Breast-conserving surgery with intraoperative radiotherapy in recurrent breast cancer: the patient's perspective.

PURPOSE: When ipsilateral breast-tumor recurrence (IBTR) following breast-conserving surgery (BCS) occurs, the cure of a potentially life-threatening disease is the main goal. If, however, this is diagnosed early, prognosis is still good and patient-reported outcomes become more important. Despite the fact that many patients would prefer a further BCS, international breast cancer guidelines still recommend mastectomy, mainly because previous radiation implies limited options. Our comparative study evaluates the long-term quality-of-life and outcome in patients with IBTR who received BCS plus intraoperative radiotherapy (IORT) versus mastectomy. METHODS: Patients with IBTR were retrospectively divided into three groups according to the local treatment: group 1 (n = 26) was treated with BCS + IORT; group 2 (n = 35) received a standard mastectomy; group 3 (n = 52) had a mastectomy with subsequent reconstruction. Outcomes were analyzed after a mean follow-up of 5 years after IBTR. Quality-of-life was evaluated by the validated questionnaire BREAST-Q in 50 patients who fulfilled the inclusion criteria. RESULTS: Quality-of-life scores varied within the groups, ranging from 51.4 to 91.3 (out of 100 points). We observed satisfactory scores in all items, with no statistical difference within the groups. Disease-free survival of all groups did not statistically differ, and overall mortality was very low (0.9%). The postinterventional complication rate was lower after BCS (19.2% versus 34.3% after mastectomy and 30.8% after mastectomy with reconstruction). CONCLUSION: For patients with previous surgery and radiation who demand a second BCS in the recurrent situation, this surgical technique can be offered in combination with IORT. Our long-term results imply oncological safety, lower complication rate, and good patient satisfaction.

Correction to: Comparative analysis of confocal microscopy on fresh breast core needle biopsies and conventional histology.

Following publication of the original article [1], the authors reported an added data on Table 1 in their paper. The original article [1] has been updated.

Prognostic impact of PIK3CA protein expression in triple negative breast cancer and its subtypes.

BACKGROUND: Triple negative breast cancer (TNBC) harbors a heterogeneous group of carcinomas with poor prognosis and high genetic variability. As a potential aim for targeted therapy, genetic mutations leading to an activation of the phosphoinositide 3-kinase pathway in a catalytic subunit (PIK3CA) in breast cancer have been analyzed currently. Little is known about the clinical impact and prognostic or predictive value of this marker in TNBC subtypes. METHODS: Samples from 119 TNBC cases were submitted to immunohistochemical PIK3CA protein expression analysis and scored semi-quantitatively as negative, weak (1 +), or strongly expressed (2 +). Expression scores were correlated to patient's characteristics, imaging features, and TNBC subtypes. TNBC subtypes were categorized into four subtypes: basal like, mesenchymal like, luminal androgen receptor (LAR), and immunomodulatory. RESULTS: We did not observe differences in clinical aspects and imaging features between TNBC with and without PIK3CA expression. PIK3CA expression was in general higher in the LAR subtype. The disease-free survival and overall survival were significantly better in TNBC with PIK3CA protein expression, independent of TNBC subtypes. CONCLUSION: Despite conflicting results in the literature, our study clearly shows a better outcome of PIK3CA-expressing TNBC, independent of TNBC subtypes. PIK3CA expression in TNBC is not associated with specific clinical or diagnostic features. Further molecular studies and meta-analysis are warranted to clarify the prognostic and predictive role of PIK3CA protein expression.

Comparative analysis of confocal microscopy on fresh breast core needle biopsies and conventional histology.

BACKGROUND: Evaluation of core needle biopsies (CNB) is a standard procedure for the diagnosis of breast cancer. However, tissue processing and image preparation is a time- consuming procedure and instant on-site availability of high-quality images could substantially improve the efficacy of the diagnostic procedure. Conventional microscopic methods, such as frozen section analysis (FSA) for detection of malignant cells still have clear disadvantages. In the present study, we tested a confocal microscopy scanner on fresh tissue from CNB with intention to develop an alternative device to FSA in clinical practice. PATIENTS AND METHODS: In 24 patients with suspicious breast lesions standard of care image-guided biopsies were performed. Confocal images have been obtained using the Histolog™ Scanner and evaluated by two independent pathologists. Hematoxylin-Eosin (H&E) histological sections of the biopsies were routinely processed in a blinded fashion with respect to the confocal images. RESULTS: In total 42 confocal images were generated from 24 biopsy specimens, and available for analysis within a few minutes of taking the biopsy. This resulted in 2 × 42 = 84 pathologic evaluations. In four cases, a pathologic diagnosis was not possible with confocal microscopy. An exact correlation based on the B-classification was reached in 41 out of 80 examinations and in another 35 cases in a broader sense of correspondence definition (i.e. malignant vs. benign). CONCLUSIONS: As a reliable on-site method, the Histolog™ Scanner provides a visualization of cellular details equivalent to the H&E standards, permitting rapid and accurate diagnosis of malignant and benign breast lesions. Furthermore, this device offers great potential for immediate margin analysis of specimen in breast conserving therapy.

