One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene.

BACKGROUND: Gene panel testing has become the norm for assessing breast cancer (BC) susceptibility, but actual cancer risks conferred by genes included in panels are not established. Contrarily, deciphering the missing hereditability on BC, through identification of novel candidates, remains a challenge. We aimed to investigate the mutation prevalence and spectra in a highly selected cohort of Greek patients with BC, questioning an extensive number of genes, implicated in cancer predisposition and DNA repair, while calculating gene-specific BC risks that can ultimately lead to important associations. METHODS: To further discern BC susceptibility, a comprehensive 94-cancer gene panel was implemented in a cohort of 1382 Greek patients with BC, highly selected for strong family history and/or very young age (<35 years) at diagnosis, followed by BC risk calculation, based on a case-control analysis. RESULTS: Herein, 31.5% of patients tested carried pathogenic variants (PVs) in 28 known, suspected or candidate BC predisposition genes. In total, 24.8% of the patients carried BRCA1/2 loss-of-function variants. An additional 6.7% carried PVs in additional genes, the vast majority of which can be offered meaningful clinical changes. Significant association to BC predisposition was observed for ATM, PALB2, TP53, RAD51C and CHEK2 PVs. Primarily, compared with controls, RAD51C PVs and CHEK2 damaging missense variants were associated with high (ORs 6.19 (Exome Aggregation Consortium (ExAC)) and 12.6 (Fabulous Ladies Over Seventy (FLOSSIES)), p<0.01) and moderate BC risk (ORs 3.79 (ExAC) and 5.9 (FLOSSIES), p<0.01), respectively. CONCLUSION: Studying a large and unique cohort of highly selected patients with BC, deriving from a population with founder effects, provides important insight on distinct associations, pivotal for patient management.

Characterization and prevalence of two novel CHEK2 large deletions in Greek breast cancer patients.

Germline CHEK2 mutations confer increased cancer risk, for breast and other types, which is variable depending on the specific mutation. Of these, Large Genomic Rearrangements (LGRs) have been rarely reported; to date only eight LGRs have been published with just the Czech founder mutation, the deletion of exons 9 and 10, being molecularly characterized and studied extensively. The present study aimed to molecularly define and determine the contribution of two rare, apparently novel CHEK2 LGRs, among Greek breast cancer patients. These specifically involve a ~6 kb in-frame deletion of exons 2 & 3 that removes CHEK2's FHA domain and a ~7.5 kb in-frame deletion of exon 6, which removes an α-helix of CHEK2's kinase domain. The latter was identified in 5 out of 2355 (0.22%) patients tested, while haplotype analysis revealed a common disease-associated haplotype, suggesting a single common ancestor and a Greek founder. Although in-frame, this LGR is predicted to be damaging by a yeast-based functional assay and structure-function predictions. The present study highlights the existence of rare, population-specific, genomic events in a known breast cancer predisposing gene, which can explain a proportion of hereditary breast cancer. Identification of such mutation carriers is rather important since appropriate clinical actionability will be inferred.

Imaging of the Reconstructed Breast.

The incidence of breast cancer and, therefore, the need for breast reconstruction are expected to increase. The many reconstructive options available and the changing aspects of the field make this a complex area of plastic surgery, requiring knowledge and expertise. Two major types of breast reconstruction can be distinguished: breast implants and autologous flaps. Both present advantages and disadvantages. Autologous fat grafting is also commonly used. MRI is the modality of choice for evaluating breast reconstruction. Knowledge of the type of reconstruction is preferable to provide the maximum amount of pertinent information and avoid false positives. Early complications include seroma, hematoma, and infection. Late complications depend on the type of reconstruction. Implant rupture and implant capsular contracture are frequently encountered. Depending on the implant type, specific MRI signs can be depicted. In the case of myocutaneous flap, fat necrosis, fibrosis, and vascular compromise represent the most common complications. Late cancer recurrence is much less common. Rarely reported late complications include breast-implant-associated large cell anaplastic lymphoma (BIA-ALCL) and, recently described and even rarer, breast-implant-associated squamous cell carcinoma (BIA-SCC). In this review article, the various types of breast reconstruction will be presented, with emphasis on pertinent imaging findings and complications.

CHEK2 Pathogenic Variants in Greek Breast Cancer Patients: Evidence for Strong Associations with Estrogen Receptor Positivity, Overuse of Risk-Reducing Procedures and Population Founder Effects.

CHEK2 germline pathogenic variants predispose to breast cancer and possibly to other malignancies, with their spectrum and frequency being variable among populations. Τhe majority of CHEK2-associated breast tumors are hormone receptor positive; however, relevant clinical outcomes are not well defined. Herein, we illustrate the histopathological characteristics and clinical outcomes of 52 Greek breast cancer patients who are CHEK2 carriers. Genetic analysis was performed by Sanger/massively parallel sequencing, followed by MLPA. Subsequent haplotype analysis investigated possible founder effects. Blood relatives were offered cascade testing. CHEK2 variant spectrum was characterized by variability, while influenced by founder effects. The majority of carriers, i.e., 60.8%, were diagnosed with breast cancer before the age of 45. Notably, 91.5% of breast tumors were hormone receptor positive. Hormone therapy and mastectomy at diagnosis seem to have a positive trend on overall survival, after a median follow-up of 9.5 years. Remarkably, 41.9% of patients underwent risk-reducing surgery, one third of which involved salpingo-oophorectomy. Nearly half of families responded to cascade testing. Our data highlight the need for guideline-adherent choices, based on the evidence that CHEK2 carriers are at moderate risk for breast cancer and no risk for ovarian cancer, while underscore the possible role of chemoprevention with tamoxifen.

Immediate breast reconstruction using biodimensional anatomical permanent expander implants: a prospective analysis of outcome and patient satisfaction.

