONCLUSIONS: Axillary ultrasonography (with or without biopsy) and SLN biopsy are safe and feasible options for breast cancer staging and may facilitate treatment decisions for surgery, chemotherapy, and radiation therapy. Multidisciplinary review may also significantly influence treatment and timing of staging and therapy. An integrated approach to diagnosis and treatment is beneficial for both patients and providers.

Selective application of routine preoperative axillary ultrasonography reduces costs for invasive breast cancers.

PURPOSE: Preoperative axillary sonography with fine needle aspiration (FNA) in patients with invasive breast cancer identifies patients with nodal metastasis who can be spared further surgery. Indiscriminate use of the diagnostic modality can increase costs and yield inaccurate results. We evaluate the costs associated with the use of highly sensitive axillary ultrasonography in patients with stage ≥T2 tumors. PATIENTS AND METHODS: We constructed a decision analysis tree using TreeAge Pro 2009 software comparing direct hospital charges between patients with and without routine use of axillary ultrasound. Base case estimates were derived from our institutional data and compared with those derived from the literature. One- and two-way sensitivity analyses were performed to check the validity of our inferences. RESULTS: We found that, for the base case estimate with 35% lymph node positivity in stage ≥T2 tumors and sensitivity of the axillary ultrasound set at 86% with a specificity of 40%, the strategy to perform preoperative axillary ultrasound yielded rollback costs of $15,215, compared with $15,940 for surgery plus sentinel lymph node biopsy (cost difference, $725 per patient favoring axillary ultrasound). On two-way sensitivity analysis, the cost benefit for axillary ultrasound was not seen in patients with a low risk for nodal metastasis. CONCLUSION: The adoption of routine preoperative axillary sonography with FNA is a lower-cost strategy than conventional strategies in patients with stage ≥T2 invasive breast cancer.

Consequences of axillary ultrasound in patients with T2 or greater invasive breast cancers.

BACKGROUND: Axillary ultrasound (AUS) with needle biopsy is used to detect metastasis in patients with invasive breast cancers. Our hypothesis is that preoperative AUS significantly reduces sentinel node biopsy (SLNB) use in patients with invasive breast tumors >2 cm upon clinical examination. METHODS: A single-institution database of patients with breast cancer and AUS was reviewed. Patients with incomplete records, clinical tumor <2 cm, or postoperative AUS were excluded. A control cohort of non-AUS patients with clinical T2 (cT2) or greater disease was identified. Clinicopathologic data were collected. Simple Kappa coefficient and chi-square statistical analyses were performed. RESULTS: AUS was performed in 153 patients vs. 370 controls. Of AUS patients, 112 (73.2%) had cT2 disease vs. 272 (73.5%) controls. Median AUS patient age was 53.7 (range, 22.8-85.8) years vs. 53.8 (range, 26.7-91.6) years; median pathologic tumor was 3.8 (range, 1.0-20.0) cm in AUS patients vs. 2.5 (range, 0.1-11.0) cm. Among AUS patients, 78% had needle biopsy; 85 of 120 (70.8%) were positive. Sixty-eight patients had SLNB: 33 after negative AUS and 35 after negative needle biopsy. Twenty-three SLNB (37.3%) were positive; 15 of 33 after negative AUS and 8 of 35 after a negative needle biopsy. Axillary dissection was performed in 102 of 153 vs. 225 of 370 controls. Sensitivity and specificity of AUS was 86.2% and 40.5%. Sensitivity of AUS plus needle biopsy was 89.3% with 100% specificity. Neoadjuvant chemotherapy was given to 49.7% of AUS patients. AUS reduced costs by more than $4,000 per patient. CONCLUSIONS: AUS reduces SLNB use and affects treatment in patients with cT2 or greater breast cancer. Routine AUS should be considered in this population.

A Phase I Trial of Talimogene Laherparepvec in Combination with Neoadjuvant Chemotherapy for the Treatment of Nonmetastatic Triple-Negative Breast Cancer.

PURPOSE: Talimogene laherparepvec (TVEC) is an oncolytic herpes simplex 1 virus approved for treatment of melanoma. We hypothesized intratumoral TVEC may enhance response to neoadjuvant chemotherapy (NAC). This article reports the results of a trial combining NAC with TVEC for triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Patients with stage II-III TNBC enrolled in a 3+3 phase I trial (NCT02779855) of two TVEC dose levels [DL; DL 1 = 106 plaque-forming units (PFU) × 5 doses; DL 2 = 106 PFUs first dose, then 108 PFUs × 4 doses] on weeks 1, 4, 6, 8, and 10 plus weekly paclitaxel (80 mg/m2) for 12 weeks, followed by doxorubicin/cyclophosphamide (60/600 mg/m2) every 2 weeks for 8 weeks. Postoperative response assessment using residual cancer burden (RCB) was performed. Primary endpoints were safety and MTD. Secondary endpoints were RCB0 rate and immune correlates. Dose-limiting toxicity (DLT) rule was grade 3-5 adverse events due to TVEC during first 5 weeks. RESULTS: Nine patients [DL 1 (n = 3); DL 2 (n = 6)] were enrolled. Six had stage II disease, and 3 had stage III (6 clinically N+). No DLTs occurred, and MTD was DL 2. Most common toxicities with TVEC were fever (n = 8), chills (n = 3), hematomas (n = 3), and injection site pain (n = 3). Thromboembolic events (n = 2) and bradycardia (n = 1) occurred during or after NAC. Five patients (55%) achieved RCB0, 2 had RCB1 (22%), and 2 had RCB2 (22%). CONCLUSIONS: The addition of TVEC to NAC was feasible at the approved dose, with manageable toxicity. The complete response rate was 55%.

Concurrent BRAF and PTEN mutations in melanoma of unknown origin presenting as a breast mass.

BACKGROUND: Metastases represent a small percentage of the malignancies affecting the breast, and only 5% of melanomas originate from non-cutaneous sites. Multiple genetic aberrations have been associated with the development of melanocytic lesions, including BRAF V600E mutation. Mutations in PTEN gene have also been related to the pathogenesis of multiple malignancies. PURPOSE/METHOD: This is the case of a 28-year-old female who presented with a tender, palpable mass in the upper outer quadrant of the right breast. Ultrasound showed a 1-cm solid mass, initially diagnosed as invasive ductal carcinoma on biopsy. During pre-operative workup, a second mass was identified and biopsied. Immunohistochemical stains performed on the second mass biopsy demonstrated that the neoplastic cells were positive for cytokeratin AE1/3, pan-melanoma, tyrosinase, and SOX-10 and negative for CK7, CAM5.2, and GATA-3. Subsequent workup showed widespread metastatic disease involving the liver, lungs, bones, and brain. The brain metastasis tested positive for BRAF p.V600E and PTEN p.R130Efs*4 mutations. Thorough skin and eye examination did not reveal a primary melanoma. CONCLUSION: Only few reports have been published of melanoma presenting as a breast mass. This is an interesting case due to the clinical presentation, diagnostic challenges, and genetic mutations profile.

Male Breast: Clinical and Imaging Evaluations of Benign and Malignant Entities with Histologic Correlation.

Breast cancer is an uncommon disease in men. As a result, the diagnosis may not initially be considered. Understanding the common benign and malignant entities affecting the male breast is critical for timely and accurate diagnosis in the primary care setting. Most patients present with a palpable breast mass or pain. The usual etiology is gynecomastia, the most common breast condition in males, but breast cancer must always be excluded through careful imaging evaluation when physical examination findings are suspicious or inconclusive. Imaging of the male breast generally relies on mammography and ultrasound, with mammography employed as the initial imaging modality of choice and ultrasound when a mass is detected or suspected. Here we describe the normal male breast anatomy and present an evaluation algorithm for the male patient with breast signs or symptoms. The most common benign and malignant entities are described.

Papillary endothelial hyperplasia arising in the irradiated breast: A diagnostic dilemma.

Papillary endothelial hyperplasia (PEH) is a benign proliferative lesion that may occur in any site of the body, but most commonly affects the skin and subcutaneous tissues. In the breast, PEH has been documented but is rare. PEH is notorious for being misdiagnosed as angiosarcoma due to its complex growth pattern, papillary processes and interlacing vascular channels. The occurrence of PEH years after breast irradiation constitutes a pathological and clinical diagnostic challenge because angiosarcoma is far more common in this setting. The most important features that differentiate papillary endothelial hyperplasia from angiosarcoma are its presentation as a round nodule without infiltrative borders, its localization inside a vessel or in association with thrombus, and the lack of significant cytologic atypia or areas of solid growth, even in the presence of a complex architecture. Clinical history and site of involvement (cutaneous versus parenchymal) are usually of help to establish a correct diagnosis. Herein, we describe two cases of PEH presenting in patients with history of breast carcinoma and breast radiation therapy. The clinical and morphological features as well as the differential diagnoses are discussed. To our knowledge, no other cases of PEH of the breast occurring in the post-radiation setting have been described in the literature.

Short-term imaging follow-up of patients with concordant benign breast core needle biopsies: is it really worth it?

PURPOSE: Women with histologically proven concordant benign breast disease are often followed closely after biopsy for a period of two years, and they are considered to be at high-risk for cancer development. Our goal was to evaluate the utility of short-term (six-month) imaging follow-up and determine the incidence of breast cancer development in this population. METHODS: Retrospective review of concordant benign breast pathology was performed in 558 patients who underwent multimodality breast core biopsy. A total of 339 patients (60.7%) with 393 biopsies qualified for the study. The six-, 12-, and 24-month incidence rates of breast cancer development were estimated with 95% confidence intervals (CI), using the exact method binomial proportions. RESULTS: No cancer was detected in 285 of 339 patients (84.1%) returning for the six-month follow-up. No cancer was detected in 271 of 339 patients (79.9%) returning for the 12-month follow-up. Among 207 follow-up exams (61.1%) performed at 24 months, three patients were detected to have cancer in the ipsilateral breast (1.45% [95% CI, 0.30%-4.18%]) and two patients were detected to have cancer in the contralateral breast (0.97% [95% CI, 0.12%-3.45%]). Subsequent patient biopsy rate was 30 of 339 (8.85%, [95% CI, 6.05%-12.39%]). Three ipsilateral biopsies occurred as a sole result of the six-month follow-up of 285 patients (1.05%, [95% CI, 0.22%-3.05%]). CONCLUSION: Short-term imaging follow-up did not contribute to improved breast cancer detection, as all subsequent cancers were detected on annual mammography. Annual diagnostic mammography after benign breast biopsy may be sufficient.