Purpose
To investigate the effect of lactation on breast cancer conspicuity on dynamic contrast-enhanced (DCE) MRI in comparison with diffusion tensor imaging (DTI) parametric maps.
Materials and ...methods
Eleven lactating patients with 16 biopsy-confirmed pregnancy-associated breast cancer (PABC) lesions were prospectively evaluated by DCE and DTI on a 1.5-T MRI for pre-treatment evaluation. Additionally, DCE datasets of 16 non-lactating age-matched breast cancer patients were retrospectively reviewed, as control. Contrast-to-noise ratio (CNR) comprising two regions of interests of the normal parenchyma was used to assess the differences in the tumor conspicuity on DCE subtraction images between lactating and non-lactating patients, as well as in comparison against DTI parametric maps of λ1, λ2, λ3, mean diffusivity (MD), fractional anisotropy (FA), and maximal anisotropy index, λ1–λ3.
Results
CNR values of breast cancer on DCE MRI among lactating patients were reduced by 62% and 58% (
p
< 0.001) in comparison with those in non-lactating patients, when taking into account the normal contralateral parenchyma and an area of marked background parenchymal enhancement (BPE), respectively. Among the lactating patients, DTI parameters of λ1, λ2, λ3, MD, and λ1–λ3 were significantly decreased, and FA was significantly increased in PABC, relative to the normal lactating parenchyma ROIs. When compared against DCE in the lactating cohort, the CNR on λ1, λ2, λ3, and MD was significantly superior, providing up to 138% more tumor conspicuity, on average.
Conclusion
Breast cancer conspicuity on DCE MRI is markedly reduced during lactation owing to the marked BPE. However, the additional application of DTI can improve the visualization and quantitative characterization of PABC, therefore possibly suggesting an additive value in the diagnostic workup of PABC.
Key Points
• Breast cancer conspicuity on DCE MRI has decreased by approximately 60% among lactating patients compared with non-lactating controls.
• DTI-derived diffusion coefficients and the anisotropy indices of PABC lesions were significantly different than those of the normal lactating fibroglandular tissue.
• Among lactating patients, breast cancer conspicuity on DTI-derived parametric maps provided up to 138% increase in contrast-to-noise ratio compared with DCE imaging.
Triple negative breast cancer (TNBC) is a heterogeneous group of tumors which lack estrogen receptor, progesterone receptor, and HER2 expression. Targeted therapies have limited success in treating ...TNBC, thus a strategy enabling effective targeted combinations is an unmet need. To tackle these challenges and discover individualized targeted combination therapies for TNBC, we integrated phosphoproteomic analysis of altered signaling networks with patient-specific signaling signature (PaSSS) analysis using an information-theoretic, thermodynamic-based approach. Using this method on a large number of TNBC patient-derived tumors (PDX), we were able to thoroughly characterize each PDX by computing a patient-specific set of unbalanced signaling processes and assigning a personalized therapy based on them. We discovered that each tumor has an average of two separate processes, and that, consistent with prior research, EGFR is a major core target in at least one of them in half of the tumors analyzed. However, anti-EGFR monotherapies were predicted to be ineffective, thus we developed personalized combination treatments based on PaSSS. These were predicted to induce anti-EGFR responses or to be used to develop an alternative therapy if EGFR was not present.In-vivo experimental validation of the predicted therapy showed that PaSSS predictions were more accurate than other therapies. Thus, we suggest that a detailed identification of molecular imbalances is necessary to tailor therapy for each TNBC. In summary, we propose a new strategy to design personalized therapy for TNBC using pY proteomics and PaSSS analysis. This method can be applied to different cancer types to improve response to the biomarker-based treatment.
Differentiation events contribute to phenotypic cellular heterogeneity within tumors and influence disease progression and response to therapy. Here, we dissect mechanisms controlling intratumoral ...heterogeneity within triple-negative basal-like breast cancers. Tumor cells expressing the cytokeratin K14 possess a differentiation state that is associated with that of normal luminal progenitors, and K14-negative cells are in a state closer to that of mature luminal cells. We show that cells can transition between these states through asymmetric divisions, which produce one K14+ and one K14− daughter cell, and that these asymmetric divisions contribute to the generation of cellular heterogeneity. We identified several regulators that control the proportion of K14+ cells in the population. EZH2 and Notch increase the numbers of K14+ cells and their rates of symmetric divisions, and FOXA1 has an opposing effect. Our findings demonstrate that asymmetric divisions generate differentiation transitions and heterogeneity, and identify pathways that control breast cancer cellular composition.
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•Triple-negative breast cancers display phenotypic cellular heterogeneity•Asymmetric divisions that produce K14+ and K14− daughter cells generate heterogeneity•K14+ cancer cells display a progenitor-associated tumorigenic phenotype•EZH2, Notch, KLF5, and NFIB increase K14+ cell numbers and FOXA1 decreases them
Granit et al. study the sources of phenotypic cellular heterogeneity in triple-negative breast cancers. They find that cancer cells can undergo asymmetric divisions that produce K14+ and K14− daughters and thereby generate heterogeneity. K14+ cells possess a progenitor-associated, tumorigenic phenotype, and the authors identify regulators that control their relative numbers.
Germline
pathogenic variant (PV) carriers have high lifetime risk of developing breast cancer and therefore subjected to intense lifetime screening. However, solid data on the effectiveness of ...high-risk screening of the
carrier population is limited.
Retrospectively, we analyzed 346 women diagnosed with breast tumors. Patients were divided according to the timing of
PVrecognition, before (BRCA-preDx awareness, N = 62) or after (BRCA-postDx awareness group, N = 284) cancer diagnosis.
Median follow-up times were 131.42 and 93.77 months in the BRCA-preDx awareness and BRCA-postDx awareness groups, respectively. In the BRCA-preDx awareness group, 78.7% of the patients had invasive tumors and 21.3% were diagnosed with pure ductal carcinoma
. In contrast, in the BRCA-postDx awareness group over 93% of women were diagnosed with invasive cancer and only 6.4% had
disease. The mode of tumor detection differed significantly between the groups: 71.9% in the BRCA-postDx awareness group and 26.2% in the BRCA-preDx awareness group were diagnosed after personally palpating a lump. Tumor size and nodal involvement were significantly more favorable in the BRCA-preDx awareness group. T stage was significantly lower in the BRCA-preDx awareness group: 54.84% at T1 and 20.96% at Tis. In the BRCA-postDx awareness group, only 37.54% were at T1 and 6.49% at Tis. The N stage was also significantly lower in the BRCA-preDx awareness group: 71% had no lymph node metastases, compared with 56.1% in the BRCA-postDx awareness group. Additionally, therapeutic procedures varied between the groups: BRCA-preDx awareness group patients underwent more breast conserving surgeries. Axillary lymph node dissection was done in 38% of women in the BRCA-postDx awareness group and in only 8.7% of the BRCA-preDx awareness group patients. Interestingly, improved survival was found among patients who underwent high-risk screening (hazard ratio=0.34).
High-risk screening might facilitate downstaging of detected breast tumor among
carrier population.
Background. There is not yet an agreed adjuvant treatment for melanoma patients with American Joint Committee on Cancer stages III B and C. We report administration of an autologous melanoma vaccine ...to prevent disease recurrence. Patients and Methods. 126 patients received eight doses of irradiated autologous melanoma cells conjugated to dinitrophenyl and mixed with BCG. Delayed type hypersensitivity (DTH) response to unmodified melanoma cells was determined on the vaccine days 5 and 8. Gene expression analysis was performed on 35 tumors from patients with good or poor survival. Results. Median overall survival was 88 months with a 5-year survival of 54%. Patients attaining a strong DTH response had a significantly better ( p = 0.0001 ) 5-year overall survival of 75% compared with 44% in patients without a strong response. Gene expression array linked a 50-gene signature to prognosis, including a cluster of four cancer testis antigens: CTAG2 (NY-ESO-2), MAGEA1, SSX1, and SSX4. Thirty-five patients, who received an autologous vaccine, followed by ipilimumab for progressive disease, had a significantly improved 3-year survival of 46% compared with 19% in nonvaccinated patients treated with ipilimumab alone ( p = 0.007 ). Conclusion. Improved survival in patients attaining a strong DTH and increased response rate with subsequent ipilimumab suggests that the autologous vaccine confers protective immunity.
Introduction
There has been increased interest in direct-to-implant (DTI) reconstruction in recent years. The goal of this study was to focus on the re-operation rate of DTI in comparison with ...two-stage tissue expander (TE) reconstruction.
Patients and Methods
In total, 165 consecutive patients (222 breasts) underwent skin sparing mastectomy and immediate implant-based reconstruction between January 2010 and December 2019. Patients were divided to TE procedure and DTI (42,180 breasts, respectively).
Data collected included demographics, operative details and oncological medical treatment, complications classified according to Clavien–Dindo, capsular contracture Baker 3-4 and re-operation due to complication or due to patient’s wish to improve aesthetic appearance.
Results
There were significantly more prophylactic mastectomies and BRCA gene mutation in the DTI breast reconstruction group, and more smokers and diabetic patients in the TE group.
No significant difference was found in the complication rates between the groups (DTI—26.1%, TE—40.5%). However, major complication and re-operation rate due to complications were significantly different ( DTI—16.7% and 10.6%, TE—26.2% and 31%, respectively,
p
= 0.035,
p
= 0.008). No significant differences were found in Clavien–Dindo stages between the groups except for Grade 3b.
Re-operation due to desire for aesthetic improvement was significantly higher in the TE group (DTI—38%. TE—69%,
p
=0.0003).
Conclusion
DTI immediate breast reconstruction can provide a good alternative to the traditional two-stage TE/implant operation. Both patients and surgeons can be reassured that the majority of the cases are one-stage reconstruction.
Level of Evidence IV
This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors
www.springer.com/00266.
Introduction
Oncoplastic breast surgery following breast conservation surgery (BCS) utilizes aesthetic breast reduction techniques, and these reconstructions entail either volume displacement or ...volume replacement depending on the size and location of the excised tumor. The anterior Intercostal flap (AICAP) for immediate reconstruction after BCS is scarcely described in the literature. In this study, we present our experience with the Anterior Intercoastal Artery Perforator flap in 16 patients with small breast sizes.
Patients and Methods
Sixteen patients underwent lumpectomy followed by immediate reconstruction with Anterior ICAP flap between 2019 and 2021 at Hadassah University Hospital. Median age was 49 (range 28–67). Breast cup size, lumpectomy to breast size ration, defect measurements and location are provided. Flap design and flap in‐setting was planned and executed according to the size and location of the defect determined at the time of surgery. Surgical technique is described. Diagram of proposed reconstruction according to defect location is proposed.
Results
Flap dimensions clinically matched the defect size or were slightly larger due to anticipated shrinkage of tissue post radiation with mean of 5.4 × 3.9 × 3.75 cm (range of 2.5–13 × 2–13.2 × 0.8–4.5 cm). Complications, namely one seroma and one mild infection, were seen in two patients. Median follow up was 3 months after completion of radiation. All reconstructions were satisfactory by both surgeon and patient at last post‐operative follow‐up visit.
Conclusion
The anterior ICAP flap is an important addition to the armamentarium of immediate reconstruction options after BCS, particularly in patients smaller size breast sizes.
DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes
. Current datasets ...typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells
. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell type are more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.
Objectives
Current surgical policy recommends comprehensive excision of tumorous calcifications in breast cancer patients following neoadjuvant chemotherapy (NAC) regardless of MRI outcomes, despite ...MRI defining tumor response superior to mammography. The current study examines MRI prediction of response in tumors with vs without calcifications, using post-NAC surgical pathology as the standard of reference.
Methods
Retrospective analysis of 114 NAC patients between 2011 and 2018 including demographics, mammography, 3 T-MRI, and pathology compared two sub-groups: without (
n
= 62) or with (
n
= 52) mammographic calcifications. In the calcification cohort, the mammographic extent of calcifications and MRI enhancement overlapped. MRI prediction of response to NAC was correlated with pathology. Two-tailed paired
T
and Fisher’s exact tests and Cohen’s kappa coefficient were applied for analysis.
Results
There was no significant difference between the two sub-groups regarding demographics. Tumors demonstrated equivalent features regarding size, lymph node involvement, and DCIS component. ER-negative/HER2-positive tumors more commonly exhibited calcifications (33%
n
= 17 calcified vs 13%
n
= 8 non-calcified;
p
< 0.05); triple negative pathology rarely calcified (6%
n
= 3 calcified vs 33%
n
= 20 non-calcified;
p
< 0.05). NME was more common with calcifications (62%
n
= 32 calcified vs 29%
n
= 18 non-calcified;
p
< 0.05) and mass enhancement without (90%
n
= 56 non-calcified vs 81%
n
= 42 calcified;
p
< 0.05). Both groups responded similarly to NAC (pCR = 37% non-calcified vs 38% calcified); response on MRI equally correlated with pathology (69% both subgroups;
p
= 0.988).
Conclusion
We propose utilizing post-NAC MRI findings rather than mammography in planning surgery, as MRI prediction is independent of the presence or absence of calcifications. Prospective studies to evaluate this approach are warranted.
Key Points
•
No difference was found in demographic, clinical, pathology, or imaging characteristics between patients with or without tumoral calcifications on mammography prior to neoadjuvant chemotherapy
.
•
Residual mammographic calcifications are inadequate predictors of residual invasive disease. MRI accurately recognized complete response and correctly correlated with post-treatment surgical pathology in 69% of patients, regardless of the presence or absence of mammographic calcifications
.
•
We propose utilizing post-NAC MRI findings rather than mammography in planning post-NAC surgery, as MRI prediction of response is independent of the presence or absence of calcifications
.
OBJECTIVESThe purpose of this study was to assess the incremental value of preoperative breast MRI over mammography and US in depicting the accurate extent of disease in invasive duct carcinoma (IDC) ...compared to invasive lobular carcinoma (ILC). PATIENTS AND METHODSRetrospective analysis of pre-operative mammography, US and MRI was performed in 239 patients with either IDC (n = 193) or ILC (n = 46). Images were evaluated for solitary, multifocal or multi centric disease and compared for concordance with postsurgical pathology. Discordance was documented as either overestimation or underestimation. Two tailed paired T and Fischer's exact tests were used for analysis. RESULTSMultifocality was present on pathology in 35% and 61% of patients with IDC and ILC (P < .05) and multicentricity in 23% and 41% respectively (P = .84). In ILC, MRI demonstrated better concordance with pathology compared to mammography and US (89%, 44%, 49% for multifocality P < .05 and 80.5%, 63%, 71% for multicentricity P = .3). For IDC, concordance with pathology for all modalities was similar (65%-76%). Among discordant cases, underestimation was significantly more common for mammography and US, while MRI more frequently overestimated disease extent. MRI very rarely overestimated multifocal disease in ILC (2%). CONCLUSIONMRI demonstrates an 80% to 90% concordance rate with pathology for ILC, superior to mammography and US. The addition of MRI in IDC patients may decrease underestimation of disease extent and potentially contribute to a reduction in post-operative residual disease.
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