Gerald Gui

Nipple‐sparing mastectomy

Although effective local control is the primary goal of surgery for breast cancer, the long‐term aesthetic outcome is also important. Nipple‐sparing mastectomy aims to address this, but there is no consensus on its clinical application. Evidence relating to oncological safety, surgical technique and early data on aesthetic outcome was reviewed.

Early changes in apoptosis and proliferation following primary chemotherapy for breast cancer

Patients undergoing primary chemotherapy for invasive breast cancer consented to a core biopsy of the invasive breast primary pre- and 24 h postchemotherapy. The resulting tissue was analysed for apoptosis, Ki67, ER and HER-2 using immunohistochemical techniques. These data were then used to evaluate the relationship between these biological markers and response to chemotherapy and overall survival. Response rate to chemotherapy in this group was 86%, 16 patients (25%) achieved a clinical complete response and 41 (63%) a partial response. Prechemotherapy there was a significant correlation between Ki67 and apoptotic index (AI), r=0.6, (P<0.001). A significant rise in AI (P<0.001), and fall in Ki67 (P=0.002) was seen 24 h following chemotherapy. No relationship was seen between pretreatment AI and clinical response, but higher Ki67 and growth index (Ki67/AI ratio, GI) did correlate with clinical response (both r=0.31, P<0.025). No correlation was seen between the change in AI or Ki67 at 24 h and clinical response or survival. Significant changes in apoptosis and proliferation can be demonstrated 24 h following chemotherapy, but these changes do not relate to clinical response or outcome in this study. Pretreatment proliferation and GI are however predictive of response to chemotherapy in breast cancer.

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

&NA; 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 R 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. (Plast. Reconstr. Surg. 111: 125, 2003.)

Is Surgery Necessary After Complete Clinical Remission Following Neoadjuvant Chemotherapy for Early Breast Cancer

PURPOSE This retrospective analysis aimed to identify whether breast cancer patients receiving radiotherapy alone following a complete clinical remission (cCR) to neoadjuvant chemotherapy had a worse outcome than those treated with surgery. PATIENTS AND METHODS One hundred thirty-six patients who had achieved a cCR to neoadjuvant chemotherapy for early breast cancer were identified from a prospectively maintained database of 453 patients. Of these, 67 patients had undergone surgery as their primary locoregional therapy, and 69 patients had radiotherapy alone. Outcome was assessed in relation to local recurrence-free survival, disease-free survival, and overall survival. RESULTS Median follow-up was 63 months in the surgery group and 87 months in the no surgery group. Prognostic characteristics were well balanced between the two groups. For surgery and no surgery, respectively, there were no significant differences in disease-free survival or overall survival (5-year, 74% v 76%; 10-year, 60% v 70%, P =.9) between the two groups. There was a nonsignificant trend toward increased locoregional-only recurrence for the no surgery group (21% v 10% at 5 years; P =.09), but no long-term failures of local control. Patients in the no surgery group who also achieved an ultrasound complete remission had a 5-year local recurrence rate of only 8%. CONCLUSION In patients achieving a cCR to neoadjuvant chemotherapy, radiotherapy alone achieve survival rates as good as with surgery, but with higher local recurrence rates. Ultrasound may identify a low recurrence rate subgroup for assessing no surgery in a prospective trial.

The Intraductal Approach to Breast Cancer Biomarker Discovery

Established methods of breast cancer detection have well-described limitations, and new diagnostic techniques are evolving continually to improve diagnostic accuracy. The intraductal approach encompasses the modalities of nipple aspiration, ductal lavage, and duct endoscopy, and is a means of directly accessing the microenvironment of the breast and either sampling or visualizing this intraductal milieu. The aim of sampling this mammary microenvironment is to obtain samples from the physical surroundings of cells that are undergoing malignant transformation, thereby providing a new method of detection before the development of a clinically or radiologically discernible mass. A literature review was conducted to investigate the evolution of the intraductal approach and its particular application in the field of biomarker discovery, primarily using the intraductal technique of nipple aspiration, in combination with emerging protein profiling techniques.

Late Toxicity Is Not Increased in BRCA1/BRCA2 Mutation Carriers Undergoing Breast Radiotherapy in the United Kingdom

Purpose: To undertake the first substantial clinical study of breast radiotherapy toxicity in BRCA1 and BRCA2 mutation carriers in the United Kingdom. Experimental Design: Acute and late radiation effects were evaluated in a retrospective study of 55 BRCA1 and BRCA2 mutation carriers treated with radiotherapy for breast cancer at four centers between 1983 and 2002. Individual matching with controls who had sporadic breast cancer was undertaken for age at diagnosis, time since completion of radiation, and treatment variables. Detailed assessments were undertaken by one examiner. Median follow-up was 6.75 years for carriers and 7.75 years for controls. Rates of late events (rib fractures, lung fibrosis, necrosis of soft tissue/bone, and pericarditis) as well as LENT-SOMA scores and clinical photography scores of breast size, shape, and skin telangiectasia were the primary end points. Results: No increase in clinically significant late toxicity was seen in the mutation carriers. Conclusions: These data add substantial weight to the evidence that the outcomes in the treated breast from radiotherapy in women with BRCA1 or BRCA2 mutations are comparable with those in women with sporadic breast cancer.

The incidence of breast cancer from screening women according to predicted family history risk: does annual clinical examination add to mammography?

