Clinical significance of HER2-low expression in early breast cancer: a nationwide study from the Korean Breast Cancer Society

There is an increasing interest in HER2-low breast cancer with promising data from clinical trials using novel anti-HER2 antibody–drug conjugates. We explored the differences in clinicopathological characteristics and survival outcomes between HER2-low and HER2-IHC 0 breast cancer. Using nationwide data from the Korean Breast Cancer Registry between 2006 and 2011, 30,491 patients with stages I to III breast cancer were included in the analysis: 9,506 (31.2%) in the HER2-low group and 20,985 (68.8%) in the HER2-IHC 0 group. Kaplan–Meier and Cox proportional hazards regression survival analysis were used to compare breast cancer-specific survival between the two groups. HER2-low breast cancer was more frequent in patients with hormone receptor-positive breast cancer than in those with triple-negative breast cancer. In patients with hormone receptor-positive breast cancer, HER2-low breast cancer was associated with fewer T4 tumors, higher histological grade, and a negative lymphatic invasion. In patients with triple-negative breast cancer, HER2-low breast cancer was associated with a high lymph node ratio and positive lymphatic invasion. HER2-low breast cancer was significantly associated with a lower Ki-67 labeling index. No significant difference was observed in overall survival between the two groups. HER2-low breast cancer showed significantly better breast cancer-specific survival than HER2-IHC 0 breast cancer, regardless of the hormone receptor status. In multivariate analysis, the impact of low HER2 expression on breast cancer-specific survival was significant only in triple-negative breast cancer (HRs, 0.68; 95% CI, 0.49–0.93; P = 0.019). These findings suggest that the biology and clinical impact of low HER2 expression can differ according to the hormone receptor status and support the need for further investigation on the understanding of the biology of HER2-low breast cancer

Value of accurate diagnosis for metastatic supraclavicular lymph nodes in breast cancer: assessment with neck US, CT, and 18F-FDG PET/CT

PURPOSENeck ultrasonography (US), computed tomography (CT), and 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) are all known to be useful imaging modalities for detecting supraclavicular lymph node (SCN) metastasis in breast cancer. The authors compared the diagnostic values of neck US, CT, and PET/CT in the detection of SCN metastasis in breast cancer.METHODSSCN metastases identified in neck US, CT, or PET/CT during follow-up visits of patients with breast cancer were pathologically confirmed with the use of US-guided fine-needle aspiration cytology. The clinicopathological factors of the patients were analyzed, and the statistical parameters including sensitivity, specificity, positive and negative predictive values, false-positive and false-negative rates, and accuracy of neck US, CT, and PET/CT were compared.RESULTSAmong 32 cases of suspicious SCNs, 24 were pathologically confirmed as metastasis of breast cancer. The sensitivity of US + CT was 91.7%, which was the same as that of PET/CT, while the sensitivity rates of US alone and CT alone were 87.5% and 83.3%, respectively. Accuracy was 99.8% in PET/CT alone and 98.1% in US + CT. The false-negative rate was 0.1% in US + PET/CT, while it was 0.2% in PET/CT and US + CT, 0.3% in US alone and 0.4% in CT alone.CONCLUSIONPET/CT can be the first choice for detecting SCN metastases in breast cancer. However, if PET/CT is unavailable for any reason, US + CT could be a good second option to avoid false-negative results

Knowledge, attitudes, and behaviors toward fertility preservation in patients with breast cancer: A cross-sectional survey of physicians

BackgroundFertility is an important issue for young women with breast cancer, but studies about physicians’ knowledge, attitudes, and practices toward fertility preservation (FP) are largely based on Western populations and do not reflect recent international guidelines for FP. In this international study, we aimed to assess the knowledge, attitudes, and practices of physicians from South Korea, other Asian countries, and Latin America toward FP in young women with breast cancer, and identify the related barriers.MethodsThe survey was conducted anonymously among physicians from South Korea, other Asian countries, and Latin America involved in breast cancer care between November 2020 and July 2021. Topics included knowledge, attitudes, and perceptions toward FP; practice behaviors; barriers; and participant demographics. We grouped related questions around two main themes—discussion with patients about FP, and consultation and referral to a reproductive endocrinologist. We analyzed the relationships between main questions and other survey items.ResultsA total of 151 physicians completed the survey. Most participants’ overall knowledge about FP was good. More than half of the participants answered that they discussed FP with their patients in most cases, but that personnel to facilitate discussions about FP and the provision of educational materials were limited. A major barrier was time constraints in the clinic (52.6%). Discussion, consultations, and referrals were more likely to be performed by surgeons who primarily treated patients with operable breast cancer (FP discussion odds ratio [OR]: 2.90; 95% confidence interval [CI]: 1.24–6.79; FP consultation and referral OR: 2.98; 95% CI: 1.14–7.74). Participants’ knowledge and attitudes about FP were significantly associated with discussion, consultations, and referrals.ConclusionPhysicians from South Korea, other Asian countries, and Latin America are knowledgeable about FP and most perform practice behaviors toward FP well. Physicians’ knowledge and favorable attitudes are significantly related to discussion with patients, as well as consultation with and referral to reproductive endocrinologists. However, there are also barriers, such as limitations to human resources and materials, suggesting a need for a systematic approach to improve FP for young women with breast cancer