Immediate breast reconstruction is offered to the majority of women requiring a mastectomy for cancer treatment. Improvements in implant technology have seen the evolution of shaped, fixed-volume implants and permanent expanders. The theoretical benefits of biodimensional anatomical expander implants include better reconstructed breast form, the potential for achieving this at a single procedure, and the avoidance of a contralateral procedure as a result of improved ipsilateral cosmesis. The aim of the present study was to assess outcome after immediate breast reconstruction using the McGhan 150 permanent expander implant. A total of 107 consecutive patients (129 breast reconstructions) were studied over a 30-month period; 49 patients (68 reconstructions) had submuscular implant placement alone, and 58 patients (61 reconstructions) had an implant in conjunction with a latissimus dorsi flap. The mean patient age was 47 years (range, 22 to 72 years) and the mean follow-up was 18 months (range, 6 to 40 months). Outcome was assessed in the following four ways: geometric measurements, evaluation of photographs by four independent observers, linear numerical analogue scale, and a quality-of-life questionnaire. Geometric measurements after surgery showed median differences that were highly consistent with good symmetry. Transverse breast width difference between breasts was 0.35 cm, vertical breast height difference was 0.8 cm, sternal notch-to-nipple distance difference was 0.6 cm, midclavicular line-to-nipple distance difference was 0.5 cm, nipple-to-inframammary crease distance difference was 0.5 cm, midline-to-nipple distance difference was 0 cm, and projection difference was 0 cm. Photographic assessment by four observers who evaluated shape, cleavage, symmetry, and overall outcome produced correlation values of 0.73 to 0.81. More than 75 percent of each of these parameters was scored as good or excellent. A numerical analogue scale (from 1 to 10) assessing overall result by the surgeon and patient revealed good (7 to 8) or excellent (9 to 10) scores in 83 and 82 percent of respondents, respectively. Quality-of-life data showed that 81 and 88 percent of women felt "a little" or "not at all" less feminine, respectively, and 88 percent were satisfied with the appearance of their breasts. A total of 88 percent of women would also choose the same reconstructive procedure if faced with the same cancer diagnosis. Complication rates were low; infections occurred in 6.2 percent of reconstructions, hematoma occurred in 1.6 percent, and implant loss occurred in 3.9 percent. Only 24 of 107 patients (22 percent) elected to have a synchronous contralateral breast adjustment, and four of 107 (4 percent) chose to have a subsequent procedure for symmetry. Biodimensional expander implants used in immediate breast reconstruction are associated with high levels of patient and surgeon satisfaction. Optimum breast form can be achieved during a single operation with a low incidence of complications.

Long-term quality-of-life assessment following one-stage immediate breast reconstruction using biodimensional expander implants: the patient's perspective.

BACKGROUND: Biodimensional devices may provide a superior breast form when an implant is considered for immediate breast reconstruction for breast cancer. The authors prospectively report patient perception of outcome using a permanent anatomical expander implant following a planned one-stage procedure. METHODS: The Quality of Life Questionnaire BR-23 was modified to measure body image perception, physical effects, cancer worry, and surgical choice. Responses were classified into four categories. A subset of patients completed the questionnaire 1 and 6 years after surgery. Data were compared using nonparametric analyses. RESULTS: One hundred ten patients were studied, with a mean follow-up of 63 months (range, 25 to 108 months); 46 patients had submuscular implant reconstruction and 64 had an implant-assisted latissimus dorsi flap. The mean patient age was 46 years (range, 20 to 76 years). There was no difference in patient perception of outcome between the two groups, although the latissimus dorsi group found it easier to fit into bras (p = 0.03, Mann-Whitney test). For patient perception of body image, the median score was within the most favorable category in four of six fields. Restricted arm movement and pain in the treated breast had resolved completely by 5 years after surgery. More than 80 percent of patients would choose the same surgical option if the cancer scenario presented itself again. CONCLUSIONS: A biodimensional permanent expander implant, when used appropriately, can achieve high levels of patient satisfaction. The authors' data provide long-term outcome measures with which to counsel patients about one-stage implant-assisted immediate breast reconstruction using an anatomical device.

Evaluation of outcome after immediate breast reconstruction: prospective comparison of four methods.

BACKGROUND: Little is known about the association among different methods to assess outcome following breast reconstruction. The aim of this study was to comprehensively compare four distinct methods of outcome evaluation following immediate breast reconstruction. METHODS: There were 102 women who were prospectively evaluated: 46 patients had submuscular implants, and 56 patients had implant-assisted latissimus dorsi breast reconstruction. The mean patient age at the time of operation was 46 years (range, 22 to 72 years), with a mean follow-up of 18 months (range, 12 to 24 months). All patients were evaluated using geometric measurements, photographs, linear analogue scores, and a quality-of-life questionnaire. The Wilcoxon signed rank test, Spearman's correlation, and factor analysis statistics were used. RESULTS: Transverse breast width, vertical breast height, sternal notch-nipple, midclavicular line-nipple, nipple-inframammary crease, midline-nipple, internipple, and intermammary measurements were reproducible and reliable. Median differences of absolute vertical and horizontal differences were less than 1 cm and were associated with high levels of patient satisfaction. Assessors asked to score photographs without being specifically requested to consider shape, cleavage, or symmetry would focus mainly on vertical and horizontal differences. There was a high correlation between surgeon and patient linear analogue scores. Quality-of-life questionnaires provide valuable information on body image, physical effects, and continued cancer worry. Factor analyses failed to identify components to compress data fields to obtain equivalent information from fewer questions. CONCLUSIONS: Evaluation of immediate breast reconstruction is complex. Cumbersome data collection has to be balanced against practical variables that individual units can collect to evaluate outcome for audit and research.