Complication rates in patients with negative axillary nodes 10 years after local breast radiotherapy after either sentinel lymph node dissection or axillary clearance.

BACKGROUND: We assess complication rates in node negative breast cancer patients treated with breast radiotherapy (RT) only after sentinel lymph node dissection (SLND) or axillary lymph node dissection (ALND). MATERIALS AND METHODS: Between 1995 and 2001, 226 women with AJCC stage I-II breast cancer were treated with lumpectomy, either SLND or SLND+ALND, and had available toxicities in follow-up: 111/136 (82%) and 115/129 (89%) in SLND and ALND groups, respectively. RT targeted the breast to median dose of 48.2 Gy (range, 46.0 to 50.4 Gy) without axillary RT. Chi-square tests compared complication rates of 2 groups for axillary web syndrome (AWS), seroma, wound infection, decreased range of motion of the ipsilateral shoulder, paresthesia, and lymphedema. RESULTS: Median follow-up was 9.9 years (range, 8.3-15.3 y). Median number of nodes assessed was 2 (range, 1-5) in SLND and 18 (range, 7-36) in ALND (P < 0.0001). Acute complications occurred during the first 2 years and were AWS, seroma, and wound infection. Incidences of seroma 5/111 (4.5%) in SLND and 16/115 (13.9%) in ALND (P < 0.02, respectively) and wound infection 3/111 (2.7%) in SLND and 10/115 (8.7%) in ALND (P < 0.05, respectively) differed significantly. AWS was not statistically different between the groups. At 10 years, the only chronic complications decreased were range of motion of the shoulder 46/111 (41.4%) in SLND and 92/115 (80.0%) in ALND (P < 0.0001), paresthesia 12/111 (10.8%) in SLND and 39/115 (33.9%) in ALND (P < 0.0001), and lymphedema assessed by patients 10/111 (10.0%) in SLND and 39/115 (33.9%) in ALND (P < 0.0001). Chronic lymphedema, assessed by clinicians, occurred in 6/111 (5.4%) in SLND and 21/115 (18.3%) in ALND cohorts, respectively (P < 0.0001). CONCLUSIONS: Our mature findings support that in patients with negative axillary nodal status SLND and breast RT provide excellent long-term cure rates while avoiding morbidities associated with ALND or addition of axillary RT field.

A 10-year follow-up of treatment outcomes in patients with early stage breast cancer and clinically negative axillary nodes treated with tangential breast irradiation following sentinel lymph node dissection or axillary clearance.

We compare long-term outcomes in patients with node negative early stage breast cancer treated with breast radiotherapy (RT) without the axillary RT field after sentinel lymph node dissection (SLND) or axillary lymph node dissection (ALND). We hypothesize that though tangential RT was delivered to the breast tissue, it at least partially sterilized occult axillary nodal metastases thus providing low nodal failure rates. Between 1995 and 2001, 265 patients with AJCC stages I-II breast cancer were treated with lumpectomy and either SLND (cohort SLND) or SLND and ALND (cohort ALND). Median follow-up was 9.9 years (range 8.3-15.3 years). RT was administered to the whole breast to the median dose of 48.2 Gy (range 46.0-50.4 Gy) plus boost without axillary RT. Chi-square tests were employed in comparing outcomes of two groups for axillary and supraclavicular failure rates, ipsilateral in-breast tumor recurrence (IBTR), distant metastases (DM), and chronic complications. Progression-free survival (PFS) was compared using log-rank test. There were 136/265 (51%) and 129/265 (49%) patients in the SLND and ALND cohorts, respectively. The median number of axillary lymph nodes assessed was 2 (range 1-5) in cohort SLND and 18 (range 7-36) in cohort ALND (P < 0.0001). Incidence of AFR and SFR in both cohorts was 0%. The rates of IBTR and DM in both cohorts were not significantly different. Median PFS in the SLND cohort is 14.6 years and 10-year PFS is 88.2%. Median PFS in the ALND group is 15.0 years and 10-year PFS is 85.7%. At a 10-year follow-up chronic lymphedema occurred in 5/108 (4.6%) and 40/115 (34.8%) in cohorts SLND and ALND, respectively (P = 0.0001). This study provides mature evidence that patients with negative nodes, treated with tangential breast RT and SLND alone, experience low AFR or SFR. Our findings, while awaiting mature long-term data from NSABP B-32, support that in patients with negative axillary nodal status such treatment provides excellent long-term cure rates while avoiding morbidities associated with ALND or addition of axillary RT field.

