Therapeutic mammaplasty is a safe and effective alternative to mastectomy with or without immediate breast reconstruction.

BACKGROUND: Therapeutic mammaplasty (TM) may be an alternative to mastectomy, but few well designed studies have evaluated the success of this approach or compared the short-term outcomes of TM with mastectomy with or without immediate breast reconstruction (IBR). Data from the national iBRA-2 and TeaM studies were combined to compare the safety and short-term outcomes of TM and mastectomy with or without IBR. METHODS: The subgroup of patients in the TeaM study who underwent TM to avoid mastectomy were identified, and data on demographics, complications, oncology and adjuvant treatment were compared with those of patients undergoing mastectomy with or without IBR in the iBRA-2 study. The primary outcome was the percentage of successful breast-conserving procedures in the TM group. Secondary outcomes included postoperative complications and time to adjuvant therapy. RESULTS: A total of 2916 patients (TM 376; mastectomy 1532; mastectomy and IBR 1008) were included in the analysis. Patients undergoing TM were more likely to be obese and to have undergone bilateral surgery than those having IBR. However, patients undergoing mastectomy with or without IBR were more likely to experience complications than the TM group (TM: 79, 21·0 per cent; mastectomy: 570, 37·2 per cent; mastectomy and IBR: 359, 35·6 per cent; P < 0·001). Breast conservation was possible in 87·0 per cent of patients who had TM, and TM did not delay adjuvant treatment. CONCLUSION: TM may allow high-risk patients who would not be candidates for IBR to avoid mastectomy safely. Further work is needed to explore the comparative patient-reported and cosmetic outcomes of the different approaches, and to establish long-term oncological safety.

ANTECEDENTES: La mamoplastia terapéutica (therapeutic mammaplasty, TM) puede ser una alternativa a la mastectomía, pero hay pocos estudios bien diseñados que hayan evaluado el éxito de esta estrategia o hayan comparado los resultados a corto plazo de la TM con la mastectomía con o sin (+/-) reconstrucción mamaria inmediata (immediate breast reconstruction, IBR). Para comparar la seguridad y los resultados a corto plazo de la TM y la mastectomía +/- IBR se combinaron los datos de los estudios nacionales iBRA-2 y TeaM. MÉTODOS: En el estudio TeaM se identificó el subgrupo de pacientes al que se realizó una TM para evitar la mastectomía y se compararon los datos demográficos, las complicaciones, los resultados oncológicos y el tratamiento adyuvante con las pacientes sometidas a mastectomía +/- IBR del estudio iBRA-2. La variable principal fue el porcentaje de éxito de la cirugía conservadora de mama en el grupo TM. Las variables secundarias fueron las complicaciones postoperatorias y el intervalo de tiempo hasta el inicio del tratamiento adyuvante. RESULTADOS: Se incluyeron en el análisis 2.916 pacientes (TM n = 376; mastectomía n = 1.532; IBR n = 1.008). La TM era más frecuente en pacientes obesas o en las sometidas a cirugía bilateral en comparación con las pacientes con IBR. Sin embargo, las pacientes sometidas a una mastectomía +/- IBR tenían más probabilidades de desarrollar complicaciones que las del grupo TM (TM n = 79, 21,0%; mastectomía n = 570, 37,2%; mastectomía y IBR n = 359, 35,6%; P < 0,001). La conservación de la mama fue posible en el 87% de las pacientes con TM y el procedimiento no retrasó el inicio del tratamiento adyuvante. CONCLUSIÓN: La TM puede permitir que pacientes de alto riesgo que no serían candidatas a IBR eviten la mastectomía de una forma segura. Se necesitan más trabajos para comparar los resultados percibidos por las pacientes y los estéticos de las diferentes estrategias terapéuticas y establecer la seguridad oncológica a largo plazo.

Current practice and short-term outcomes of therapeutic mammaplasty in the international TeaM multicentre prospective cohort study.

