Growth Factor Receptor 2-positive Cancer Research Articles

Triple-Negative Breast Cancer: Histopathologic Features, Genomics, and Treatment.

Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive group of tumors that are defined by the absence of estrogen and progesterone receptors and lack of ERBB2 (formerly HER2 or HER2/neu) overexpression. TNBC accounts for 8%-13% of breast cancers. In addition, it accounts for a higher proportion of breast cancers in younger women compared with those in older women, and it disproportionately affects non-Hispanic Black women. TNBC has high metastatic potential, and the risk of recurrence is highest during the 5 years after it is diagnosed. TNBC exhibits benign morphologic imaging features more frequently than do other breast cancer subtypes. Mammography can be suboptimal for early detection of TNBC owing to factors that include the fast growth of this cancer, increased mammographic density in young women, and lack of the typical features of malignancy at imaging. US is superior to mammography for TNBC detection, but benign-appearing features can lead to misdiagnosis. Breast MRI is the most sensitive modality for TNBC detection. Most cases of TNBC are treated with neoadjuvant chemotherapy, followed by surgery and radiation. MRI is the modality of choice for evaluating the response to neoadjuvant chemotherapy. Survival rates for individuals with TNBC are lower than those for persons with hormone receptor-positive and human epidermal growth factor receptor 2-positive cancers. The 5-year survival rates for patients with localized, regional, and distant disease at diagnosis are 91.3%, 65.8%, and 12.0%, respectively. The early success of immunotherapy has raised hope regarding the development of personalized strategies to treat TNBC. Imaging and tumor biomarkers are likely to play a crucial role in the prediction of TNBC treatment response and TNBC patient survival in the future. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

Prospective Evaluation of Ultrafast Breast MRI for Predicting Pathologic Response after Neoadjuvant Therapies.

Background Ultrafast dynamic contrast-enhanced (DCE) MRI parameters are associated with breast cancer aggressiveness. However, the role of these parameters as predictive biomarkers for pathologic response after neoadjuvant chemotherapy (NAC) has been poorly investigated. Purpose To assess whether semiquantitative perfusion parameters calculated at initial ultrafast DCE MRI are associated with early prediction for pathologic response after NAC in participants with breast cancer. Materials and Methods This prospective single-center study included consecutive women with nonmetastatic invasive breast cancer treated with NAC followed by surgery who underwent initial ultrafast DCE MRI between December 2020 and August 2021. Six semiquantitative ultrafast DCE MRI parameters were calculated for each participant from the fitted time-signal intensity curve. Multivariable logistic regression was used to identify independent predictors of pathologic complete response (pCR) and residual cancer burden (RCB). Results Fifty women (mean age, 49 years ± 12 [SD]) were included in the study; 20 achieved pCR and 25 achieved low RCB (RCB-0 and I). A wash-in slope (WIS) cutoff value of 1.6% per second had a sensitivity of 94% (17 of 18 participants) and a specificity of 59% (19 of 32 participants) for pCR. A WIS of more than 1.6% per second (odds ratio [OR], 8.4 [95% CI: 1.5, 48.2]; P = .02), human epidermal growth factor receptor 2 (HER2) positivity (OR, 6.3 [95% CI: 1.5, 27.4]; P = .01), and tumor-infiltrating lymphocytes of more than 10% (OR, 6.9 [95% CI: 1.3, 37.7]; P = .03) were independent predictive factors of pCR. The area under the receiver operating characteristic curve of the three-component model, which included WIS, tumor-infiltrating lymphocytes, and HER2 positivity, was 0.92 (95% CI: 0.84, 0.99). A WIS of more than 1.6% per second was associated with higher pCR rates in the HER2-positive (OR, 21.7 [95% CI: 1.8, 260.6]; P = .02) breast cancer subgroup. For luminal HER2-negative and triple-negative breast cancers, a WIS of more than 1.6% per second was associated with low RCB (OR, 11.0 [95% CI: 1.1, 106.4]; P = .04). Conclusion The wash-in slope (WIS) assessment at initial ultrafast dynamic contrast-enhanced MRI may be used to predict pathologic complete response (pCR) in participants with breast cancer. The WIS value was used to identify two subsets of human epidermal growth factor receptor 2-positive cancers with distinct pCR rates. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Lee and Moy in this issue.

Effects of Germline Pathogenic Variants, Cancer Subtypes, Tumor-related Characteristics, and Pregnancy-associated Diagnosis on Outcomes

BackgroundAlthough breast cancer (BC) is uncommon in women age ≤ 35 years, women in this age group may have more aggressive cancer subtypes and high-risk pathogenic variants (HRPVs). Higher recurrence and mortality rates in young patients may be related to differences in tumor biology, pathologic mutation status, or treatment. The purpose of this study was to evaluate germline mutation status and other factors that affect recurrence-free survival (RFS) and overall survival (OS) in young women with BC. Materials and MethodsThis was a retrospective study of women diagnosed with BC at age ≤ 35 years at Allina Health System from 2000 through 2017 (n = 306). Information was collected on germline mutation status, tumor characteristics (grade, hormone receptor, and human epidermal growth factor receptor 2), molecular subtype, pregnancy-associated cancers, and treatment. Survival analyses using Kaplan-Meier curves were conducted for RFS and OS. ResultsWith mean follow-up of 6.5 years, OS was 87.0% for invasive cancers, RFS was 84.7%; 69% obtained genetic testing, and 26.9% had HRPVs. There were no differences in RFS or OS between patients with HRPV versus unknown/low/moderate risk variants. Recurrence analysis showed increased recurrence rates in luminal B-like cancers followed by triple negative and human epidermal growth factor receptor 2-positive cancers (P = .041). Pregnancy-associated BC diagnoses, angiolymphatic invasion, and tumor stage were associated with reduced OS. In spite of young age at diagnosis, nearly one-third of patients did not receive germline genetic testing. ConclusionsSimilar survival patterns were found between women with HRPV versus no known mutations. Luminal B-like subtype, pregnancy-associated BC, angiolymphatic invasion, and cancer stage were associated with reduced OS.

Differential expression of micro-RNAs in breast cancer with relapsed disease: A clinical data base study.

e12514 Background: Micro-RNAs (miRNAs) are small, noncoding RNA molecules that play important role in RNA silencing and post-transcriptional regulation of gene expression that are dysregulated in cancer. miRNAs are divided into oncogenic and tumor suppressor miRNAs. Both of these subtypes are known to regulate breast cancer development and progression. We studied the expression of these miRNAs before and after treatment in patients with breast cancer with relapsed disease. Methods: Data was obtained from the TCGA database. 11 patients with biopsy proven diagnosis of invasive ductal adenocarcinoma of the breast receiving adjuvant chemotherapy with relapsed disease who had tissue biopsy post-treatment were included in the study. miRNA expression was assessed in the pre- and post-treatment tissue samples. A total of 178 miRNA were analyzed after filtering out miRNA expression counts < 10. A pair-wise comparison of the differential expression of miRNA before and after treatment with adjuvant chemotherapy was analyzed using a quasi-likelihood F test implemented by bioconductor package, edgeR. This package is well documented for analyzing RNA-seq data due to adjustment for biological variations and measuring error using a negative binomial distribution. The expression of miRNA |Log2FC| > 1 and P value < 0.05 were obtained. Results: Out of 11 female patients, 10 were Caucasian. 9 out of 11 patients’ tumors were Estrogen Receptor positive; 8 patients had progesterone Receptor positive and 1 patient had Human epidermal growth factor receptor2 positive cancer. Of the 178 miRNAs of interest, we found 14 miRNA that are differentially expressed. The miRNA that are up-regulated post-treatment were hsa-miR-148a, hsa-miR-126, hsa-miR-142, hsa-miR-210, hsa-miR-374a, hsa-miR-192. The miRNA that were down-regulated were hsa-miR-197, hsa-miR-155, hsa-miR-149, hsa-miR-365a, hsa-miR-365b, hsa-miR-484, hsa-miR-339 and hsa-miR-3653. Among the miRNA up-regulated post-treatment, miR-148 and miR-126 are known major tumor suppresser miRNA whereas miR-210 and miR-374a are major oncogenic miRNA in breast cancer. Among the miRNA down-regulated post treatment, miR-155 is major oncogenic miRNA whereas miR-365 is major tumor suppressor miRNA in breast cancer. Conclusions: There is mixed expression profile of tumor suppressor miRNA and oncogenic miRNA molecules between before and after treatment in patients with breast cancer with relapsed disease. Further studying these miRNA molecules can help us better understand about the tumor progression and disease relapse.

Optoacoustic Imaging and Gray-Scale US Features of Breast Cancers: Correlation with Molecular Subtypes.

Background Optoacoustic imaging can assess tumor hypoxia coregistered with US gray-scale images. The combination of optoacoustic imaging and US may have a role in distinguishing breast cancer molecular subtypes. Purpose To investigate whether optoacoustic US feature scores correlate with breast cancer molecular subtypes. Materials and Methods A total of 1972 women (with a total of 2055 breast masses) underwent prebiopsy optoacoustic US in a prospective multi-institutional study between December 2012 and September 2015. Seven readers blinded to pathologic diagnosis scored gray-scale US and optoacoustic US features of the known cancers. Optoacoustic US features within (internal) and outside of the tumor boundary (external) were scored. Immunohistochemistry findings were obtained from pathology reports. Multinomial logistic regression analysis was used to fit the US scores, adding optoacoustic US features to the model to investigate the incremental benefit of each feature. Kruskal-Wallis tests were used to analyze the relationship between molecular subtypes and feature scores. Results Among 653 invasive cancers identified in 629 women, a total of 532 cancers in 519 women, all of which had molecular markers available, were included in the analysis. Mean age ± standard deviation was 57.9 years ± 12.6. Mean total external optoacoustic US feature scores of luminal (A and B) breast cancers were higher (9.9 vs 8.8; P < .05) and total internal scores were lower (6.8 vs 7.7; P < .001) than those of triple-negative and human epidermal growth factor receptor 2-positive (HER2+) cancers. A multinomial logistic regression model showed that optoacoustic internal vessel (odds ratio [OR], 0.6; 95% confidence interval [CI]: 0.5, 0.8; P = .002), optoacoustic internal blush (OR, 0.7; 95% CI: 0.5, 0.9; P = .02), and optoacoustic internal hemoglobin (OR, 0.6; 95% CI: 0.5, 0.8; P = .001) were associated with classification of luminal versus triple-negative and HER2+ cancer subtypes. Conclusion Combined optoacoustic US imaging and gray-scale US features may help distinguish luminal breast cancers from triple-negative and human epidermal growth factor receptor 2-positive cancers. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Mann in this issue.

Microfluidic Preparation of a 89Zr-Labeled Trastuzumab Single-Patient Dose.

(89)Zr-labeled antibodies are being investigated in several clinical trials; however, the time requirement for synthesis of clinical doses can hinder patient throughput because of scheduling difficulties. Additionally, low specific activity due to poor labeling efficiency can require larger amounts of the radiopharmaceutical to be administered, possibly leading to adverse side effects. Here, we describe the design and evaluation of a microfluidic reactor capable of synthesizing a single clinical dose of (89)Zr-labeled antibody. (89)Zr-labeled trastuzumab was chosen for this validation because it is currently being evaluated in clinical trials for imaging human epidermal growth factor receptor 2-positive cancer patients. A microreactor fabricated from polydimethylsiloxane/glass was silanated with trimethoxy(octadecyl) silane to reduce antibody adsorption. Desferrioxamine-p-benzyl-isothiocyanate (DFO-Bz-NCS) was conjugated to trastuzumab in an 8:1 molar ratio following the literature procedures using aseptic techniques. Radiolabeling was performed by pumping (89)Zr-oxalate and DFO-Bz-trastuzumab into the microfluidic reactor at a total rate of 20 μL/min in ratios varying from 1:37 to 1:592 mg:MBq at 37°C to achieve optimal labeling. Silanated reactors showed low antibody adsorption in comparison to unmodified reactors (95% monoclonal antibody recovered vs. 0% recovered). Labeling of the modified trastuzumab was shown to be achievable at a specific activity above the reported literature value of 220 MBq/mg. A high radiochemical purity was achieved without an incubation period at specific activities of less than 148 MBq/mg; however, specific activities up to 592 MBq/mg could be achieved with an incubation period. Clinical doses were able to be prepared and passed all quality control guidelines set by the Food and Drug Administration. Samples were sterile, colorless, and radiochemically pure (100%); maintained the ability to bind to the intended receptor; formed a minimal amount of aggregates (1%-4%); and were completed within 45-60 min. (89)Zr-labeled trastuzumab for use in a clinical setting was synthesized in a microfluidic reactor in under an hour while reducing the amount of handling required by a technician. Use of this compact platform not only could enable the use of radiolabeled antibodies to become a common practice, but also could spread the use of radiolabeled antibodies beyond locations with cyclotron facilities.