Expression of BAG-1 protein correlates with aggressive behavior of prostate cancers.

BACKGROUND: Differences in tumor behavior, ranging from indolent to aggressive, create a need for novel prognostic biomarkers. BAG-1 is a co-chaperone that regulates the activity of Hsp70, Bcl-2, Raf-1, growth factor, and steroid receptors (e.g., the Androgen Receptor). METHODS: Using immunohistochemical method, we explored BAG-1 expression in prostate cancers and its association with clinicopathological parameters. RESULTS: BAG-1 immunostaining was elevated in prostate cancer compared to normal prostatic epithelium. Higher nuclear BAG-1 in hormone-refractory (n = 34) compared to localized untreated tumors (n = 58) (P < 0.0001) suggested that upregulation of the nuclear isoform may contribute to disease progression. In 64 early-stage patients (T2N0M0) treated with external-beam irradiation, cytosolic BAG-1 correlated with higher pretreatment levels of serum Prostate specific antigen (P = 0.04) and shorter time to disease progression (P = 0.00004). CONCLUSIONS: Increased cytosolic and nuclear BAG-1 expression may denote more aggressive variants of prostate cancer.

The fragile histidine triad/common chromosome fragile site 3B locus and repair-deficient cancers.

In various studies of sporadic breast cancers, 40-70% were strongly positive for fragile histidine triad (Fhit) protein expression, whereas only 18% of BRCA2 mutant breast cancers demonstrated strong Fhit expression, suggesting that the BRCA2 repair function may be necessary to retain intact fragile common chromosome fragile site 3B(FRA3B)/FHITloci. In the current study, 22 breast tumors with deleterious BRCA1 mutations were analyzed for Fhit expression by immunohistochemistry in a case-control matched pair analysis. Loss of Fhit expression was significantly more frequent in the BRCA1 cancers compared with sporadic breast tumors (9% Fhit positive versus 68% Fhit positive), suggesting that the BRCA1 pathway is also important in protecting the FRA3B/FHIT locus from damage. To investigate the relationship between repair gene deficiencies and induction of chromosome fragile sites in vitro, we have analyzed the frequency of aphidicolin induction of chromosome gaps and breaks in PMS2-, BRCA1-, MSH2-, MLH1-, FHIT-, and TP53-deficient cell lines. Each of the repair-deficient cell lines showed elevated expression of chromosome gaps and breaks, consistent with the proposal that proteins involved in mismatch and double-strand break repair are important in maintaining the integrity of common fragile regions. Correspondingly, genes at common fragile sites may sustain elevated levels of DNA damage in cells with deficient DNA repair proteins such as those mutated in several familial cancer syndromes.

Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status.

BACKGROUND: Management of early-stage breast cancer in young women with mutations in BRCA1 or BRCA2 remains controversial. This study assessed the long-term risks of ipsilateral and contralateral breast cancer in a cohort of young women who underwent breast-conserving surgery followed by radiotherapy. METHODS: Between 1975 and 1998, 290 women with breast cancer diagnosed at age 42 years or younger underwent lumpectomy followed by radiotherapy at our hospital. We recruited 127 of these women for complete sequencing of BRCA1 and BRCA2. Demographic, clinical, pathological, and outcome data were recorded. The primary endpoints were rates of ipsilateral and contralateral breast cancer, in relation to germline BRCA1/2 status. FINDINGS: 105 women were classified as having sporadic disease (94 with wild-type or known polymorphisms and 11 with variants of unclear significance) and 22 as having genetic predisposition (deleterious mutations in BRCA1 [15] or BRCA2 [seven]). At 12 years of follow-up, the genetic group had significantly higher rates of ipsilateral (49% vs 21%, p=0.007) and contralateral events (42% vs 9%, p=0.001) than the sporadic group. The majority of events were classified as second primary tumours. No patient in the genetic group had undergone oophorectomy or was taking prophylactic agents such as tamoxifen. INTERPRETATION: Patients with germline mutations in BRCA1 or BRCA2 have a high risk of developing late ipsilateral and contralateral second primary tumours. With breast-conserving therapy, chemoprophylaxis or other interventions to reduce the rate of second cancers may be valuable. Alternatively, bilateral mastectomy may be considered, to minimise the risk of second tumours in the breasts.