The impact of distinct triple-negative breast cancer subtypes on misdiagnosis and diagnostic delay.

BACKGROUND: Triple-negative breast cancer (TNBC) includes mostly aggressive types of breast cancer with poor prognosis. Due to its growth pattern, misinterpretation in clinical imaging is more frequent than in non-TNBC. As the group of TNBC contains heterogeneous types of tumors, marker expression-based subtypes have recently been established. We analyzed clinical features and false-negative imaging findings that could potentially lead to diagnostic delay within the subtypes. METHODS: An exploratory analysis compared the imaging features across the a priori defined subtypes and related these findings to molecular subtype, disease stage, potential diagnostic delay, and patient outcome. RESULTS: TNBC cases were categorized into basal-like (BL; 38.6%), mesenchymal-like (ML; 19.9%), luminal androgen receptor (LAR; 28.3%), and immunomodulatory (IM; 13.3%) subtype. In almost every third patient, malignant classification was missed in at least one imaging method. Misclassification in mammogram was more frequent in ML, while benign ultrasound features were reported more often in the BL subtype. Diagnostic delay due to misclassification in imaging led to tumor growth and/or upgrading of the tumor stage in 8.9% of BL tumors, which had the lowest overall survivals. Despite misclassification rate was higher in the ML subtype it showed better outcomes. Misdiagnosis of axillary lymph node metastasis was higher in LAR; however, this subtype showed a higher percentage of affected axillary lymph nodes. CONCLUSION: TNBC subtypes have different clinical features, benign appearances, and diagnostic delay, which can lead to tumor stage upgrade. Future clinical studies on TNBC outcomes might consider the confounder of clinical delay in the subtypes.

Global Disparities in Breast Cancer Genetics Testing, Counselling and Management.

Hereditary breast cancers, mainly due to BRCA1 and BRCA2 mutations, account for only 5-10% of this disease. The threshold for genetic testing is a 10% likelihood of detecting a mutation, as determined by validated models such as BOADICEA and Manchester Scoring System. A 90-95% reduction in breast cancer risk can be achieved with bilateral risk-reducing mastectomy in unaffected BRCA mutation carriers. In patients with BRCA-associated breast cancer, there is a 40% risk of contralateral breast cancer and hence risk-reducing contralateral mastectomy is recommended, which can be performed simultaneously with surgery for unilateral breast cancer. Other options for risk management include surveillance by mammogram and breast magnetic resonance imaging, and chemoprevention with hormonal agents. With the advent of next-generation sequencing and development of multigene panel testing, the cost and time taken for genetic testing have reduced, making it possible for treatment-focused genetic testing. There are also drugs such as the PARP inhibitors that specifically target the BRCA mutation. Risk management multidisciplinary clinics are designed to quantify risk, and offer advice on preventative strategies. However, such services are only possible in high-income settings. In low-resource settings, the prohibitive cost of testing and the lack of genetic counsellors are major barriers to setting up a breast cancer genetics service. Family history is often not well documented because of the stigma associated with cancer. Breast cancer genetics services remain an unmet need in low- and middle-income countries, where the priority is to optimise access to quality treatment.

Can axillary reverse mapping avoid lymphedema in node positive breast cancer patients?

BACKGROUND: Tracing lymphatic drainage of the ipsilateral arm of node positive breast cancer patients, termed "axillary reverse mapping" (ARM), has recently been described in several reports. We analyzed our experience with this new technique in patients scheduled for axillary lymph node dissection (ALND) and evaluated its usefulness for reducing the incidence of lymphedema. METHODS: Blue dye was injected subcutaneously along the intermuscular groove of the upper inner arm; radioisotope was injected subcutaneously in the interdigital webspace of the hand. All blue and radioactive lymph vessels and lymph nodes were recorded. Only unsuspicious "ARM lymph nodes" located in the lateral part of the axillary basin were preserved. All other level I and II axillary lymph nodes were removed. Resected ARM nodes were immediately separated from all other lymph nodes. RESULTS: ARM was performed in 143 patients subsequently undergoing ALND. ARM lymph nodes were successfully identified in 112 cases (78%). In 55 patients at least one ARM lymph node had to be removed. In 14 of these, tumor involvement was confirmed. In 71 patients one or more ARM nodes were preserved. During a median follow-up time of 19 months no axillary recurrence was noted. 35 of 114 evaluated patients developed lymphedema. Preservation of ARM lymph nodes did not significantly decrease the incidence of lymphedema. CONCLUSION: ARM is feasible for patients with node positive breast cancer. However, we found no evidence that it reduces the incidence of lymphedema.

Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA).

BACKGROUND: Pertuzumab (P) combined with trastuzumab (H)-based chemotherapy improves efficacy in early and advanced HER2-positive breast cancer. We assessed the tolerability, with particular focus on cardiac safety, of H and P with chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer. PATIENTS AND METHODS: In this multicenter, open-label phase II study, patients with operable, locally advanced, or inflammatory breast cancer were randomized 1 : 1 : 1 to receive six neoadjuvant cycles q3w (Arm A: 5-fluorouracil, epirubicin, cyclophosphamide [FEC] + H + P ×3 → docetaxel [T] + H + P ×3; Arm B: FEC ×3 → T + H + P ×3; Arm C: T + carboplatin + H [TCH]+P ×6). pCR was assessed at surgery and adjuvant therapy given to complete 1 year of H. RESULTS: Two hundred twenty-five patients were randomized. During neoadjuvant treatment, two patients (2.7%; Arm B) experienced symptomatic left ventricular systolic dysfunction (LVSD) and 11 patients (Arm A: 4 [5.6%]; Arm B: 4 [5.3%]; Arm C: 3 [3.9%]) had declines in left ventricular ejection fraction of ≥10% points from baseline to <50%. Diarrhea was the most common adverse event. pCR (ypT0/is) was reported for 61.6% (Arm A), 57.3% (Arm B), and 66.2% (Arm C) of patients. CONCLUSION: The combination of P with H and standard chemotherapy resulted in low rates of symptomatic LVSD.

Lymphatic mapping in patients with primary or recurrent breast cancer following previous axillary surgery.

AIMS: To evaluate the feasibility of lymphatic mapping in breast cancer patients after previous axillary surgery and to identify parameters associated with mapping failure. METHODS: Lymphatic mapping using peritumoural injection of blue dye and a radiocolloid was attempted in 30 patients with primary (n=7) or recurrent (n=23) breast cancer and a history of previous axillary lymph node dissection or sentinel node biopsy. RESULTS: Lymphatic mapping identified a mean number of 1.6 (range 1-3) lymph nodes in 19 of 30 patients (identification rate 63%). The lymph nodes were removed from the ipsilateral axilla (n=13), the internal mammary chain (n=2), both the internal mammary nodes and the axilla (n=2), the interpectoral space (n=1) and the contralateral axilla (n=1). Four of 19 patients revealed a positive lymph node. Fifteen of 19 patients had a negative lymph node. Axillary lymph node dissection was done in 13 of 15 patients but found no positive nodes (false negative rate=0). A negative lymphoscintigram (p<0.001) and a number of more than 10 lymph nodes removed at the time of initial surgery (p=0.02) were significantly associated with a mapping failure. CONCLUSION: Lymphatic mapping following prior axillary surgery was accurate but associated with a low identification rate. The lymphatic drainage pattern was unpredictable and the use of a radionuclide was necessary for a successful mapping procedure.

Breast-conserving surgery with resection of the nipple-areola complex for subareolar breast carcinoma.

INTRODUCTION: Breast-conserving therapy for centrally located tumours has in the past been viewed with reservation, but is now an accepted treatment. There is little published evidence, however, to show that it is safe and cosmetically acceptable. METHODS: In a prospective investigation carried out between 1996 and 2002, 44 women had surgery for 45 breast carcinomas with suspected nipple involvement. The breast was conserved and the nipple-areola complex removed. Secondary mastectomy was performed in three women because the tumour was found to reach the resection margin. Forty-one women underwent further observation. The mean tumour size at the time of operation was 18 (range 4-50) mm. Six women received preoperative chemotherapy. RESULTS: Histologically, there were seven preinvasive and 35 invasive cancers. No local failure had occurred at a median follow-up of 51 months. Six women developed distant metastasis, of whom five died. The mean score for cosmetic results (evaluated on a scale of 1-5 where a score of 1 was excellent) was 1.5 for patients and 1.7 for physicians. CONCLUSION: Breast-conserving therapy is a safe and cosmetically acceptable alternative to mastectomy for subareolar breast cancer.

The impact of preoperative breast biopsy on the risk of sentinel lymph node metastases: analysis of 2502 cases from the Austrian Sentinel Node Biopsy Study Group.