In breast cancer, mutations of predisposition genes such as BRCA-1/2 and other genes as yet uncharacterised are manifest in up to 10% of cases. Although the prior probability of the presence of a breast cancer predisposing gene can be calculated for individual women, there is no published evidence to justify predicted risk as a selection criteria for screening. This study aims to define which patient groups with a significant family history should be screened, and whether clinical examination is necessary in addition to mammography. The Claus model was used to predict breast cancer risk in women with a family history. Women were divided into two groups according to their predicted risk: group I consisted of women at standard risk (lifetime risk less than 1:6) and group II with moderate/high risk (lifetime risk greater than or equal to 1:6). Women were cancer-free at the point of entry, and screening consisted of annual clinical examination and mammography from the age of 35 years. This study consisted of 1500 women in group I and 1078 in group II. The period of observation was 5902.0 and 4327.8 women years, respectively. A total of 31 cancers were detected, 12 in group I and 19 in group II. The median age at diagnosis in group II was 45 years (range 26-66 years) compared with 54.5 years (range 38-63 years) in group I (P=0.03). The relative risk of developing breast cancer in group II was 2.6 (95% confidence interval (CI) 1.2-5.8). When compared with breast cancer incidence in the normal population, the standardised incidence ratio in group II was significantly higher at 2.8 (95% CI: 1.7-4.2). The standardised incidence ratio of women in group I was similar to that of the general population (1.1 (95% CI: 0.6-1.8)). A total of 26/31 (84%) cancers detected were palpable, of which 14 (54%) were not visible on mammography. Approximately one-third of all palpable cancers were detected at routine follow-up. Mammography correctly identified 17/31 cancers (55%), but 29% of these were not palpable. Family history screening programmes are effective and women should be selected for screening according to predicted risk. The younger age of diagnosis in group II justifies screening from an earlier age using both annual clinical examination and mammography.

Gene promoter hypermethylation in ductal lavage fluid from healthy BRCA gene mutation carriers and mutation-negative controls

IntroductionFemale germline BRCA gene mutation carriers are at increased risk for developing breast cancer. The purpose of our study was to establish whether healthy BRCA mutation carriers demonstrate an increased frequency of aberrant gene promoter hypermethylation in ductal lavage (DL) fluid, compared with predictive genetic test negative controls, that might serve as a surrogate marker of BRCA1/2 mutation status and/or breast cancer risk.MethodsThe pattern of CpG island hypermethylation within the promoter region of a panel of four genes (RAR-β, HIN-1, Twist and Cyclin D2) was assessed by methylation-specific polymerase chain reaction using free DNA extracted from DL fluid.ResultsFifty-one DL samples from 24 healthy women of known BRCA mutation status (7 BRCA1 mutation carriers, 12 BRCA2 mutation carriers and 5 controls) were available for methylation analysis. Eight of 19 (42.1%) BRCA mutation carriers were found to have at least one hypermethylated gene in the four-gene panel. Two BRCA mutation carriers, in whom aberrant methylation was found, also had duct epithelial cell atypia identified. No hypermethylation was found in DL samples from 5 negative controls(p = 0.13).ConclusionWe found substantial levels of aberrant methylation, with the use of a four-gene panel, in the fluid from the breasts of healthy BRCA mutation carriers compared with controls. Methylation analysis of free DNA in DL fluid may offer a useful surrogate marker for BRCA1/2 mutation status and/or breast cancer risk. Further studies are required for the evaluation of the specificity and predictive value of aberrant methylation in DL fluid for future breast cancer development in BRCA1/2 mutation carriers.

Nipple-sparing mastectomy in women with large or ptotic breasts

Nipple-sparing mastectomy has been shown to have equivalent oncological outcome to skin-sparing mastectomy in carefully selected patients and acceptable rates of nipple necrosis. Its role in risk-reducing mastectomy is established. However, it is widely considered that nipple-sparing mastectomy is only suitable for women with small and non-ptotic breasts. The reasons cited are that an excessive skin envelope may result in higher rates of nipple necrosis or in nipples that are poorly positioned on the reconstructed breast mound. A malpositioned, preserved nipple may result in a significant aesthetic compromise compared with a correctly positioned reconstructed nipple. Skin-reducing mastectomy utilising a Wise pattern approach has been described for women undergoing immediate implant reconstruction. It is most suitable for women with ptotic or large breasts who can accommodate a mastopexy or reduction and are willing to consider contralateral symmetrising surgery. We report a modification of the skin-reducing mastectomy to allow preservation of the nipple in women who would not otherwise be considered for this technique because of unsuitable breast shape.

Gene expression profiling after radiation-induced DNA damage is strongly predictive of BRCA1 mutation carrier status.

Purpose: The impact of the presence of a germ-line BRCA1 mutation on gene expression in normal breast fibroblasts after radiation-induced DNA damage has been investigated. Experimental Design: High-density cDNA microarray technology was used to identify differential responses to DNA damage in fibroblasts from nine heterozygous BRCA1 mutation carriers compared with five control samples without personal or family history of any cancer. Fibroblast cultures were irradiated, and their expression profile was compared using intensity ratios of the cDNA microarrays representing 5603 IMAGE clones. Results: Class comparison and class prediction analysis has shown that BRCA1 mutation carriers can be distinguished from controls with high probability (∼85%). Significance analysis of microarrays and the support vector machine classifier identified gene sets that discriminate the samples according to their mutation status. These include genes already known to interact with BRCA1 such as CDKN1B, ATR, and RAD51. Conclusions: The results of this initial study suggest that normal cells from heterozygous BRCA1 mutation carriers display a different gene expression profile from controls in response to DNA damage. Adaptations of this pilot result to other cell types could result in the development of a functional assay for BRCA1 mutation status.