BACKGROUND: Therapeutic mammaplasty, which combines breast reduction and mastopexy techniques with tumour excision, may extend the boundaries of breast-conserving surgery and improve outcomes for patients, but current practice is unknown and high-quality outcome data are lacking. This prospective multicentre cohort study aimed to explore the practice and short-term outcomes of the technique. METHODS: Consecutive patients undergoing therapeutic mammaplasty at participating centres between 1 September 2016 and 30 June 2017 were recruited to the study. Demographic, preoperative, operative, oncological and complication data were collected. The primary outcome was unplanned reoperation for complications within 30 days of surgery. Secondary outcomes included re-excision rates and time to adjuvant therapy. RESULTS: Overall, 880 patients underwent 899 therapeutic mammaplasty procedures at 50 centres. The most common indications were avoidance of poor cosmetic outcomes associated with standard breast-conserving surgery (702 procedures, 78·1 per cent) or avoidance of mastectomy (379, 42·2 per cent). Wise-pattern skin incisions were the most common (429 of 899, 47·7 per cent), but a range of incisions and nipple-areola pedicles were used. Immediate contralateral symmetrization was performed in one-third of cases (284 of 880, 32·3 per cent). In total, 205 patients (23·3 per cent) developed a complication, but only 25 (2·8 per cent) required reoperation. Median postoperative lesion size was 24·5 (i.q.r. 16-38) mm. Incomplete excision was seen in 132 procedures (14·7 per cent), but completion mastectomy was required for only 51 lesions (5·7 per cent). Median time to adjuvant therapy was 54 (i.q.r. 42-66) days. CONCLUSION: Therapeutic mammaplasty is a safe and effective alternative to mastectomy or standard breast-conserving surgery. Further work is required to explore the impact of the technique on quality of life, and to establish cost-effectiveness.

Oncoplastic and reconstructive breast surgery in the elderly.

BACKGROUND: The recommendations of the UK All Party Parliamentary Group on Breast Cancer (2013) have been endorsed recently by the UK Association of Breast Surgeons and are in line with the 2007 Cancer Reform Strategy, which states that treatment in older British women should be equivalent to that in younger patients unless precluded by co-morbidity or patient choice. Oncoplastic and reconstructive techniques are increasingly available to women with breast cancer. A review of the literature was carried out to investigate use of these techniques in older patients. METHODS: A MEDLINE search was conducted to identify studies relating to oncoplastic and reconstructive surgery in the elderly. RESULTS AND CONCLUSION: Nine studies were identified and included in the review. Older patients undergoing reconstruction, particularly autologous reconstruction, have outcomes that are at least as good as those achieved in younger patients, yet are far less likely to be offered these techniques. Issues influencing oncoplastic and reconstructive surgery in the elderly include: lack of standard pathways of care, concerns regarding higher operative risk, lack of evidence regarding outcomes, preconceptions regarding body image and lack of engagement with the decision-making process. A minority of older women are likely to accept reconstruction, but those who do are pleased with the results and experience good quality of life. There is now a range of safe oncoplastic and reconstructive options that could be considered as an alternative to standard mastectomy or wide local excision in older patients.

Qualitative mammographic findings and outcomes of surveillance mammography after partial breast reconstruction with an autologous flap.

BACKGROUND: This study describes the qualitative mammographic features after partial breast reconstruction with an autologous flap, and evaluates the diagnostic accuracy and recall rates of surveillance mammography after volume replacement in breast conserving surgery. METHODS: Patients who had autologous partial breast reconstruction (N = 102) after breast-conserving surgery using either the myocutaneous latissimus dorsi mini-flap (N = 39) or fasciocutaneous chest wall perforator flap (N = 63) were reviewed. Mammograms done at one-year post surgery were analysed for characteristic qualitative features. All surveillance mammograms, diagnostic imaging and medical records were retrospectively reviewed. RESULTS: Mammograms of partially reconstructed breasts had distinctive features that correlated well with the surgical procedures. Median follow-up was 3 years, range 0-11 years. Of 295 surveillance mammograms, six (2%) resulted in a recall for further imaging and 3 (1%) proceeded to needle biopsy. Diagnostic imaging was performed for 13 (13/102, 12.7%) patients with symptoms, and only one (1/102, 1%) required a diagnostic biopsy. CONCLUSIONS: A conserved breast with an autologous flap within has characteristic mammographic features that differ from those after standard breast conserving surgery. Surveillance mammography after partial breast reconstruction is accurate, and recall/biopsy rates are low. Diagnostic breast ultrasound examination is effective evaluation for the symptomatic patient.

