Impact of factors affecting the residual tumor size diagnosed by MRI following neoadjuvant chemotherapy in comparison to pathology.

BACKGROUND AND OBJECTIVES: To investigate accuracy of magnetic resonance imaging (MRI) for measuring residual tumor size in breast cancer patients receiving neoadjuvant chemotherapy (NAC). METHODS: Ninety-eight patients were studied. Several MRI were performed during NAC for response monitoring, and the residual tumor size was measured on last MRI after completing NAC. Covariates, including age, tumor characteristics, biomarkers, NAC regimens, MRI scanners, and time from last MRI to operation, were analyzed. Univariate and Multivariate linear regression models were used to determine the predictive value of these covariates for MRI-pathology size discrepancy as the outcome measure. RESULTS: The mean (±SD) of the absolute difference between MRI and pathological residual tumor size was 1.0 ± 2.0 cm (range, 0-14 cm). Univariate regression analysis showed tumor type, morphology, HR status, HER2 status, and MRI scanner (1.5 T or 3.0 T) were significantly associated with MRI-pathology size discrepancy (all P < 0.05). Multivariate regression analyses demonstrated that only tumor type, tumor morphology, and biomarker status considering both HR and HER-2 were independent predictors (P = 0.0014, 0.0032, and 0.0286, respectively). CONCLUSION: The accuracy of MRI in evaluating residual tumor size depends on tumor type, morphology, and biomarker status. The information may be considered in surgical planning for NAC patients.

Evaluation of ultra-deep targeted sequencing for personalized breast cancer care.

INTRODUCTION: The increasing number of targeted therapies, together with a deeper understanding of cancer genetics and drug response, have prompted major healthcare centers to implement personalized treatment approaches relying on high-throughput tumor DNA sequencing. However, the optimal way to implement this transformative methodology is not yet clear. Current assays may miss important clinical information such as the mutation allelic fraction, the presence of sub-clones or chromosomal rearrangements, or the distinction between inherited variants and somatic mutations. Here, we present the evaluation of ultra-deep targeted sequencing (UDT-Seq) to generate and interpret the molecular profile of 38 breast cancer patients from two academic medical centers. METHODS: We sequenced 47 genes in matched germline and tumor DNA samples from 38 breast cancer patients. The selected genes, or the pathways they belong to, can be targeted by drugs or are important in familial cancer risk or drug metabolism. RESULTS: Relying on the added value of sequencing matched tumor and germline DNA and using a dedicated analysis, UDT-Seq has a high sensitivity to identify mutations in tumors with low malignant cell content. Applying UDT-Seq to matched tumor and germline specimens from the 38 patients resulted in a proposal for at least one targeted therapy for 22 patients, the identification of tumor sub-clones in 3 patients, the suggestion of potential adverse drug effects in 3 patients and a recommendation for genetic counseling for 2 patients. CONCLUSION: Overall our study highlights the additional benefits of a sequencing strategy, which includes germline DNA and is optimized for heterogeneous tumor tissues.

Breast cancer: evaluation of response to neoadjuvant chemotherapy with 3.0-T MR imaging.

PURPOSE: To assess how the molecular biomarker status of a breast cancer, including human epidermal growth factor receptor 2 (HER2), hormone receptors, and the proliferation marker Ki-67 status, affects the diagnosis at 3.0-T magnetic resonance (MR) imaging. MATERIALS AND METHODS: This study was approved by the institutional review board and was HIPAA compliant. Fifty patients (age range, 28-82 years; mean age, 49 years) receiving neoadjuvant chemotherapy were monitored with 3.0-T MR imaging. The longest dimension of the residual cancer was measured at MR imaging and correlated with pathologic findings. Patients were further divided into subgroups on the basis of HER2, hormone receptor, and Ki-67 status. Pathologic complete response (pCR) was defined as when there were no residual invasive cancer cells. The Pearson correlation was used to correlate MR imaging-determined and pathologic tumor size, and the unpaired t test was used to compare MR imaging-pathologic size discrepancies. RESULTS: Of the 50 women, 14 achieved pCR. There were seven false-negative diagnoses at MR imaging. The overall sensitivity, specificity, and accuracy for diagnosing invasive residual disease at MR imaging were 81%, 93%, and 84%, respectively. The mean MR imaging-pathologic size discrepancy was 0.5 cm ± 0.9 (standard deviation) for HER2-positive cancer and 2.3 cm ± 3.5 for HER2-negative cancer (P = .009). In the HER2-negative group, the size discrepancy was smaller for hormone receptor-negative than for hormone receptor-positive cancers (1.0 cm ± 1.1 vs 3.0 cm ± 4.0, P = .04). The size discrepancy was smaller in patients with 40% or greater Ki-67 expression (0.8 cm ± 1.1) than in patients with 10% or less Ki-67 expression (3.9 cm ± 5.1, P = .06). CONCLUSION: The diagnostic accuracy of breast MR imaging is better in more aggressive than in less aggressive cancers. When MR imaging is used for surgical planning, caution should be taken with HER2-negative hormone receptor-positive cancers.

Motility induction in breast carcinoma by mammary epithelial laminin 332 (laminin 5).

Host interactions with tumor cells contribute to tumor progression by several means. This study was done to determine whether mammary epithelium could interact with breast carcinoma by producing substances capable of inducing motility in the cancer cells. Conditioned medium of immortalized 184A1 mammary epithelium collected in serum-free conditions induced dose-dependent motility in the MCF-7 breast carcinoma cell line by both a semiquantitative scattering assay and a Boyden chamber assay. Purification of the motility factor revealed that it was laminin 332 (formerly laminin 5) by mass spectroscopy. A Western blot of the 184A1 conditioned medium using a polyclonal antibody confirmed the presence of laminin 332 in the conditioned medium. Blockage of the motility with antibodies to the laminin 332 and its receptor components, alpha(3) and beta(1) integrins, provided further evidence that tumor cell motility was caused by the laminin 332 in the conditioned medium. Invasion of MCF-7, BT-20, and MDA-MB-435 S was induced by purified laminin 332 and 184A1 conditioned medium and blocked by an anti-alpha(3) integrin antibody. Staining of carcinoma in situ from breast cancer specimens revealed that laminin 332 in the myoepithelium adjacent to the preinvasive cells provided a source of laminin 332 that could potentially encourage the earliest steps of stromal invasion. In metaplastic breast carcinomas, the presence of laminin 332-producing cells coexpressing alpha(3) integrin and the greater metastatic potential of tumors with higher laminin 332 levels suggest that laminin 332 expression is associated with aggressive features in these human breast cancers.

Spindle cell carcinoma of the breast managed with neoadjuvant AIM: A case report.

Spindle cell carcinoma (SpC), also known as metaplastic carcinoma-spindle cell type, is a subtype of metaplastic carcinoma. Metaplastic carcinomas of the breast are rare but are thought to be more aggressive than invasive ductal carcinomas. Due to their rarity, there are few randomized trials that can inform any standardized approaches to treatment. Treatment is instead extrapolated from other types of breast cancer or metaplastic carcinomas of different locations. Here we present the first known case report of a patient with spindle cell carcinoma of the breast successfully treated with a standard sarcoma neoadjuvant regimen of doxorubicin, ifosfamide, and mesna (AIM) that resulted in >99% necrosis of the tumor and negative margins at the time of resection.

Associations Between Placental Corticotropin-Releasing Hormone, Maternal Cortisol, and Birth Outcomes, Based on Placental Histopathology.

