The role of ipsilateral breast radiotherapy in management of occult primary breast cancer presenting as axillary lymphadenopathy

Aim

To assess the role of ipsilateral breast radiotherapy (IBR) in women with occult primary breast cancer presenting with axillary metastases (OPBC).

Methods

Patients with axillary nodal metastases and histological diagnosis of breast cancer without palpable, mammographic or ultrasonographic evidence of a breast primary were identified from a prospectively maintained single institution database. Imaging, surgery, radiotherapy, recurrence and survival data were collected. Patients whose breast cancer primary was detected on MRI (but occult on clinical examination and other imaging) were excluded from the analyses of IBR and outcome, but were included in other exploratory analyses.

Results

Fifty-five patients were included between 1975 and 2009. Median follow up was 68 months. Twenty patients had breast magnetic resonance imaging (MRI) in addition to other imaging. A primary breast cancer was detected in 7 of these 20. 48/55 patients had no detectable breast primary. 35/48 patients (73%) were treated with radiotherapy to the conserved breast, and 13/48 (27%) with observation. Patients who had IBR had better 5 year local recurrence free survival (LRFS) (84% versus 34%, p < 0.001), and relapse free survival (RFS) (64% versus 34%, p = 0.05), but no difference in overall survival (OS) (84% versus 85%, p = 0.2). There was no difference in 5 year LRFS (80% versus 90%: p = 0.3) between patients who received radiation of 50 Gy in 25 fractions versus ?60 Gy.

Conclusion

Patients with OPBC should be managed with IBR and breast conservation, or mastectomy. Our data suggest it is not necessary to irradiate the breast to more than 50 Gy in 25 fractions.     

Current technological clinical practice in breast radiotherapy; results of a survey in EORTC-Radiation Oncology Group affiliated institutions

Purpose

To evaluate the current technological clinical practice of radiation therapy of the breast in institutions participating in the EORTC-Radiation Oncology Group (EORTC-ROG).

Materials and methods

A survey was conducted between August 2008 and January 2009 on behalf of the Breast Working Party within the EORTC-ROG. The questionnaire comprised 32 questions on 4 main topics: fractionation schedules, treatment planning methods, volume definitions and position verification procedures.

Results

Sixty-eight institutions out of 16 countries responded (a response rate of 47%). The standard fraction dose was generally 2 Gy for both breast and boost treatment, although a 2.67 Gy boost fraction dose is routinely given in British institutions. The main boost modality was electrons in 55%, photons in 47% and brachytherapy in 3% of the institutions (equal use of photon and electron irradiation in 5% of the institutions). All institutions used CT-based treatment planning. Wide variations are seen in the definition of the breast and boost target volumes, with margins around the resection cavity, ranging from 0 to 30 mm. Inverse planned IMRT is available in 27% and breath-hold techniques in 19% of the institutions. The number of patients treated with IMRT and breath-hold varied per institution. Electronic portal imaging for patient set-up is used by 92% of the institutions.

Conclusions

This survey provides insight in the current practice of radiation technology used in the treatment of breast cancer among institutions participating in EORTC-ROG clinical trials.     

Breast radiotherapy as part of loco-regional treatments in stage IV breast cancer patients with oligometastatic disease

Background

Local treatments seem to improve metastasis progression-free survival (MPFS) and overall survival (OS) when added to systemic therapies in stage IV breast cancer.

Methods

From 1990 to 2003, we reviewed 9138 cases treated and registered in the Institut Gustave-Roussy breast cancer database. Among them, 308 had presented with stage IV disease. Eighty percent of patients (n = 239) had received a loco-regional treatment and they were categorized into two groups: loco-regional radiotherapy (LRRT) alone (Group 1; n = 147) or breast and axillary surgery ± LRRT (Group 2; n = 92).

Results

The median follow-up was 6.5 years. LRRT obtained a long-standing loco-regional clinical response in 85% of patients. The 3-year MPFS rates were 20% in Group 1 and 39% in Group 2; the 3-year OS rates were 39% and 57%, respectively. However, no significant differences in MPFS or OS were observed between the two groups when adjusted on prognostic factors.

Conclusions

Radiation therapy alone provides long-standing local control and yields MPFS and OS rates equivalent to those obtained when radiation therapy is combined with surgery, whatever the prognostic factors. Loco-regional therapies, especially radiation therapy alone, may have an important role to play in the treatment of selected patients with stage IV breast cancer.     