Prognostic and biological significance of proliferation and HER2 expression in the luminal class of breast cancer.

The definition of Luminal-B subclass of breast cancer (BC) varies in literature. In this study, we have compared the proliferation status; assessed using KI67 labeling index (KI67-LI), and HER2-expression in estrogen receptor positive (ER+) BC to assess their impact on the biological and clinical characteristics of luminal-BC. 1547 (73.8 %) well-characterized clinically annotated stage I-III ER + BC were assessed for expression of KI67, HER2 (ASCO guidelines), and a large panel of relevant biomarkers (no = 37). 46.3 % of the cases show high KI67-LI (>13 %) and 8.4 % show HER2+ and both markers are positively associated with younger age, higher tumor grade and poorer outcome. High KI67-LI and HER2+ are associated with upregulation of ER-coactivators and proliferation-related markers and with downregulation of good prognostic markers. High KI67-LI is associated with larger size, advanced stage, and lymphovascular invasion (LVI) and with downregulation of luminal-enriched and DNA-damage repair markers. In contrast, HER2+ is associated with upregulation of ER-regulated proteins and E-cadherin. When analysis is restricted to high KI67-LI subgroup, HER2+ shows an association with upregulation of differentiation-associated proteins and E-cadherin. Conversely, within HER2+ class, high KI67-LI maintains its association with downregulation of differentiation-associated/luminal-enriched proteins. Outcome analyses indicate that both markers are independently associated with shorter survival but HER2+ is associated with a worse outcome. Although both are associated with high proliferation and poor prognosis within ER + BC, HER2+ is less frequent than high KI67-LI. Unlike KI67, HER2 seems to independently drive the aggressive behavior of ER+ tumors without downregulation of luminal proteins.

Therapeutic mammaplasty.

Therapeutic mammaplasty is a term for the oncoplastic application of breast reduction and mastopexy techniques to treat selected breast tumours by breast conserving surgery (BCS). It has the potential to increase the indications for BCS as well as achieve more acceptable aesthetic results from it in suitable women. Now an established technique in the range of oncoplastic options for women with breast cancer, it finds common application and is associated with good oncological and quality of life outcomes.

Identification of key clinical phenotypes of breast cancer using a reduced panel of protein biomarkers.

BACKGROUND: Breast cancer is a heterogeneous disease characterised by complex molecular alterations underlying the varied behaviour and response to therapy. However, translation of cancer genetic profiling for use in routine clinical practice remains elusive or prohibitively expensive. As an alternative, immunohistochemical analysis applied to routinely processed tissue samples could be used to identify distinct biological classes of breast cancer. METHODS: In this study, 1073 archival breast tumours previously assessed for 25 key breast cancer biomarkers using immunohistochemistry and classified using clustering algorithms were further refined using naïve Bayes classification performance. Criteria for class membership were defined using the expression of a reduced panel of 10 proteins able to identify key molecular classes. We examined the association between these breast cancer classes with clinicopathological factors and patient outcome. RESULTS: We confirm patient classification similar to established genotypic biological classes of breast cancer in addition to novel sub-divisions of luminal and basal tumours. Correlations between classes and clinicopathological parameters were in line with expectations and showed highly significant association with patient outcome. Furthermore, our novel biological class stratification provides additional prognostic information to the Nottingham Prognostic Index. CONCLUSION: This study confirms that distinct molecular phenotypes of breast cancer can be identified using robust and routinely available techniques and both the luminal and basal breast cancer phenotypes are heterogeneous and contain distinct subgroups.

Calpain system protein expression in basal-like and triple-negative invasive breast cancer.