Preterm birth remains the leading cause of neonatal morbidity and mortality, with complex biochemical pathways requiring continued understanding and assessment. The objective of this study is to assess the associations between maternal cortisol and placental corticotropin-releasing hormone (placental CRH) concentrations with birth outcomes when stratified by placental histopathology. We conducted an analysis of 112 singleton pregnancies who received betamethasone between 23 and 34 weeks' gestation. Maternal blood and saliva were collected prior to betamethasone administration and samples assayed for plasma cortisol (pCort), salivary cortisol (sCort), and placental CRH levels. Placental findings were characterized as inflammatory, maternal vascular underperfusion (MVU), or no pathology, and compared for the outcomes of placental CRH, pCort, and sCort levels, gestational age at birth (GAB), and birthweight percentiles (BWP). Thirty-six subjects were characterized as inflammatory, 38 as MVU, and 38 without placental abnormalities. Histopathology groups differed significantly on placental CRH levels, GAB, and BWP. Post hoc tests suggested that the MVU group had higher placental CRH than the inflammatory or no pathology groups, and despite delivering earlier than the other two groups, the inflammatory group had infants with significantly higher BWP. No differences existed between groups in terms of mean plasma or sCort levels. Higher placental CRH and pCort levels were associated with earlier GAB in the overall sample, but when split by group, these associations remained significant only among the MVU group. Higher placental CRH was also associated with lower BWP in the overall sample but did not remain significant when split by group. Higher sCort was associated with lower BWP only in the MVU group. There is differentiation of placental CRH, cortisol, and birth outcomes when evaluated by placental histopathology. This highlights the importance of evaluating birth outcomes within the context of placental histopathology.

Residual breast cancer diagnosed by MRI in patients receiving neoadjuvant chemotherapy with and without bevacizumab.

PURPOSE: To investigate the impact of antiangiogenic therapy with bevacizumab on pathological response and the diagnostic performance of magnetic resonance imaging (MRI) in breast cancer patients. METHODS: Thirty-six patients (aged 31-69 years) with breast cancer were included. Sixteen patients received neoadjuvant chemotherapy (NAC) containing bevacizumab, and 20 patients received the same NAC protocol without bevacizumab. Serial MRI studies were performed to evaluate response. All patients received surgery after completing NAC. The extent of residual disease was examined by histopathology, and classified into three types (pCR-pathologic complete response, confined nodules, and scattered cells). Fisher's exact test and general logistic regression models were applied to analyze differences between two groups. RESULTS: pCR rates and residual disease (nodular and scattered cell) patterns were comparable between the two groups. The diagnostic accuracy rate of MRI (true positive and true negative) was 13/17 (76%) for patients with bevacizumab, and 14/20 (70%) for patients without bevacizumab. The size measured on MRI was accurate for mass lesions that shrank down to nodules, showing <0.7 cm discrepancy from pathological size. For residual disease presenting as scattered cells within a large fibrotic region, MRI could not predict them correctly, resulting in a high false-negative rate and a large size discrepancy. CONCLUSION: The pathological response and the diagnostic performance of MRI are comparable between patients receiving NAC with and without bevacizumab. In both groups MRI has a limitation in detecting residual disease broken down to small foci and scattered cells/clusters. When MRI is used to evaluate the extent of residual disease for surgical treatment, the limitations, particularly for nonmass lesions, should be considered.

Rational and successful use of carboplatin and albumin-bound paclitaxel in a patient with recurrent metaplastic carcinoma who presented with multi-organ tumor emboli.

We demonstrate successful treatment of recurrent chondroid-metaplastic breast cancer. Breast cancer recurrence was diagnosed when a patient with a history of metaplastic breast cancer presented with recurrent acute strokes. A diagnosis of tumor embolism was suspected when a chest radiograph performed as part of a work-up for stroke demonstrated several lung nodules, with 1 lung nodule invading the pulmonary vein and extending into the left atrium-the source of tumor emboli. This was followed by timely surgery to remove the embolizing metastatic lesion and local radiation to prevent growth and recurrent embolization. Subsequently, the patient received carboplatin and albumin-bound paclitaxel and experienced complete remission.

Laminin 5 expression in metaplastic breast carcinomas.