Preoperative breast biopsy might cause disaggregation of tumour cells and tumour cell spread. The purpose of this study was to investigate the impact of preoperative biopsy on the rate of metastases to the sentinel lymph node (SLN) of patients with primary breast cancer. We report the results of 2502 patients with primary breast cancer, who were operated, and a sentinel node biopsy was performed. The association of preoperative biopsy with the risk of SLN metastases was examined by regression analyses and tested for possible confounding well-known factors for axillary node metastases. In all, 1890 patients were available for final analyses; 1048 (55.4%) patients had a preoperative diagnosis performed by fine-needle aspiration or core biopsy; 641 (33.9%) patients had a positive SLN when conventional H&E and IHC staining was performed. Patients with preoperative breast biopsy showed a 1.37 times (95% CI, 1.13-1.66) increased risk of SLN metastases on univariate analysis, but this result was not persistent when analysis was adjusted for other relevant factors for axillary node metastases, OR 1.09 (95% CI, 0.85-1.40). In addition, subgroup analyses of the risk for occult micro metastases to the SLN (detected by IHC only) on H&E-negative cases also showed no increased risk associated with preoperative biopsy, OR 1.07 (95% CI, 0.69-1.65). The conclusion, based on the present data, is that preoperative breast biopsy does not cause artificial tumour cell spread to the SLN, with possible negative impact on the prognosis of breast cancer.

[Early experience with the advanced breast biopsy instrumentation system in a multicentre study]. / Zwischenbericht über die Anwendung des 'Advanced Breast Biopsy Instrumentation'- Systems im Rahmen einer Multizenterstudie.

Early Experience with the Advanced Breast Biopsy Instrumentation System in a Multicentre Study In an Austrian multicentre trial between September 1998 and December 2001, 474 procedures were performed with the Advanced Breast Biopsy Instrumentation (ABBI), and 389 were entered in the protocol. For reasons of patient comfort, radiological accuracy and low complication rate, the stereotactic excision biopsy with the ABBI system is a useful alternative to 'open' biopsy of non-palpable breast lesions, although there are technical limitations. The question of the therapeutic option in breast cancer cannot be answered yet.

[The value of F-18 fluorodeoxyglucose in positron emission tomography diagnosis of breast carcinoma]. / Wertigkeit der F-18-Fluorodeoxy-Glukose-Positronenemissionstomographie-Diagnostik beim Mammakarzinom.

Fluorodeoxyglucose-positron emission tomography (F-18-FDG-PET) has become an important issue in the diagnosis of malignant tumors within the last years. In breast cancer PET has been established in the diagnosis of the primary tumor as well as in recurrences with a sensitivity of 90% and a specificity of 75%-100%; additional a sensitivity of more than 90% and a specificity of about 75% is also seen in axillary lymph nodes detection. With our own results we were able to prove sensitivity of positron emission tomography in diagnosing the primary lesion, locoregional lymph nodes and the staging of metastases. Furthermore, positron emission tomography seems to be superior to conventional imaging modalities in staging primary and recurrent breast cancer, distant metastases and lymph nodes outside the axilla.

Is sentinel lymph node biopsy reliable and indicated after preoperative chemotherapy in patients with breast carcinoma?

BACKGROUND: Many studies support the concept and accuracy of sentinel lymph node biopsy (SNB) for staging patients with breast carcinoma, which can be performed with low morbidity in lymph node negative patients. Preoperative chemotherapy (PC) plays an important role in the treatment of patients with operable breast carcinoma and is another approach with which to reduce radical surgery in patients with more advanced disease. It is of interest whether the sentinel lymph node accurately represents the axillary status after PC and, thus, whether the sentinel node concept can be applied to both groups. METHODS: Thirty-three patients underwent SNB after chemotherapy and prior to axillary lymph node dissection. RESULTS: The average greatest tumor dimension before chemotherapy (33 mm +/- 2 mm) was significantly larger (P = 0.000) than after therapy (20 mm +/- 3 mm). Histopathologic complete remission was seen in only three patients. One or two sentinel lymph nodes (average, 1.7 lymph nodes) were identified with certainty in 29 of 33 procedures and accurately predicted axillary lymph node status in all of these patients. Breast-conserving surgery was possible in 21 patients (64%), and axillary lymph nodes were involved in 22 patients (67%). CONCLUSIONS: Even after patients undergo PC, SNB seems to be a reliable method for accurate staging of the axilla in those more advanced breast carcinoma. Thus, axillary dissection may be avoided in certain patients. Lymph node involvement seems to be likely in women with suspicious axillary findings before chemotherapy who have no visible sentinel lymph nodes on preoperative lymphosintigraphy and in patients without recurrent tumors. Further investigation of the SNB concept in this patient group should be evaluated in larger studies.

[Therapy studies of the Austrian Breast Cancer Group (ABC)]. / Die Therapiestudien der Austrian Breast Cancer Group (ABC).

The Austrian Breast Cancer Group (ABC) consisting of more than 60 participating centers in Austria has randomized more than 5800 patients in 11 randomized trials since 1984. At present, roughly 30% of all patients with the diagnosis primary breast cancer are accrued in protocols throughout the country. Due to specific activities, the breast conservation rate raised from an initial 20% to more than 60% in the last years. