Intraoperative high dose rate brachytherapy during breast-conserving surgery: A prospective pilot study.

PURPOSE: To evaluate feasibility, quality of life, toxicity, and cosmetic outcome for intraoperative breast cancer brachytherapy after breast-conserving surgery using high dose rate brachytherapy. METHODS: Fifty-two consecutive women, ⩾50 years old, diagnosed with a unifocal non-lobular breast cancer ⩽3 cm, N0, underwent breast-conserving surgery and sentinel node biopsy. Twenty-five women received intraoperative brachytherapy pre-pathology at primary surgery and the others post-pathology, during a second procedure. An applicator, connected to a high dose rate afterloader, was used. Two of the women were excluded due to metastases found per-operatively at a frozen section from the sentinel node. Quality of life was evaluated using two validated health questionnaires. Treatment toxicity was documented according to the LENT-SOMA scale by two oncologists. The cosmetic result was evaluated using the validated freely available software BCCT.core 2.0. RESULTS: The clinical procedure worked out well logistically. Seven women received supplementary external radiotherapy due to insufficient margins and, in one case, poor adaptation of the breast parenchyma to the applicator. No serious adverse effects from irradiation were registered. The results from the health questionnaires showed no major differences compared with reference groups from the Swedish population. Only two women were registered as having a "poor" cosmetic result while a majority of the women had a "good" outcome. CONCLUSIONS: This pilot study shows that intraoperative brachytherapy is a feasible procedure and encourages further trials evaluating its role in treatment of early breast cancer.

Influence of the subtype on local recurrence risk of breast cancer with or without radiation therapy.

PURPOSE: To investigate if intrinsic subtypes of breast cancer predict different risks of ipsilateral breast tumor recurrence (IBTR) following breast-conserving surgery (BCS) with and without postoperative radiation therapy. PATIENTS AND METHODS: We randomized 381 women with a unifocal T1N0M0 breast cancer to BCS alone (197 women) or BCS plus postoperative radiation therapy (XRT) (184 women). All available histopathological material was re-analyzed with modern immunohistochemical methods (223 women). After 20 years of complete follow-up we analyzed the risk of IBTR by intrinsic breast cancer subtypes (luminal A, luminal B/HER2-negative, luminal B/HER2-positive, HER2-positive and triple negative). We used Cox regression analyses to estimate hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: In a multivariate analysis the luminal B/HER2-negative subtype, compared with the luminal A subtype, was associated with a higher risk of IBTR overall (HR 3.04; 95% CI 1.38-6.71) and in both the XRT-group (HR 5.08 95% CI 1.31-19.7) and the non-XRT-group (HR 2.58 95%CI 1.07-6.20); (p for interaction = 0.37). The risk of IBTR in the XRT- and non-XRT group, stratified by intrinsic subtype, revealed an absolute risk difference at 20 years to the benefit of XRT of 14% (95% CI 1.0%-26%) for luminal A, 17% (95% CI -6.0% to 39%) for luminal B/HER2 negative and 22% (95% CI -7.0-51%) for the high-risk group. CONCLUSIONS: Among breast cancer patients treated with BCS, the luminal B/HER2-negative subtype predicts an about 3-fold higher risk for IBTR compared to other intrinsic subtypes independent of postoperative radiation therapy.

Omitting radiotherapy in women ≥ 65 years with low-risk early breast cancer after breast-conserving surgery and adjuvant endocrine therapy is safe.

PURPOSE: The aim of this study was to verify if radiotherapy (RT) safely can be omitted in older women treated for estrogen-receptor positive early breast cancer with breast-conserving surgery (BCS) and endocrine therapy (ET). PATIENTS AND METHODS: Eligibility criteria were: consecutive patients with age ≥65 years, BCS + sentinel node biopsy, clear margins, unifocal T1N0M0 breast cancer tumor, Elston-Ellis histological grade 1 or 2 and estrogen receptor-positive tumor. After informed consent, adjuvant ET for 5 years was prescribed. Primary endpoint was ipsilateral breast tumor recurrence (IBTR). Secondary endpoints were contralateral breast cancer and overall survival. RESULTS: Between 2006 and 2012, 603 women were included from 14 Swedish centers. Median age was 71.1 years (range 65-90). After a median follow-up of 68 months 16 IBTR (cumulative incidence at five-year follow-up; 1.2%, 95% CI, 0.6% to 2.5%), 6 regional recurrences (one combined with IBTR), 2 distant recurrences (both without IBTR or regional recurrence) and 13 contralateral breast cancers were observed. There were 48 deaths. One death (2.1%) was due to breast cancer and 13 (27.1%) were due to other cancers (2 endometrial cancers). Five-year overall survival was 93.0% (95% CI, 90.5% to 94.9%). CONCLUSION: BCS and ET without RT seem to be a safe treatment option in women ≥ 65 years with early breast cancer and favorable histopathology. The risk of IBTR is comparable to the risk of contralateral breast cancer. Moreover, concurrent morbidity dominates over breast cancer as leading cause of death in this cohort with low-risk breast tumors.