Metaplastic carcinoma of the breast shows squamous, sarcomatous, or chondromatous differentiation and has a poor prognosis. Laminin 5 is a heterotrimer of alpha3, beta3, and gamma(2) [corrected] chains and induces aggressive properties in cancer cells including motility, invasion, and epithelial to mesenchymal transition. Twenty-five cases included 7 squamous, 4 sarcomatous, 8 chondroid, 1 fibromatosislike metaplastic carcinomas, and 5 cases with 2 metaplastic components. Tumors were stained with laminin 5-specific beta3 and gamma(2) [corrected] chain, p63, and cytokeratin 5/6 (CK 5/6) antibodies. All 4 antibodies stained normal myoepithelium. Both laminin 5 antibodies stained 24/25 (96%) of the tumors, with an identical distribution of the 2 chains in 87.5% of the positively staining cases. In contrast, p63 and CK 5/6 stained 68% and 64% of the tumors, respectively. By comparison, only 16% of high-grade carcinoma controls stained for laminin 5. Similar to the metaplastic carcinomas, all 12 triple negative tumors, those negative for estrogen receptor, progesterone receptor, and Her2/neu, expressed laminin 5. None of 4 breast sarcomas stained for either of the laminin 5 chains or CK 5/6, but 1 (25%) stained for p63. Laminin 5 expression in metaplastic and other basal-like carcinomas is of interest for several reasons. First, these data provide additional evidence of the myoepithelial and basal-like phenotype of these carcinomas. Second, these are the only breast carcinoma subtypes to demonstrate laminin 5 staining in a large proportion of cases. Third, expression of laminin 5 in metaplastic carcinomas may suggest a mechanism for their increased aggressiveness and epithelial to mesenchymal transition phenotype. Finally, compared with other myoepithelial markers, laminin 5 is more sensitive than those previously published. Thus laminin 5 may be helpful for making the diagnosis of metaplastic carcinomas in biopsies, allowing the potential for aggressive early treatment. Further study of other basal-like tumors for laminin 5 expression is warranted to determine the usefulness of laminin 5 in their diagnosis.

Laminin 332 expression and prognosis in breast cancer.

The purpose of this study was to determine the distribution of and potential significance of laminin 332 (LM332) in breast cancer. Specimens from a population-based cohort (N = 297) from 1994 to 1995 were stained for estrogen receptor (ER), progesterone receptor (PgR), HER2 and the LM332 ß3 chain. Seventy-five tumors were LM332-positive and 222 were negative. LM332 ß3 stained 16.0% of ER and/or PgR-positive tumors and 73.2% of triple-negative breast cancers (TNBC). Immunoblotting revealed LM332 in TNBC and HER2-positive samples, but not in an ER-positive breast carcinoma or a phyllodes tumor. After 20 years, 172 patients were alive, 43 had died of breast cancer and 82 of other causes. Patients with LM332-positive tumors had significantly worse 5 (P < .0001) and 10-year (P < .05) overall and breast cancer specific survival. Among patients with LM332 ß3-expressing and ER/PgR-negative carcinomas, 10-year survival was significantly reduced (P < .0450). In a multivariate analysis LM332-positive patients had significant hazard ratios of 3.9 with 95% confidence intervals (CI) of 2.0-7.7 and 2.2 with 95% CI of 1.3-3.8 for 5 and 10-year overall survival, respectively. Because tumor cell motility is required for metastasis, the effect of LM332 on MDA-MB-231 migration was determined using siRNA. Knockdown of LM332-specific ß3 and γ2 chains reduced motility without affecting viability. Our observation that LM332 in breast carcinoma is associated with decreased survival provides evidence that LM332 may have a role in the aggressive phenotype of some breast cancers.

Tissue oxygen saturation predicts response to breast cancer neoadjuvant chemotherapy within 10 days of treatment.

Ideally, neoadjuvant chemotherapy (NAC) assessment should predict pathologic complete response (pCR), a surrogate clinical endpoint for 5-year survival, as early as possible during typical 3- to 6-month breast cancer treatments. We introduce and demonstrate an approach for predicting pCR within 10 days of initiating NAC. The method uses a bedside diffuse optical spectroscopic imaging (DOSI) technology and logistic regression modeling. Tumor and normal tissue physiological properties were measured longitudinally throughout the course of NAC in 33 patients enrolled in the American College of Radiology Imaging Network multicenter breast cancer DOSI trial (ACRIN-6691). An image analysis scheme, employing z-score normalization to healthy tissue, produced models with robust predictions. Notably, logistic regression based on z-score normalization using only tissue oxygen saturation (StO2) measured within 10 days of the initial therapy dose was found to be a significant predictor of pCR (AUC = 0.92; 95% CI: 0.82 to 1). This observation suggests that patients who show rapid convergence of tumor tissue StO2 to surrounding tissue StO2 are more likely to achieve pCR. This early predictor of pCR occurs prior to reductions in tumor size and could enable dynamic feedback for optimization of chemotherapy strategies in breast cancer.

Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer.

Background: Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer. Methods: The STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Rao's quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics. Results: A statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P < .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio [HR] = 1.98, 95% confidence interval [CI] = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI = 1.18 to 4.99). Conclusions: Patients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors.

Auricular angioleiomyoma: a case report and review of the literature.

A 29-year-old woman presented with an unusual lesion on the right auricular antihelix. The mass was purple and painful, and it had been present for 17 years. Preoperatively, the presumptive diagnosis was a venous malformation. The mass was resected, and a staged reconstruction was performed. Microscopic analysis of the specimen revealed that the lesion was an angioleiomyoma. Most cases of angioleiomyoma involve the extremities; few have been described in the head and neck region, and very few of those have been reported on the ear. Among those auricular angioleiomyomas that have been reported, most were distinctly painless. We report a new, atypical case of this unusual tumor.

T1ρ/T2 mapping and histopathology of degenerative cartilage in advanced knee osteoarthritis.

AIM: To investigate whether normal thickness cartilage in osteoarthritic knees demonstrate depletion of proteoglycan or collagen content compared to healthy knees. METHODS: Magnetic resonance (MR) images were acquired from 5 subjects scheduled for total knee arthroplasty (TKA) (mean age 70 years) and 20 young healthy control subjects without knee pain (mean age 28.9 years). MR images of T1ρ mapping, T2 mapping, and fat suppressed proton-density weighted sequences were obtained. Following TKA each condyle was divided into 4 parts (distal medial, posterior medial, distal lateral, posterior lateral) for cartilage analysis. Twenty specimens (bone and cartilage blocks) were examined. For each joint, the degree and extent of cartilage destruction was determined using the Osteoarthritis Research Society International cartilage histopathology assessment system. In magnetic resonance imaging (MRI) analysis, 2 readers performed cartilage segmentation for T1ρ/T2 values and cartilage thickness measurement. RESULTS: Eleven areas in MRI including normal or near normal cartilage thickness were selected. The corresponding histopathological sections demonstrated mild to moderate osteoarthritis (OA). There was no significant difference in cartilage thickness in MRI between control and advanced OA samples [medial distal condyle, P = 0.461; medial posterior condyle (MPC), P = 0.352; lateral distal condyle, P = 0.654; lateral posterior condyle, P = 0.550], suggesting arthritic specimens were morphologically similar to normal or early staged degenerative cartilage. Cartilage T2 and T1ρ values from the MPC were significantly higher among the patients with advanced OA (P = 0.043). For remaining condylar samples there was no statistical difference in T2 and T1ρ values between cases and controls but there was a trend towards higher values in advanced OA patients. CONCLUSION: Though cartilage is morphologically normal or near normal, degenerative changes exist in advanced OA patients. These changes can be detected with T2 and T1ρ MRI techniques.

Migration of breast cancer cell lines in response to pulmonary laminin 332.