BACKGROUND: Basal-like and triple-negative breast tumours encompass an important clinical subgroup and biomarkers that can prognostically stratify these patients are required. MATERIALS AND METHODS: We investigated two breast cancer tissue microarrays for the expression of calpain-1, calpain-2 and calpastatin using immunohistochemistry. The first microarray was comprised of invasive tumours from 1371 unselected patients, and the verification microarray was comprised of invasive tumours from 387 oestrogen receptor (ER)-negative patients. RESULTS: The calpain system contains a number of proteases and an endogenous inhibitor, calpastatin. Calpain activity is implicated in important cellular processes including cytoskeletal remodelling, apoptosis and survival. Our results show that the expression of calpastatin and calpain-1 are significantly associated with various clinicopathological criteria including tumour grade and ER expression. High expression of calpain-2 in basal-like or triple-negative disease was associated with adverse breast cancer-specific survival (P = 0.003 and <0.001, respectively) and was verified in an independent cohort of patients. Interestingly, those patients with basal-like or triple-negative disease with a low level of calpain-2 expression had similar breast cancer-specific survival to non-basal- or receptor- (oestrogen, progesterone or human epidermal growth factor receptor 2 (HER2)) positive disease. CONCLUSIONS: Expression of the large catalytic subunit of m-calpain (calpain-2) is significantly associated with clinical outcome of patients with triple-negative and basal-like disease.

The prognostic significance of B lymphocytes in invasive carcinoma of the breast.

Although the favourable role of T lymphocyte populations in different tumour types is established, that of B cells is still a matter of debate and needs further clarification. The presence of tumour-infiltrating B cells may represent an antibody response against breast tumour antigens. We used immunohistochemistry to investigate the density and localisation of B lymphocytes infiltrating 1470 breast tumours and to identify any prognostic significance and relationship to various clinicopathological factors. Higher numbers of CD20(+) cells were found in the stroma away from the carcinoma (mean 12 cells) compared with either intratumoural or adjacent stromal compartments (mean 1 cell). The majority of tumours showed a diffuse pattern of B cells rather than aggregates. There was a positive correlation between higher numbers of total CD20(+) B cells and higher tumour grade (r (s) = 0.20, P < 0.001), ER and PgR negativity (P < 0.001), and basal phenotype (P < 0.001) subclass. In univariate survival analysis, higher total number of infiltrating CD20(+) cells, irrespective of location, was associated with significantly better BCSS (P = 0.037) and longer DFI (P = 0.001). In multivariate analysis, total CD20(+) B cell count (HR = 0.75, 95% CI = 0.58-0.96 for BCSS and HR = 0.72, 95% CI = 0.58-0.89, for DFI), tumour size, nodal stage, grade, vascular invasion, HER-2 status, and total CD8(+) T cell count were independently associated with outcome. This suggests that humoral immunity, in addition to the cell mediated immunity, may be important in breast cancer. This should be considered in breast cancer immunotherapy and vaccine strategies.

The proteins FABP7 and OATP2 are associated with the basal phenotype and patient outcome in human breast cancer.

The basal-like or basal phenotype (BP) class of breast cancers have recently attracted attention as a poor prognostic form of breast cancer. However, BP appears to encompass biologically and clinically heterogeneous tumours, resulting in a lack of consensus definition of BP. We analysed 48,000 gene transcripts in 132 invasive breast carcinomas to identify two novel genes (OATP2 and FABP7) significantly associated with BP [defined by cytokeratin (CK)5/6 and/or CK14 positivity]. Using a series of invasive breast carcinoma cases (n = 899), prepared as tissue microarrays, we assessed OATP2 and FABP7 protein expression using immunohistochemistry to investigate associations with clinicopathological variables, patients' outcome and ability to refine BP classification. A total of 7.9 and 15.6% cases were OATP2 and FABP7 positive, respectively. OATP2 was associated with tumours of high histological grade (p < 0.01), ER and PgR negativity (p < 0.01) and shorter breast cancer-specific survival (p = 0.04). FABP7 expression was associated with lower lymph node stage (p < 0.01), ER and PgR negativity (p < 0.01). BP tumours which were FABP7 positive had a significantly longer BCSS (p = 0.05) and disease-free survival (p = 0.01) compared with FABP7 negative basal tumours (p < 0.01). OATP2 positive tumours were associated with adverse survival and increased risk of early recurrence. This study confirms the biological and clinical heterogeneity of the BP in breast cancer. We have identified a novel subgroup of basal tumours showing FABP7 expression that have significantly better clinical outcome. Further studies analysing the role of FABP7 are therefore warranted.