Ductal Breast Carcinoma In Situ: Mammographic Features and Its Relation to Prognosis and Tumour Biology in a Population Based Cohort.

Casting-type calcifications and a histopathological picture with cancer-filled duct-like structures have been presented as breast cancer with neoductgenesis. We correlated mammographic features and histopathological neoductgenesis with prognosis in a DCIS cohort with long follow-up. Mammographic features were classified into seven groups according to Tabár. Histopathological neoductgenesis was defined by concentration of ducts, lymphocyte infiltration, and periductal fibrosis. Endpoints were ipsilateral (IBE) in situ and invasive events. Casting-type calcifications and neoductgenesis were both related to high nuclear grade, ER- and PR-negativity, and HER2 overexpression but not to each other. Casting-type calcifications and neoductgenesis were both related to a nonsignificant lower risk of invasive IBE, HR 0.38 (0.13-1.08) and 0.82 (0.29-2.27), respectively, and the HR of an in situ IBE was 0.90 (0.41-1.95) and 1.60 (0.75-3.39), respectively. Casting-type calcifications could not be related to a worse prognosis in DCIS. We cannot explain why a more aggressive phenotype of DCIS did not correspond to a worse prognosis. Further studies on how the progression from in situ to invasive carcinoma is driven are needed.

Self-perceived, but not objective lymphoedema is associated with decreased long-term health-related quality of life after breast cancer surgery.

BACKGROUND: The primary aim was to compare long-term health-related quality of life (HRQoL) in patients undergoing sentinel lymph node biopsy (SLNB) alone versus axillary lymph node dissection (ALND), with or without axillary metastases. Secondary aims were to a) investigate agreement between objectively measured and self-reported lymphoedema and b) compare, with respect to HRQoL, women with objective arm lymphoedema without subjective ratings and those with no objective but subjective ratings of arm lymphoedema. METHODS: The three study groups were defined by axillary surgery: 1) SLNB alone (N = 140), 2) ALND in patients without axillary metastases (N = 125) and 3) ALND in patients with axillary metastases (N = 155). Preoperatively, one and three years postoperatively arm volume was measured and questionnaires regarding self-perceived symptoms of arm lymphoedema and HRQoL were completed (The Swedish Short Form-36 Health Survey, SF-36). RESULTS: Out of the original 516 who had axillary surgery, 420 (81%) completed the study. There were no statistically significant differences in HRQoL between the three study groups. No statistically significant agreement was found between self-perceived and objectively measured arm lymphoedema. Women without self-perceived arm lymphoedema, regardless of objective arm lymphoedema or not, scored higher on all eight SF-36 domains than those who reported self-perceived arm lymphoedema. CONCLUSION: Women reporting self-perceived arm lymphoedema, regardless of objective lymphoedema or not, have a decreased long-term health-related quality of life. This indicates that more attention should be given to the subjective reports of symptom in order to better help these women.

Sector resection with or without postoperative radiotherapy for stage I breast cancer: 20-year results of a randomized trial.

PURPOSE: To investigate how radiotherapy (XRT) adds to tumor control using a standardized surgical technique with meticulous control of surgical margins in a randomized trial with 20 years of follow-up. PATIENTS AND METHODS: Three hundred eighty-one women with pT1N0 breast cancer were randomly assigned to sector resection with (XRT group) or without (non-XRT group) postoperative radiotherapy to the breast. With follow-up through 2010, we estimated cumulative proportion of recurrence, breast cancer death, and all-cause mortality. RESULTS: The cumulative probability of a first breast cancer event of any type after 20 years was 30.9% in the XRT group and 45.1% in the non-XRT group (hazard ratio [HR], 0.58; 95% CI, 0.41 to 0.82). The benefit of radiotherapy was achieved within the first 5 years. After 20 years, 50.4% of the women in the XRT group died compared with 54.0% in the non-XRT group (HR, 0.92; 95% CI, 0.71 to 1.19). The cumulative probability of contralateral cancer or death as a result of cancer other than breast cancer was 27.1% in the XRT group and 24.9% in the non-XRT group (HR, 1.17; 95% CI, 0.77 to 1.77). In an anticipated low-risk group, the cumulative incidence of first breast cancer of any type was 24.8% in the XRT group and 36.1% in the non-XRT group (HR, 0.61; 95% CI, 0.35 to 1.07). CONCLUSION: Radiotherapy protects against recurrences during the first 5 years of follow-up, indicating that XRT mainly eradicates undetected cancer foci present at primary treatment. The similar rate of recurrences beyond 5 years in the two groups indicates that late recurrences are new tumors. There are subgroups with clinically relevant differences in risk.