Because tumor cell motility is a requirement for metastasis, we hypothesized that lung tissue harbors substances that induce tumor cell migration. MCF-7 breast carcinoma cells exposed to small airway epithelial cells and conditioned medium exhibited dose-dependent tumor cell migration. Among the extracellular matrix proteins in the conditioned medium identified by mass spectrometry, laminin 332 (LM332) had the greatest contribution to the migration of MCF-7 cells. Immunoblotting and immunohistochemistry for LM332-specific chains identified LM332 in the lung and in pulmonary epithelial cells. Antibodies to either LM332 or its integrin receptor inhibited MCF-7 motility, and knockdown of LM332 chains also reduced its migration-inducing activity. Taken together, these findings implicate LM332 as a component of lung tissue that can induce motility in breast carcinoma cells that have been transported to lung during metastasis. Earlier studies on LM332 in tumor progression have examined LM332 expression in tumor cells. This investigation, in comparison, provides evidence that the tumor promoting potential of LM332 may originate in the lung microenvironment rather than in tumor cells alone. Furthermore, this study provides evidence that the motility-inducing properties of the microenvironment can reside in epithelial cells. The findings raise the possibility that LM332 plays a role in the pulmonary metastases of breast carcinoma and may provide a target for antimetastasis therapy.

Increased epithelial cadherin expression among Japanese intestinal-type gastric cancers compared with specimens from American patients of European descent.

The different patterns of gastric cancer in the Far East and West have evolved to the extent that it has been suggested that the disease in Japan is biologically less aggressive than in the West. We studied paraffin-embedded, formalin-fixed tissue blocks from Japanese patients and American patients of European descent who had undergone gastrectomy for gastric cancer not involving the gastroesophageal junction. Specimens were staged (T stage), graded (Lauren classification), and biomarker expression (epithelial cadherin [E-cadherin], c-erbB2, Ki67, and p53) was quantified using immunohistochemistry without knowledge of the country of origin. E-cadherin was expressed in 49 per cent of malignant cells from Japanese specimens compared with 27 per cent of malignant cells from American specimens (P = 0.04). The expression of E-cadherin on diffuse cancers from the two countries was similar (34.4 in Japanese vs 41.5 in American, P = 0.92). E-cadherin expression, however, was significantly higher among intestinal cancers from the two countries: 56.3 per cent of cells from intestinal or mixed cancers from Japan (n = 32) expressed E-cadherin compared with 22.2 per cent of American specimens (n = 12; P = 0.008).-c-erbB2 was expressed on a higher proportion of malignant cells from American specimens (30% vs 22%; P = 0.20). E-cadherin expression, a favorable prognostic factor, is more common in Japanese intestinal-type gastric cancer not involving the gastroesophageal junction. If the biology of gastric cancer in the Far East is less aggressive than that in the United States, it is likely that treatments need to be individualized.

Predicting Responses to Neoadjuvant Chemotherapy in Breast Cancer: ACRIN 6691 Trial of Diffuse Optical Spectroscopic Imaging.

The prospective multicenter ACRIN 6691 trial was designed to evaluate whether changes from baseline to mid-therapy in a diffuse optical spectroscopic imaging (DOSI)-derived imaging endpoint, the tissue optical index (TOI), predict pathologic complete response (pCR) in women undergoing breast cancer neoadjuvant chemotherapy (NAC). DOSI instruments were constructed at the University of California, Irvine (Irvine, CA), and delivered to six institutions where 60 subjects with newly diagnosed breast tumors (at least 2 cm in the longest dimension) were enrolled over a 2-year period. Bedside DOSI images of the tissue concentrations of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctHbO2), water (ctH2O), lipid, and TOI (ctHHb × ctH2O/lipid) were acquired on both breasts up to four times during NAC treatment: baseline, 1-week, mid-point, and completion. Of the 34 subjects (mean age 48.4 ± 10.7 years) with complete, evaluable data from both normal and tumor-containing breast, 10 (29%) achieved pCR as determined by central pathology review. The percent change in tumor-to-normal TOI ratio (%TOITN) from baseline to mid-therapy ranged from -82% to 321%, with a median of -36%. Using pCR as the reference standard and ROC curve methodology, %TOITN AUC was 0.60 (95% CI, 0.39-0.81). In the cohort of 17 patients with baseline tumor oxygen saturation (%StO2) greater than the 77% population median, %TOITN AUC improved to 0.83 (95% CI, 0.63-1.00). We conclude that the combination of baseline functional properties and dynamic optical response shows promise for clinical outcome prediction. Cancer Res; 76(20); 5933-44. ©2016 AACR.

Background Parenchymal Enhancement of the Contralateral Normal Breast: Association with Tumor Response in Breast Cancer Patients Receiving Neoadjuvant Chemotherapy.

PURPOSE: This study investigated the association between background parenchymal enhancement (BPE) and pathologic response to neoadjuvant chemotherapy (NAC). METHODS: A total of 46 patients diagnosed with invasive breast cancer were analyzed. Each patient had three magnetic resonance imaging (MRI) studies, one pre-treatment and two follow-up (F/U) MRI studies. BPE was measured as the averaged enhancement of the whole fibroglandular tissues. The pre-treatment BPE and the changes in the F/U MRI were compared between patients achieving pathologic complete response (pCR) versus those not. Subgroup analyses based on age, estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2) status of their cancers were also performed. RESULTS: The pre-treatment BPE was higher in the pCR group than that in the non-pCR group. Compared to baseline, BPE at F/U-1 was significantly decreased in the pCR group but not in the non-pCR group. In subgroup analysis based on age, these results were seen only in the younger group (<55 years old), not in the older group (≥55 years old). Older patients had a significantly lower pre-treatment BPE than younger patients. In analysis based on molecular biomarkers, a significantly decreased BPE at F/U-1 was only found in the ER-negative pCR group but not in the non-pCR, nor in the ER-positive groups. CONCLUSIONS: A higher pre-treatment BPE showing a significant decrease early after starting NAC was related to pCR in pre/peri-menopausal patients.

"Score the Core" Web-based pathologist training tool improves the accuracy of breast cancer IHC4 scoring.

Hormone receptor status is an integral component of decision-making in breast cancer management. IHC4 score is an algorithm that combines hormone receptor, HER2, and Ki-67 status to provide a semiquantitative prognostic score for breast cancer. High accuracy and low interobserver variance are important to ensure the score is accurately calculated; however, few previous efforts have been made to measure or decrease interobserver variance. We developed a Web-based training tool, called "Score the Core" (STC) using tissue microarrays to train pathologists to visually score estrogen receptor (using the 300-point H score), progesterone receptor (percent positive), and Ki-67 (percent positive). STC used a reference score calculated from a reproducible manual counting method. Pathologists in the Athena Breast Health Network and pathology residents at associated institutions completed the exercise. By using STC, pathologists improved their estrogen receptor H score and progesterone receptor and Ki-67 proportion assessment and demonstrated a good correlation between pathologist and reference scores. In addition, we collected information about pathologist performance that allowed us to compare individual pathologists and measures of agreement. Pathologists' assessment of the proportion of positive cells was closer to the reference than their assessment of the relative intensity of positive cells. Careful training and assessment should be used to ensure the accuracy of breast biomarkers. This is particularly important as breast cancer diagnostics become increasingly quantitative and reproducible. Our training tool is a novel approach for pathologist training that can serve as an important component of ongoing quality assessment and can improve the accuracy of breast cancer prognostic biomarkers.

Nuclear morphometry and molecular biomarkers of actinic keratosis, sun-damaged, and nonexposed skin.

Computer-assisted image analysis is useful for quantifying the histologic and molecular changes of sun-induced squamous cell carcinoma progression. We used the CAS 200 image analysis system to measure nuclear morphometric parameters, p53 expression, and proliferation markers in actinic keratosis (AK), sun-exposed, and normal skin in 51 patients. Nuclear morphometry revealed significant increases in nuclear absorbance, irregularity of nuclear shape, and nuclear size in AK compared with normal and sun-damaged skin. These parameters showed significantly greater variability in AK nuclei. Argyrophyllic nucleolar organizer area and number were also significantly greater in AK compared with sun-damaged skin and normal skin. Ki67 and p53 expressions were both increased in sun-damaged skin relative to normal and greater still in AK. These data are evidence that sun damage induces proliferation and p53 abnormalities before the appearance of nuclear abnormalities and their associated DNA instability. Following these changes during a skin cancer chemopreventative trial can then help assess the efficacy of the agent and help determine where in the progression of neoplastic changes it exerts its biological effects.