Incidence of intramammary nodes in completion mastectomy specimens after axillary node sampling: implications for breast conserving surgery.

BACKGROUND: Axillary node sampling (ANS) is widely used in conjunction with breast conserving surgery in the treatment of primary breast cancers in the UK. Some evidence suggests that axillary staging techniques can miss intramammary nodes contained within the axillary tail of the breast. This study aims to assess the incidence of such nodes in completion mastectomy specimens in women who have had previous breast conserving surgery and ANS. METHODS: One hundred and fifty-seven completion mastectomy specimens were obtained from women who had previous breast conserving surgery and ANS, at the Nottingham Breast Institute over a 3-year period. The pathology samples underwent detailed histological examination to identify lymph nodes, and determine their disease status. RESULTS: Seventy-six (48%) of completion mastectomy specimens contained intramammary lymph nodes. Fifteen patients were upstaged (lymph node stage) because of the histological findings at completion mastectomy. One patient from the study population received additional systemic treatment, as a result of the upstaging. CONCLUSION: The incidence of intramammary nodes in this series correlates with previous data. This study shows that in breast cancer patients who undergo ANS, intramammary nodes, if present and more so positive, are unlikely to change systemic treatment decisions, but may increase the number of patients needing radiotherapy and or further axillary dissection.

Survival of invasive breast cancer according to the Nottingham Prognostic Index in cases diagnosed in 1990-1999.

UNLABELLED: The Nottingham Prognostic Index (NPI) is a well established and widely used method of predicting survival of operable primary breast cancer. AIMS: Primary: To present the updated survival figures for each NPI Group. Secondary: From the observations to suggest reasons for the reported fall in mortality from breast cancer. METHODS: The NPI is compiled from grade, size and lymph node status of the primary tumour. Consecutive cases diagnosed and treated at Nottingham City Hospital in 1980-1986 (n=892) and 1990-1999 (n=2,238) are compared. Changes in protocols towards earlier diagnosis and better case management were made in the late 1980s between the two data sets. RESULTS: Case survival (Breast Cancer Specific) at 10 years has improved overall from 55% to 77%. Within all Prognostic groups there are high relative and absolute risk reductions. The distribution of cases to Prognostic groups shows only a small increase in the numbers in better groups. CONCLUSION: The updated survival figures overall and for each Prognostic group for the NPI are presented.

Prognostic value of lymphovascular invasion in women with lymph node negative invasive breast carcinoma.

This study aimed to test the hypothesis that lymphovascular invasion adds prognostic information to histological grade and tumour size in node-negative invasive carcinoma of the breast. Lymphovascular invasion was assessed in haematoxylin and eosin tumour sections from 2760 patients with node-negative invasive breast carcinoma treated with definitive surgery. Patients were divided into two groups: 990 in the no adjuvant therapy series (diagnosed in 1974-1988) with median follow-up of 13 years; and 1765 in the selective adjuvant therapy series (1988-2000) with median follow-up of 6.8 years. Lymphovascular invasion was identified in 19% of tumours and was associated with larger tumour size, higher histological grade and younger age. Overall, survival was associated on multivariate analysis with lymphovascular invasion, histological grade and tumour size in both patient series, and with histological type in the no adjuvant therapy series. In conclusion, lymphovascular invasion is an independent prognostic factor in node-negative breast cancer and should be considered in decisions about adjuvant treatment in this group of women.

Accuracy of mammography in predicting histological extent of ductal carcinoma in situ (DCIS).