Increased use of regional radiotherapy is associated with improved outcome in a population-based cohort of women with breast cancer with 1-3 positive nodes

Purpose

To examine use of and outcomes from adjuvant locoregional radiotherapy (LRRT) after breast-conserving surgery (BCS) for women with breast cancer with 1-3 positive nodes (1-3 N+) before and after the 1997 publication of randomised trial evidence of a survival advantage from post-mastectomy LRRT.

Methods

Data were analysed for 2768 women diagnosed between 1989 and 2005 and referred to the British Columbia Cancer Agency with newly diagnosed pT1-3 breast cancer with 1-3 N+, treated with BCS and RT. LRRT use was analysed over time. Ten-year Kaplan-Meier locoregional control (LRC), breast cancer-specific survival (BCSS) and overall survival (OS) curves were compared using the log-rank test. Cox regression modeling of LRC and BCSS were performed.

Results

LRRT use in patients with 1-3 N+ increased from 23% before 1997 to 57% after 1997. LRRT was associated with significant improvements in LRC, but not in DRFS, BCSS, or OS. 10--year LRC was 89% with local RT alone and 93% with LRRT (p = 0.006). On multivariable analysis, LRRT was associated with improved LRC compared to local RT alone (HR 0.55, 95% CI: 0.40-0.77), but not with significant BCSS differences. Margin status, grade, % positive nodes, and hormonal therapy were significant predictors for LRC, while tumour size, grade, % positive nodes, and hormonal therapy significantly affected BCSS.

Conclusion

Post-BCS LRRT use in British Columbia increased almost threefold in patients with 1-3 N+ after 1997. Adjuvant LRRT was associated with improved LRC, but not with improved BCSS compared to breast RT alone.     

Comparison of early quality of life in patients treated with radiotherapy following mastectomy or breast conservation therapy: A prospective study

Introduction

To compare quality of life (QOL) in breast cancer patients from a developing country after breast conservation surgery (BCS) or mastectomy and adjuvant radiotherapy (RT).

Materials and methods

In a 6-month period, all consecutive early and locally advanced breast cancer patients treated with either BCS or mastectomy and treated with RT were analyzed. All patients who underwent mastectomy were treated with 45 Gray/20#/4 weeks. Patients with BCS were treated with a dose of 45-50 Gray/25#/5 weeks to whole breast followed by tumor bed boost (15 Gray/6#/6 days with suitable energy electrons). Prospective evaluation of QOL using EORTC QLQ C30 and breast cancer specific QLQ BR23 was done before starting RT (baseline), at mid-RT and at RT conclusion for all patients.

Results

One hundred and thirteen patients had mastectomy and 142 patients underwent BCS. Reliability test (Cronbach alpha) for questionnaire filling was 0.669-0.886. At pre-RT assessment, global QOL scores in mastectomy and BCS groups were 71.1 and 71.3, respectively. There was no significant difference in pre-RT EORTC QLQ C30 functional and symptom domains between mastectomy and BCS patients. However, social function domain score was higher in patients who underwent mastectomy (83 versus 73.9; p = 0.018). In QLQ BR23 domains, body image and sexual functioning domains were similar between the two groups. However, sexual enjoyment (10.9 versus 47.6; p = 0.006) and future perspective (7.4 versus 37.1; p = 0.036) domains were significantly better in BCS arm. There was no difference between systemic side effect (BRSSE), breast symptom (BRBS) and arm symptom (BRAS) domain scores between the groups. There was no significant difference in change of QOL scores between mastectomy and BCS patients at RT completion as compared to baseline.

Conclusions

There was no significant difference in quality of life in patients with BCS versus those with mastectomy. However, patients who underwent BCS had better sexual enjoyment and future perspective scores compared with mastectomy patients. There was no significant change of QOL domain scores after RT in mastectomy and BCS patients.     

Symptoms 10-17 years after breast cancer radiotherapy data from the randomised SWEBCG91-RT trial

Background

Postoperative radiotherapy decreases the risk for local recurrence and improves overall survival in women with breast cancer. We have limited information on radiotherapy-induced symptoms 10-17 years after therapy.

Material and methods

Between 1991 and 1997, women with lymph node-negative breast cancer were randomised in a Swedish multi-institutional trial to breast conserving surgery with or without postoperative radiotherapy. In 2007, 10-17 years after randomisation, the group included 422 recurrence-free women. We collected data with a study-specific questionnaire on eight pre-selected symptom groups.