Interventions for lifestyle changes to promote weight reduction, a randomized controlled trial in primary health care.

BACKGROUND: Overweight and obesity are growing public health problems in high income countries and is now growing at a dramatic pace in low and middle income countries, particularly in urban settings. The aim of this trial was to examine the effects of a weight reduction program in adults and to determine whether or not a more extensive intervention was superior to ordinary care. METHODS: Patients seeking advice for overweight/obesity or illness related to overweight/obesity at eight primary health care centers in Sweden were randomized either to intervention or control care groups with both groups given dietary advice and individualized information on increased regular physical activity. In the intervention group advice was more extensive and follow-up more frequent than in the control group during the study period of two years. Main outcome measure was reduction in body weight of five percent or more from study start. RESULTS: From October 2004 to April 2006, 133 patients, 67 in the intervention group and 66 in the control group, were randomized over a period of 18 months. Target weight was achieved at 12 months by 26.7% of the patients in the intervention group compared with 18.4% in the control group (p = 0.335). There was an average absolute weight loss of 2.5 kg in the intervention group and 0.8 kg in the control group at 12 months as compared with the weight at study entry. There were no significant differences between the groups in quality of life, blood glucose and lipids. At 24 months target weight was achieved in 21.9% versus 15.6%, with an average weight reduction of 1.9 kg and 1.2 kg in the two groups, respectively. CONCLUSIONS: Promotion of a diet with limited energy intake, appropriate composition of food and increased physical activity had limited effects on body weight in a Swedish primary care setting. More extensive advice and more frequent visits made no significant difference to the outcome. TRIAL REGISTRATION: ClinicalTrial.gov: NCT01606917.

Tumor stage affects risk and prognosis of contralateral breast cancer: results from a large Swedish-population-based study.

PURPOSE: The number of breast cancer survivors at risk of developing contralateral breast cancer (CBC) is increasing. However, ambiguity remains regarding risk factors and prognosis for women with CBC. PATIENTS AND METHODS: In a cohort of 42,670 women with breast cancer in the Uppsala/Örebro and Stockholm regions in Sweden in 1992 to 2008, we assessed risk factors for and prognosis of metachronous CBC by using survival analysis. Breast cancer-specific survival for women with CBC was evaluated and compared with results for women with unilateral breast cancer (UBC) by using time-dependent Cox-regression modeling. RESULTS: An increased risk for CBC was observed among women who had primary breast cancer with ≥ 10 involved lymph nodes compared with node-negative women (adjusted hazard ratio [HR], 1.8; 95% CI, 1.2 to 2.7). The prognosis was poorer in women with CBC than with UBC. The hazard of dying from breast cancer was especially high for women with a short interval time to CBC (adjusted HR, 2.3; 95% CI, 1.8 to 2.8 for CBC diagnosed ≤ 5 years v UBC) and gradually decreased with longer follow-up time but remained higher than the hazard originating from the primary tumor for ≥ 10 years. CONCLUSION: Women with advanced-stage primary breast cancer had an increased risk of developing CBC. CBC is associated with an increased risk of dying from breast cancer throughout a long period of follow-up after the primary tumor. Our findings suggest that the event of CBC marks a new clinical situation in terms of investigations for metastases, treatment considerations, and follow-up strategy.

Pulsed dose rate brachytherapy as the sole adjuvant radiotherapy after breast-conserving surgery of T1-T2 breast cancer: first long time results from a clinical study.

BACKGROUND AND PURPOSE: To evaluate the long time outcome with regard to local tumour control, cosmetic outcome and side effects of a short (5 days) accelerated interstitial brachytherapy treatment delivered to the surroundings of the operated sector. PATIENTS AND METHODS: Between 1993 and 2003 we treated 50 women with early T1 and T2 breast cancer. Radical sector resection was performed and followed later with an interstitial pulsed dose rate (PDR) brachytherapy of 50Gy in 5 days. The treatment was centred on the tumour with a margin of 30mm. One patient was treated bilaterally. The patients were followed for a median of 86 (32-126) months. RESULTS: Ipsilateral breast cancer recurrence was seen in 3 patients (6%). Two of them occurred outside the treated volume. The 5- and 7-year rates of actuarial local control were 96% and 96%, respectively, overall survival 88% and 85%, disease free survival 88% and 88%, respectively. A dosimetrical analysis showed that the partial breast irradiation covered a median of 31% of the total breast volume. Fat necrosis was seen in 12% and local (moderate-strong) fibrosis in 26% of the patients. Independent cosmetic scoring showed good or excellent result in 56% of the patients. CONCLUSIONS: Local outcome is favourable and very similar to other published studies of accelerated partial breast irradiation. Our long time cosmetic results are lower than other published results.

Axillary recurrence rate after negative sentinel node biopsy in breast cancer: three-year follow-up of the Swedish Multicenter Cohort Study.

BACKGROUND: Sentinel lymph node biopsy is an established staging method in early breast cancer. After a negative biopsy, most institutions will not perform a completion axillary dissection. The present study reports the current axillary recurrence (AR) rate, overall and disease-free survival in the Swedish Multicenter Cohort Study. METHODS: From 3534 patients with primary breast cancer < or =3 cm prospectively enrolled in the Swedish multicenter cohort study, 2246 with a negative sentinel node biopsy and no further axillary surgery were selected. Follow-up consisted of annual clinical examination and mammography. Twenty-six hospitals and 131 surgeons contributed to patient accrual. RESULTS: After a median follow-up time of 37 months (0-75), the axilla was the sole initial site of recurrence in 13 patients (13 of 2246, 0.6%). In another 7 patients, axillary relapse occurred after or concurrently with a local recurrence in the breast, and in a further 7 cases, it coincided with distant or extra-axillary lymphatic metastases. Thus, a total of 27 ARs were identified (27 of 2246, 1.2%). The overall 5-year survival was 91.6% and disease-free survival 92.1%. CONCLUSIONS: This is the first report from a national multicenter study that covers, not only highly specialized institutions but also small community hospitals with just a few procedures per year. Despite this heterogeneous background, the results lie well within the range of AR rates published internationally (0%-3.6%). The sentinel node biopsy procedure seems to be safe in a multicenter setting. Nevertheless, long-term follow-up data should be awaited before firm conclusions are drawn.

Factors determining esthetic outcome after breast cancer conservative treatment.

The aim of this study was to evaluate the factors that determine esthetic outcome after breast cancer conservative treatment, based on a consensual classification obtained with an international consensus panel. Photographs were taken from 120 women submitted to conservative unilateral breast cancer surgery (with or without axillary surgery) and radiotherapy. The images were sent to a panel of observers from 13 different countries and consensus on the classification of esthetic result (recorded as excellent, good, fair or poor) was obtained in 113 cases by means of a Delphi method. For each patient, data were collected retrospectively regarding patient characteristics, tumor, and treatment factors. Univariate and multivariate analysis were used to evaluate the correlation between these factors and overall cosmetic results. On univariate analysis, younger and thinner patients as well as patients with lower body mass index (BMI) and premenopausal status obtained better cosmetic results. In the group of tumor- and treatment-related factors, larger removed specimens, clearly visible scars, the use of chemotherapy and longer follow-up period were associated with less satisfactory results. On multivariate analysis, only BMI and scar visibility maintained a significant association with cosmesis. BMI and scar visibility are the only factors significantly associated with cosmetic results of breast cancer conservative treatment, as evaluated by an international consensus panel.

Topoisomerase II-alpha expression in different cell cycle phases in fresh human breast carcinomas.

Topoisomerase II-alpha (topo II alpha) is the key target enzyme for the topoisomerase inhibitor class of anti-cancer drugs. In normal cells, topo II alpha is expressed predominantly in the S/G2/M phase of the cell cycle. In malignant cells, in vitro studies have indicated that the expression of topo II alpha is both higher and less dependent on proliferation state in the cell. We studied fresh specimens from 50 cases of primary breast cancer. The expression of topo II alpha in different cell cycle phases was analyzed with two-parameter flow cytometry using the monoclonal antibody SWT3D1 and propidium iodide staining. The expression of topo II alpha was significantly higher in the S/G2/M phase of the cell cycle than in the G0/G1 phase in both DNA diploid and DNA non-diploid tumors. In 18 of 21 diploid tumors, and in 25 of 29 non-diploid tumors, >50% of the topo II alpha-positive cells were in the G0/G1 phase. This significant expression of topo II alpha in the G0/G1 phase of the cell cycle may have clinically important implications for treatment efficacy of topoisomerase II inhibitors.