UNLABELLED: Accuracy of mammography in predicting pathological extent of ductal carcinoma in situ (DCIS). BACKGROUND AND AIMS: Mammographic extent is the main determinant for offering wide local excision (WLE) for DCIS. It is recognized that this is not always accurate. Patients who prove to have larger lesions than predicted require further surgery. The aim of this study was to define the degree of variance between mammographic (MMG) and pathological (path) measurements of DCIS and to analyse the factors predicting a significant discrepancy. METHODS: The pathological and mammographic data for 174 cases of DCIS were reviewed. RESULTS: The mammographic size was bigger than the histological size in 97 (55.7%) and there was >10mm difference in 18 (10.3%) cases. The histological size was bigger than the mammographic size in 69 (39.7%) cases and >10mm difference was found in 30 (17.2%) cases. There was a significant relationship between larger MMG size, MMG size measured in two dimensions (MMG bi-dimensional product) and MMG-path size discrepancy (p<0.01). In addition, the larger the size discrepancy, the greater the chance of requiring more than one therapeutic procedure (p<0.01). There was no significant correlation between age, histological grade, mammographic density and shortest distance from nipple with degree of mammographic-pathological size discrepancy.

EMS1 gene expression in primary breast cancer: relationship to cyclin D1 and oestrogen receptor expression and patient survival.

The EMS1 and CCND1 genes at chromosome 11q13 are amplified in about 15% of primary breast cancers but appear to confer different phenotypes in ER positive and ER negative tumours. Since there are no published data on EMS1 expression in large series of breast cancers we examined the relationship of EMS1 expression with EMS1 gene copy number and expression of mRNAs for cyclin D1 and ER. In a subset of 129 patients, where matched tumour RNA and DNA was available, EMS1 mRNA overexpression was associated predominantly with gene amplification (P = 0.0061), whereas cyclin D1 mRNA overexpression was not (P = 0.3142). In a more extensive series of 351 breast cancers, there was no correlation between cyclin D1 and EMS1 expression in the EMS1 and cyclin D1 overexpressors (P = 0.3503). Although an association between EMS1 mRNA expression and ER positivity was evident (P = 0.0232), when the samples were divided into quartiles of EMS1 or cyclin D1 mRNA expression, the increase in the proportion of ER positive tumours in the ascending EMS1 mRNA quartiles was not statistically significant (P = 0.0951). In marked contrast there was a significant stepwise increase in ER positivity in ascending quartiles of cyclin D1 mRNA (P = 0.030). A potential explanation for this difference was provided by the observation that in ER positive breast cancer cells oestradiol treatment resulted in increased cyclin D1 gene expression but was without effect on EMS1. The relationship between EMS1 expression and clinical outcome was examined in a subset of 234 patients with median follow-up of 74 months. High EMS1 expression was associated with age > 50 years (P = 0.0001), postmenopausal status (P = 0.0008), lymph node negativity (P = 0.019) and an apparent trend for worse prognosis in the ER negative subgroup. These data demonstrate that overexpression of EMS1 mRNA is largely due to EMS1 gene amplification, is independent of cyclin D1 and ER expression and, in contrast to cyclin D1, is not regulated by oestrogen. Independent overexpression of these genes may confer different phenotypes and disease outcomes in breast cancer as has been inferred from recent studies of EMS1 and CCND1 gene amplification.

Oncological and cosmetic outcomes of oncoplastic breast conserving surgery.

BACKGROUND: Breast-conserving surgery and radiotherapy is firmly established as a good and safe option for most women with early breast cancer. The important outcome measures of breast conservation are survival, local recurrence, cosmesis and patient satisfaction. Partial breast reconstructive techniques may improve cosmesis and patient satisfaction without compromising the oncological outcomes. METHODS: A search of the Medline and Pubmed databases of studies on breast conserving surgery where partial breast reconstructive techniques were employed. The keywords used were breast conserving surgery, oncoplastic breast surgery, partial breast reconstruction and reduction mammoplasty. The oncological and cosmetic outcomes of these studies were analysed. RESULTS: Studies on partial breast reconstructive techniques often lack oncological outcomes and long-term results are not available. On intermediate follow-up (up to 4.5 years) local recurrence rates vary from 0 to 1.8% per year. Cosmetic failure rates vary from 0 to 18%. To date, detailed studies are small and outcome measures vary. CONCLUSIONS: Breast surgeons should be aware of the range of surgical techniques that may enhance the aesthetic results of breast-conserving surgery as well as expand the indications for its use. There is a need for routine assessment of oncological and cosmetic outcomes and long-term results of partial breast reconstructive techniques in relation to these outcomes are awaited.