Milestones in breast cancer treatment.

Modern treatment started in the 1880s with Halsted's mastectomy. The next milestone-a century later-was breast-conserving surgery, with equivalent survival but better esthetic outcomes than mastectomy. Sentinel node biopsy, introduced in the 1990s, was a milestone that permitted avoidance of axillary dissection if the sentinel node was disease-free. Chemotherapy was established for early breast cancer in the 1980s and its efficacy continues to improve; however side effects remain a concern, particularly since chemotherapy does not benefit most patients. External whole breast irradiation was introduced with conservative surgery, as it reduces recurrences. By the 2000s, 3-week regimens had been shown equivalent to standard 6-week regimens-easing pressure on patients and radiation centers. Intraoperative partial breast irradiation is potentially more beneficial as it permits complete local treatment in a single session; however, trials show that patients must be very carefully selected. From the 1990s irradiation technology was combined with imaging and computer technologies to produce equipment that directs radiation to more precisely defined target volumes, allowing increased dose to the target and markedly reduced dose to nearby tissues. Irradiation systems are evolving rapidly but are being implemented without data on long-term morbidity or efficacy, while costs rise steeply. The first targeted treatment was tamoxifen, a selective estrogen receptor inhibitor. Since its widespread use starting in the 1980s, tamoxifen has saved the lives or prolonged the survival of millions with estrogen-positive disease; it is cheap and has limited (but not negligible) side effects. The same cannot be said of newer targeted treatments like trastuzumab and pertuzumab, which, although effective against human epidermal growth factor receptor 2-positive cancer, come with important side effects and huge costs. Breast cancer mortality is declining in rich countries, but treatments have become more demanding and more expensive, so the outlook for the increasing numbers of women worldwide who develop the disease is uncertain.

Occupational Exposure to Ionizing Radiation and Risk of Breast Cancer in Western Australia

To evaluate current breast cancer risk due to occupational exposure to ionizing radiation. We analyzed data from the Western Australian population-based Breast Cancer Employment and Environment Study. The Breast Cancer Employment and Environment Study included 1205 cases with incident breast cancer during 2009-2011 and 1789 controls. Age-adjusted odds ratios (ORs) were estimated with logistic regression models. There was a weak, not statistically significant association between breast cancer and occupational exposure to ionizing radiation (OR = 1.16; 95% confidence interval, 0.86 to 1.57). The risk of human epidermal growth factor receptor 2-positive breast cancer with occupational exposure to ionizing radiation in women who were premenopausal at the time of interview was higher (OR = 2.57; 95% confidence interval, 1.09 to 6.03). This study suggests that the risk of breast cancer is low at current levels of occupational exposure to ionizing radiation, although the risk of human epidermal growth factor receptor 2-positive cancer may be a concern.

A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in the development for the treatment of human epidermal growth factor receptor 2-positive cancers. Thrombocytopenia (TCP) is the dose-limiting toxicity of T-DM1. A semimechanistic population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize the effect of T-DM1 on patient platelet counts. A PK/PD model with transit compartments that mimic platelet development and circulation was fit to concentration-platelet-time course data from two T-DM1 single-agent studies (TDM3569g; N = 52 and TDM4258g; N = 112). NONMEM(®) 7 software was used for model development. Data from a separate phase II study (TDM4374g; N = 110) were used for model evaluation. Patient baseline characteristics were evaluated as covariates of model PD parameters. The model described the platelet data well and predicted the incidence of grade ≥3 TCP. The model predicted that with T-DM1 3.6 mg/kg given every 3 weeks (q3w), the lowest platelet nadir would occur after the first dose. Also predicted was a patient subgroup (46 %) having variable degrees of downward drifting platelet-time profiles, which were predicted to stabilize by the eighth treatment cycle to platelet counts above grade 3 TCP. Baseline characteristics were not significant covariates of PD parameters in the model. This semimechanistic PK/PD model accurately captures the cycle 1 platelet nadir, the downward drift noted in some patient platelet-time profiles, and the ~8 % incidence of grade ≥3 TCP with T-DM1 3.6 mg/kg q3w. This model supports T-DM1 3.6 mg/kg q3w as a well-tolerated dose with minimal dose delays or reductions for TCP.