Results

For six symptom groups (oedema in breast or arm, erysipelas, heart symptoms, lung symptoms, rib fractures, and decreased shoulder mobility) we found similar occurrence in both groups. Excess occurrence after radiotherapy was observed for pain in the breast or in the skin, reported to occur “occasionally” by 38.1% of survivors having undergone radiotherapy and surgery versus 24.0% of those with surgery alone (absolute difference 14.1%; p = 0.004) and at least once a week by 10.3% of the radiotherapy group versus 1.7% (absolute difference 8.6%; p = 0.001). Daily life and analgesic use did not differ between the groups.

Conclusions

Ten to 17 years after postoperative radiotherapy 1 in 12 women had weekly pain that could be attributed to radiotherapy. The symptoms did not significantly affect daily life and thus the reduced risk for local recurrence seems to outweigh the risk for long-term symptoms for most women.     

TRIB3 protein denotes a good prognosis in breast cancer patients and is associated with hypoxia sensitivity

Background

Tribbles homolog 3 (TRIB3) is a pseudokinase involved in the regulation of several signaling pathways involved in cell survival and/or cell stress. Here, we determined the correlation between breast cancer prognosis and TRIB3 protein levels and established the role of TRIB3 in cell survival after hypoxia and/or radiotherapy.

Material and methods

TRIB3 mRNA and protein were quantified in a new independent breast cancer patient cohort using QPCR and a new specific avian antibody against TRIB3. In addition, we used siRNA-mediated knockdown of TRIB3 in a colony-forming assay after hypoxia and radiotherapy.

Results

TRIB3 mRNA and protein levels did not correlate in breast cancer cell lines or human breast cancer material. We validated our earlier finding that high TRIB3 mRNA denotes a poor prognosis, but found that high TRIB3 protein levels were associated with a good prognosis in breast cancer patients. We also show that knockdown of TRIB3 resulted in an increased survival under hypoxic conditions.

Conclusion

Whereas mRNA levels of TRIB3 are related with a poor prognosis, TRIB3 protein is associated with a good prognosis in human breast cancer patients, possibly due to the fact that TRIB3 is involved in hypoxia tolerance.     

Determinants of variability in waiting times for radiotherapy in the treatment of breast cancer

Purpose

To examine psycho-social and geographic determinants of delay in starting radiotherapy in early invasive breast cancer patients.

Material and methods

Waiting time was defined as the time elapsed until the beginning of radiotherapy, starting from the date of surgery (in absence of chemotherapy) or from the end of chemotherapy.

Results

Eight hundred and ninety six women aged 24-89 took part in the study. Mean waiting times were 52 days (sd = 19) between surgery and radiotherapy and 31 days (sd = 14) between chemotherapy and radiotherapy. Differences between radiotherapy centres (p < 0.0001) accounted for 30% and 12%, respectively, of total variance in waiting times. Using a multivariate mixed analysis that took into account intra-centre correlation, the time between surgery and radiotherapy was shorter for young patients (p = 0.020), those who had sought information about their illness (p = 0.024) and those who had undergone surgery and radiotherapy in the same centre (p = 0.021). On the other hand, no patient characteristic was associated with the time between chemotherapy and radiotherapy.

Conclusion

Centre is the major factor that explained longer waiting times in radiotherapy, emphasising the structural hypothesis. It is important to pursue initiatives to improve the organization within radiotherapy centres and then to verify that these initiatives have succeeded in shortening waiting times.     

Nomogram to predict ipsilateral breast relapse based on pathology review from the EORTC 22881-10882 boost versus no boost trial

Background and purpose

The EORTC 22881-10882 trial showed that for patients treated with breast conserving therapy (BCT), a 16 Gy boost dose significantly improved local control, but increased the risk of breast fibrosis. A model to estimate the risk of ipsilateral breast relapse (IBR) already exists, but now a model has been developed which takes boost treatment into account and is based on centrally reviewed pathology.

Materials and methods

A Cox model was developed based on central pathology review data and clinical data of 1603 patients from the EORTC 22881-10882 trial with a median follow-up of 11.5 years. From a predefined set of variables, predictors with a maximal effect on 10-year IBR rate >4% were retained in the model. Bootstrap re-sampling was used to assess model calibration and discrimination. The results are presented in the form of a nomogram.

Results

Apart from young age and no boost, presence of DCIS adjacent to the invasive tumor was associated with increased risk of IBR (HR 1.96, p = 0.001). Patients with high grade invasive tumors were younger than patients with low/intermediate grade (p < 0.0001). The nomogram includes histologic grade, DCIS, tumor diameter, age, tamoxifen, chemotherapy, and boost with a concordance probability estimate of 0.68.

Conclusions

The nomogram for predicting IBR 10 years after BCT includes seven factors, with young age, presence of DCIS and boost treatment as the most dominant factors. The nomogram estimates IBR and confirms the importance of a boost dose. Combined with a model to predict fibrosis published previously, the nomogram presented here may assist in decision making for individual patients.     

Limited benefit of inversely optimised intensity modulation in breast conserving radiotherapy with simultaneously integrated boost

Background and purpose

To examine whether in breast-conserving radiotherapy (RT) with simultaneously integrated boost (SIB), application of inversely planned intensity-modulated radiotherapy (IMRT-SIB) instead of three-dimensional RT (3D-CRT-SIB) has benefits that justify the additional costs, and to evaluate whether a potential benefit of IMRT-SIB depends on specific patient characteristics.

Material and methods

3D-CRT-SIB and various IMRT-SIB treatment plans were constructed and optimised for 30 patients with early stage left-sided breast cancer. Coverage of planning target volumes (PTVs) and dose delivered to organs at risk (OARs) were determined for each plan. Overlap between heart and breast PTV (OHB), size of breast and boost PTVs and boost location were examined in their ability to identify patients that might benefit from IMRT-SIB.

Results

All plans had adequate PTV coverage. IMRT-SIB generally reduced dose levels delivered to heart, lungs, and normal breast tissue relative to 3D-CRT-SIB. However, IMRT-SIB benefit differed per patient. For many patients, comparable results were obtained with 3D-CRT-SIB, while patients with OHB > 1.4 cm and a relatively large boost PTV volume (>125 cm³) gained most from the use of IMRT-SIB.

Conclusions

In breast-conserving RT, results obtained with 3D-CRT-SIB and IMRT-SIB are generally comparable. Patient characteristics could be used to identify patients that are most likely to benefit from IMRT-SIB.     

Risk for second primary non-breast cancer in pre- and postmenopausal women with breast cancer not treated with chemotherapy, radiotherapy or endocrine therapy

Introduction

We investigated the risk for a second primary cancer in pre- and postmenopausal women with breast cancer treated by surgery alone, to assess the importance of non-treatment factors and menopausal status.

Patients and methods

The cohort comprised 14,151 women with breast cancer diagnosed during 1977-2006, who did not receive radiotherapy or systemic adjuvant therapy. They were identified in the nationwide clinical database of the Danish Breast Cancer Cooperative Group. The women were followed for a second primary cancer other than breast cancer in the Danish Cancer Registry, and risk was quantified as standardised incidence ratios (SIRs).

Results

Women with breast cancer diagnosed before menopause had an 18% greater overall risk for a second primary non-breast cancer than the general female population (95% confidence interval [CI], 1.06-1.32). The excess was confined to cancers of the endometrium (1.5; 95% CI, 1.0-2.0) and ovaries (1.8; 95% CI, 1.2-2.4). Rare histological subtypes of breast cancer were associated with these two cancer sites. Women with breast cancer after menopause had no overall excess risk for a second cancer (SIR, 0.98; 95% CI, 0.92-1.04).

Conclusion

An excess risk for second non-breast cancers related to non-treatment factors is seen primarily in breast cancer patients who were premenopausal at diagnosis.     

Optimising surgical accuracy in palpable breast cancer with intra-operative breast ultrasound--feasibility and surgeons' learning curve

Aims

To evaluate if intra-operative guidance with ultrasonography (US) could improve surgical accuracy of palpable breast cancer excision, and to evaluate the performance of surgeons during training for US-guided excision.

Materials and methods

Thirty female patients undergoing breast-conserving surgery for palpable T1-T2 invasive breast cancer were recruited. Three individual breast surgeons, assisted by US, targeted and excised the tumours. The main objective was to obtain adequate resection margins with optimal resection volumes. The specimen volume, tumour diameter and histological margin status were recorded. The specimen volume was divided by the optimal resection volume, defined as the spherical tumour volume plus a 1.0-cm margin. The resulting calculated resection ratio (CRR) indicated the amount of excess tissue resected.

Results

All tumours were correctly identified during surgery, 29 of 30 tumours (96.7%) were removed with adequately negative margins, and one tumour was removed with focally positive margins. The median CRR was 1.0 (range, 0.4-2.8), implying optimal excision volume. For all breast surgeons, CRR improved during the training period. By the 8th procedure, all surgeons showed proficiency in performing intra-operative breast US.

Conclusion

Surgeons can easily learn the skills needed to perform intra-operative US for palpable breast tumour excision. The technique is non-invasive, simple, safe and effective for obtaining adequate resection margins. Within the first two cases, resections reached optimal volumes, thereby, presumably resulting in improved cosmetic outcomes. In a multicentre, randomised, clinical trial, intra-operative US guidance for palpable breast tumours will be evaluated for oncological and cosmetic outcomes.     

Preoperative radio-chemotherapy in early breast cancer patients: Long-term results of a phase II trial

Purpose

This phase II trial aimed to investigate the efficacy of concurrent radio- (RT) and chemotherapy (CT) in the preoperative setting for operable, non-metastatic breast cancer (BC) not amenable to initial breast-conserving surgery (BCS).

Patients and methods

From 2001 to 2003, 59 women were included. CT consisted of four cycles of 5-FU, 500 mg/m²/d, continuous infusion (d1-d5) and vinorelbine, 25 mg/m² (d1 and d6). Starting concurrently with the second cycle, RT delivered 50 Gy to the breast and 46 Gy to the internal mammary and supra/infra-clavicular areas. Breast surgery and lymph node dissection were then performed. Adjuvant treatment consisted of a 16 Gy boost to the tumor bed after BCS, FEC (four cycles of fluorouracil 500 mg/m², cyclophosphamide 500 mg/m², and epirubicin 100 mg/m², d1; d21) for pN1-3 and hormone-therapy for positive hormone receptors BC.

Results

The in-breast pathological complete response rate was 27%. BCS was performed in 41 (69%) pts. Overall and distant-disease free survivals at 5 years were respectively 88% [95% CI 80-98] and 83% [95% CI 74-93] whereas locoregional and local controls were 90% [95% CI 82-97] and 97% [95% CI 92-100]. Late toxicity (CTCAE-V3) was assessed in 51 pts (86%) with a median follow-up of 7 years [5-8]. Four (8%) experienced at least one grade III toxicities (one telangectasia and three fibroses). Cosmetic results, assessed in 35 of the 41 pts (85%) who retained their breasts, were poor in four pts (11%).

Conclusion

Preoperative concurrent administration of RT and CT is an effective regimen. Long-term toxicity is moderate. This association deserves further evaluations in prospective trials.     

A randomised controlled trial of forward-planned radiotherapy (IMRT) for early breast cancer: Baseline characteristics and dosimetry results

Background and purpose

This large trial was designed to investigate whether correction of dose inhomogeneities using intensity-modulated radiotherapy (IMRT) reduces late toxicity and improves quality of life in patients with early breast cancer. This paper reports baseline characteristics of trial participants and dosimetry results.

Materials and methods

Standard tangential plans of 1145 trials were analysed. Patients with inhomogeneous plans, defined by ICRU recommendations, were randomised to forward-planned IMRT or standard radiotherapy.

Results

Twenty-nine percentage of patients had adequate dosimetry with standard 2D radiotherapy. In the randomised patients, the decreases in mean volumes receiving greater than 107% (Vol > 107) and less than 95% (Vol < 95) of the prescribed dose in the IMRT compared with the control group were 34.0 cm³ (95% CI 26.4-41.6; P < 0.0001) and 48.1 cm³ (95% CI 34.4-61.9; P < 0.0001), respectively. In this study, 90% of patients who had a breast separation greater ?21 cm had Vol > 107 > 2 cm³ on standard radiotherapy plans.

Conclusion

This large trial, in which patients with all breast sizes were eligible, confirmed that breast dosimetry can be significantly improved with a simple method of forward-planned IMRT and has little impact on radiotherapy resources. It is shown that patients with larger breasts are more likely to have dose inhomogeneities and breast separation gives some indication of this likelihood. Photographic assessment of patients at 2 years after radiotherapy, as the next part of this randomised controlled trial, will show whether these results for IMRT translate into improved cosmetic outcome in patients with early breast cancer. This would provide impetus for the widespread adoption of 3D planning and IMRT.     

Nurse-led telephone follow-up and an educational group programme after breast cancer treatment: results of a 2 × 2 randomised controlled trial

Objective

To investigate whether frequent hospital follow-up in the first year after breast cancer treatment might partly be replaced by nurse-led telephone follow-up without deteriorating health-related quality of life (HRQoL), and whether a short educational group programme (EGP) would enhance HRQoL.

Patients and methods

A multicentre pragmatic randomised controlled trial (RCT) with a 2 × 2 factorial design was performed among 320 breast cancer patients who were treated with curative intent. Participants were randomised to follow-up care as usual (3-monthly outpatient clinic visits), nurse-led telephone follow-up, or the former strategies combined with an educational group programme. The primary outcome for both interventions was HRQoL, measured by EORTC QLQ-C30. Secondary outcomes were role and emotional functioning and feelings of control and anxiety.

Results

Data of 299 patients were available for evaluation. There was no significant difference in HRQoL between nurse-led telephone and hospital follow-up at 12 months after treatment (p = 0.42; 95% confidence interval (CI) for difference: −1.93-4.64) and neither between follow-up with or without EGP (p = 0.86; 95% CI for difference: −3.59-3.00). Furthermore, no differences between the intervention groups and their corresponding control groups were found in role and emotional functioning, and feelings of control and anxiety (all p-values >0.05).

Conclusion

Replacement of most hospital follow-up visits in the first year after breast cancer treatment by nurse-led telephone follow-up does not impede patient outcomes. Hence, nurse-led telephone follow-up seems an appropriate way to reduce clinic visits and represents an accepted alternative strategy. An EGP does not unequivocally affect positive HRQoL outcomes.     

Breast cancer in very young women

Aims

The purpose was to analyse the characteristics, treatment, recurrences and survival of very young women with breast cancer.

Methods

212 female breast cancer patients ≤35 years old were treated during 1997-2007. The median follow-up time was 78 months.

Results

117 patients had lymph node metastases and 14 distant metastases at diagnosis. 81 (38%) tumours were hormone receptor negative and 130 (65%) grade 3. HER2 positivity was seen in 47 (34%) and triple negativity in 35 (26%) of the 137 tumours with known HER2 status. 140 women were treated with mastectomy and 68 with breast conserving surgery. 163 patients received postoperative radiotherapy, 175 adjuvant chemotherapy, 95 endocrine therapy and 18 trastuzumab. 63 patients experienced a recurrence, of which 20 had only a locoregional recurrence. 10 (15%) of the women with breast conserving surgery experienced ipsilateral breast tumour recurrence while ipsilateral thoracic wall recurrence was seen in 8 patients (6%) after mastectomy. Seven of these eight patients did not receive postmastectomy radiotherapy. DFI was shorter in patients with hormone receptor positive tumours. At the end of follow-up 44 women had died. The 5-year OS was 80%.

Conclusions

The 5-year OS for young women has become better but is still lower than for all breast cancer patients. DFI was shorter in patients with hormone receptor positive disease. Locoregional recurrences were seen more often after breast conserving surgery.     

Mechanism of lapatinib-mediated radiosensitization of breast cancer cells is primarily by inhibition of the Raf > MEK > ERK mitogen-activated protein kinase cascade and radiosensitization of lapatinib-resistant cells restored by direct inhibition of MEK

Background and purpose

We recently showed that lapatinib, an EGFR/HER2 inhibitor, radiosensitized breast cancer cells of the basal and HER2+ subtypes. The purpose of this study was to identify the downstream signaling pathways responsible for lapatinib-mediated radiosensitization in breast cancer.

Materials and methods

Response of EGFR downstream signaling pathways was assessed by Western blot and clonogenic cell survival assays in breast tumor cells after irradiation (5 Gy), lapatinib, CI-1040, or combined treatment.

Results

In SUM102 cells, an EGFR+ basal breast cancer cell line, exposure to ionizing radiation elicited strong activation of ERK1/2 and JNK, which was blocked by lapatinib, and weak/no activation of p38, AKT or STAT3. Direct inhibition of MEK1 with CI-1040 resulted in 95% inhibition of surviving colonies when combined with radiation while inhibition of JNK with SP600125 had no effect. Lapatinib-mediated radiosensitization of SUM102 cells was completely abrogated with expression of constitutively active Raf. Treatment of lapatinib-resistant SUM185 cells with CI-1040 restored radiosensitization with 45% fewer surviving colonies when combined with radiation.

Conclusions

These data suggest that radiosensitization by lapatinib is mediated largely through inhibition of MEK/ERK and that direct inhibition of this pathway may provide an additional avenue of radiosensitization in EGFR+ or HER2+ breast cancers.     

Electronic portal images (EPIs) based position verification for the breast simultaneous integrated boost (SIB) technique

Background and purpose

To develop a method based on electronic portal images (EPIs) for the position verification of breast cancer patients that are treated with a simultaneous integrated boost (SIB) technique.

Method

3D setup errors of the breast outline and the thoracic wall were determined from EPIs of the tangential treatment fields and anterior posterior (AP) verification field. The method was verified with repeated CT scans of 38 patients with an average setup error larger than 5 mm.

Result

The 3D position deviation of the boost volume can best be determined from the position deviation of the breast outline in the ventrodorsal direction and the thoracic wall in the lateral and longitudinal directions from the tangential and AP EPIs. The method gives an average overestimation of the deviation of the boost volume in the ventrodorsal, lateral and longitudinal directions by 28%, 20% and 6%, respectively and an average underestimation of the deviation of the whole breast by 32%, 17% and 39%.

Conclusions

The described method is superior to using tangential EPIs only and is recommended for position verification of breast cancer patients that are treated with a SIB technique if no Cone beam CT (CBCT) or fiducial markers can be used.     

Randomised phase II trial of hyperbaric oxygen therapy in patients with chronic arm lymphoedema after radiotherapy for cancer

Background

A non-randomised phase II study suggested a therapeutic effect of hyperbaric oxygen (HBO) therapy on arm lymphoedema following adjuvant radiotherapy for early breast cancer, justifying further investigation in a randomised trial.

Methods

Fifty-eight patients with ?15% increase in arm volume after supraclavicular ± axillary radiotherapy (axillary surgery in 52/58 patients) were randomised in a 2:1 ratio to HBO (n = 38) or to best standard care (n = 20). The HBO group breathed 100% oxygen at 2.4 atmospheres absolute for 100 min on 30 occasions over 6 weeks. Primary endpoint was ipsilateral limb volume expressed as a percentage of contralateral limb volume. Secondary endpoints included fractional removal rate of radioisotopic tracer from the arm, extracellular water content, patient self-assessments and UK SF-36 Health Survey Questionnaire.

Findings

Of 53/58 (91.4%) patients with baseline assessments, 46 had 12-month assessments (86.8%). Median volume of ipsilateral limb (relative to contralateral) at baseline was 133.5% (IQR 126.0-152.3%) in the control group, and 135.5% (IQR 126.5-146.0%) in the treatment group. Twelve months after baseline the median (IQR) volume of the ipsilateral limb was 131.2% (IQR 122.7-151.5%) in the control group and 133.5% (IQR 122.3-144.9%) in the treatment group. Results for the secondary endpoints were similar between randomised groups.

Interpretation

No evidence has been found of a beneficial effect of HBO in the treatment of arm lymphoedema following primary surgery and adjuvant radiotherapy for early breast cancer.     

Surgical complications of skin sparing mastectomy and immediate prosthetic reconstruction after neoadjuvant chemotherapy for invasive breast cancer

Background

Neoadjuvant chemotherapy is gaining acceptance as an option for breast cancer treatment, particularly in young women. These women may seek immediate breast reconstruction after mastectomy even though it is not known whether such preoperative chemotherapy may be detrimental to post-reconstruction wound healing. Therefore, we set out to assess the influence of neoadjuvant chemotherapy for invasive breast cancer on the short-term complications after skin sparing mastectomy and immediate prosthetic reconstruction.

Methodology

The short-term surgical outcome of 48 immediate breast reconstructions in 37 women treated with neoadjuvant chemotherapy from 2006 through 2009 was prospectively compared to that of 215 immediate reconstructions in 176 women who were operated in the same period without neoadjuvant chemotherapy.

Results

The overall rate of short-term postoperative complications was significantly less among neoadjuvantly treated women (15% vs. 29%; p = 0.042) but this did not result in a reduction of loss of prostheses (8% vs. 11%; p = 0.566).

Conclusion

Because neoadjuvant chemotherapy is not associated with an increase in short-term complications after skin sparing mastectomy and immediate prosthetic reconstruction in patients with invasive breast cancer, such combined surgical therapy may be offered as treatment option for this particular group of patients also.