INK4a gene expression and methylation in primary breast cancer: overexpression of p16INK4a messenger RNA is a marker of poor prognosis.

Frequent deletions or mutations of the INK4 gene, which encodes the cyclin-dependent kinase 4 inhibitor p16INK4a, have been documented in various human cancers, but little is known about the role of this tumor suppressor gene in primary breast cancer. We examined p16INK4a mRNA expression and its relationship with cyclin D1 and estrogen receptor (ER) expression in 314 primary breast cancers using Northern blots probed with a p16 exon 1alpha-specific cDNA. Tumor samples overexpressing p16INK4a were predominantly ER negative with low levels of cyclin D1. Cyclin D1 and ER mRNA levels in the high p16INK4a expressers were significantly lower than those in the remainder of the population (P = 0.0001). Furthermore, the mean p16INK4a mRNA level in the ER-negative tumors was significantly higher than that in the ER-positive group (P = 0.0001). Because the INK4 gene is frequently inactivated by de novo methylation, we investigated the frequency of INK4a exon 1alpha methylation in a subset of 120 primary breast cancers using methylation-specific PCR; 24 of these were methylated. These findings indicate that high expression of p16INK4a and reduced expression due to de novo INK4a methylation are frequent events in primary breast cancer. In a subset of 217 patients for whom detailed clinical data were available, high p16INK4a mRNA expression was associated with high tumor grade (P = 0.006), > or = 4 axillary lymph node involvement (P = 0.004), ER negativity (P = 0.0001), and increased risk of relapse (P = 0.006). The significant negative correlation between p16INK4a and ER gene expression raises issues regarding their functional interrelationships and whether high p16INK4a expression may be associated with a lack of hormone responsiveness in breast cancer.

Germ line mutations associated with breast cancer susceptibility.

Laboratory-based research in germ line mutations associated with breast cancer susceptibility is rapidly being integrated into clinical practice with profound implications. A Medline search was performed for all relevant articles published since 1990. Where appropriate, historical articles referenced in those identified were also reviewed. The results suggested that while mutations in the BRCA1 and BRCA2 genes are the most clinically relevant, much of the data on which clinical decisions are based must be interpreted with wide confidence intervals. Between 1 in 152 and 1 in 833 individuals carry such mutations. They account for less than 5% of all breast cancer, but up to 10% of cancers in those under the age of 40 years. Founder mutations are responsible for a larger proportion of breast cancer cases within certain inbred communities. Phenotypic expression and penetrance of different mutations is not currently predictable and estimates of penetrance are largely based on highly selected populations. BRCA1 mutations are more commonly associated with ovarian cancer than BRCA2 mutations. BRCA1 cancers tend to have more distinct pathological features and are usually oestrogen receptor (ER)-negative. To conclude, the evidence in this review suggests that caution should be exercised when translating scientific progress in breast cancer germ line genetics into clinical practice. Most of the available data are derived from studies on highly selected populations. The importance of other less penetrant, but more prevalent, germ line mutations may be realised in the future.

Size of invasive breast cancer and risk of local recurrence after breast-conservation therapy.

Risk of local recurrence is one important factor that determines a woman's suitability for breast-conservation therapy. With the evolution of oncoplastic surgery, tumours of a size that traditionally require mastectomy may be treated by breast conservation and partial breast reconstruction. This article reviews the evidence relating to tumour size as a risk factor for local recurrence to assess whether this change in practice is appropriate. A literature review through Medline and Pubmed was performed. All pathological studies analysing tumour size as a predictor of multifocality and all randomised trials and large case series of breast conservation including tumours larger than 2 cm were reviewed and critically interpreted. Pathological studies report consistent evidence that tumour size is not predictive of multifocality. Randomised trials and clinical series of breast conservation report conflicting evidence relating to tumour size as a risk factor for local recurrence, although most studies report no association. Evidence relating to cancers over 3 cm is limited. There is little evidence to justify the use of tumour size alone as an exclusion criterion for breast-conservation therapy. A registration study of patients with cancers larger than 3 cm treated by breast conservation with or without partial breast reconstruction is proposed.