Toward threading polyintercalators with programmed sequence specificity

Synthetic molecules that can bind DNA in a sequence specific manner are an interesting area of molecular recognition research with the potential to develop new therapeutics. A novel class of polyintercalators, composed of 1,4,5,8- naphthalene tetracarboxylic diimide (NDI) intercalating units connected via peptide linkers, have been developed in the Iverson research group. A previous combinatorial library screen identified two different bis-intercalators with altered sequence specificity and subsequent structural studies revealed that these molecules have a unique threading mode of polyintercalation, in which the tethering linker can be in either the major or minor groove, depending on the peptide linker composition. The peptide linkers are believed to play an important role in the recognition of target sequences and several analogues were investigated using DNase I footprinting experiments. These results showed that the position of a lysine residue in the linker plays a crucial role in recognizing internal sequences of 5’-GGNNCC-3’ on DNA. Among those derivatives, the parent compound (1), H2N-Lys-NDI-Gly-Gly-Gly-Lys-NDI-Gly-OH, showed dramatic sequence reading ability on 5’-GGNNCC-3’ sequences with the order of GGTACC > GGCGCC > GGATCC ~ GGGCCC with Kd ~ 125 nM. The previous structural knowledge of the two different bis-intercalators (1, and 1.2) served as binding modules that enabled us to design threading polyintercalators with sequence specific contacts in both grooves. A trimer (4.1), a hybrid molecule of the two bis-intercalator modules was designed to block both grooves and its programmed sequence reading ability was proved in footprinting experiments. As a parallel approach to achieve polyintercalation with programmed sequences, a symmetric tetramer (5.1) that is a conjugate of two identical bis-intercalator units (1.2) with flexible aliphatic chain linker was designed. 1D 1 H-NMR titration experiment revealed that this compound binds to a 14 bp DNA sequence d(GATAAGTACTTATC)2 with 1:1 stoichiometry. 2D 1 H-NMR studies combined with restrained molecular dynamics confirmed a threading binding mode in the three-dimensional structure of the DNA-ligand complex in which β-alanine residues in one type of linker reside in the minor groove as expected, while an adipic acid linker resides in the major groove also as expected. This represents the first structural analysis of any DNA intercalating molecules larger than a bis-intercalator and confirms that the sequence specific binding of longer threading polyintercalators can be predicted from bisintercalator modules. These results will provide the molecular basis for the DNA binding properties of a new generation of threading polyintercalators.Chemistry and BiochemistryChemistr

Catalytic Contributions from Remote Regions of Enzyme Structure

Studies on the effects of distal mutations are presented that have refined perspective into the origins of enzymatic catalysis. A novel method was applied to egelin C where NMR-detected hydrogen exchange was used to measure pairwise and higher-order coupling long-range free energies that allowed for efficient analysis of a large number of couplings. In classical molecular dynamics simulations, the interaction between atoms is described by a classical force field which describes the potential energy of the protein. The complete kinetic scheme for E. coli DHFR has been determined and it is found that hydride-transfer step can also occur in the reverse direction from the occluded complex. Unlike most proteins, an extensive network of coupled residues has been characterized in DHFR. The network extends from the active site to the surface of the protein and the motions observed in the network residues span the time scales of femtoseconds to milliseconds

A Peptoid-Based Fluorescent Sensor for Cyanide Detection

Peptoids, N-substituted glycine oligomers, are versatile peptidomimetics with diverse biomedical applications. However, strategies to the development of novel fluorescent peptoids as chemical sensors have not been extensively explored, yet. Here, we synthesized a novel peptoid-based fluorescent probe in which a coumarin moiety was incorporated via copper(I)-catalyzed azide-alkyne cycloaddition reaction. Fluorescence of the newly generated coumarin-peptoid was dramatically quenched upon coordination of the Cu2+ ion, and the resulting peptoid-Cu2+ complex exhibited significant Turn-ON fluorescence following the addition of CN−. The rapid and reversible response, combined with cyanide selectivity of the synthesized peptoid, reflects a multistep photo-process and supports its utility as a new type of CN− sensor

Role of breast magnetic resonance imaging in predicting residual lobular carcinoma in situ after initial excision

Summary: Background: Breast magnetic resonance (MR) imaging is a useful screening modality in detecting suspicious lesions in patients with a history of lobular carcinoma in situ (LCIS). This study aimed to evaluate the effectiveness of breast MR imaging in detecting remnant LCIS lesions after initial excision. Methods: Between 2011 and 2015, 29 patients with LCIS who underwent initial excision were enrolled. Breast ultrasonography and breast MR imaging was conducted after initial excision. Imaging findings were compared with pathologic results. Results: There were nine (31.0%) cases with positive margins after initial excision; they were LCIS (n=8) and atypical lobular hyperplasia (n=1). Residual lesions were identified in 12 cases; they were invasive lobular carcinoma (n=1; 3.4%), LCIS (n=9; 31.0%), atypical lobular hyperplasia (n=1; 3.4%), and papillary carcinoma in situ (n=1; 3.4%). Prior to the second operation, these lesions could be detected in seven cases using ultrasonography (sensitivity, 53.3%; specificity, 100%) and in 10 cases using breast MR imaging (sensitivity, 83.3%; specificity, 100%). Conclusions: Breast MR imaging showed higher sensitivity than breast ultrasonography in detecting remnant LCIS lesions. If a suspicious lesion was found using breast MR imaging, a second operation should be considered because of the possibility of multifocality, even if LCIS was confirmed at the initial operation. Keywords: breast, carcinoma, lobular, M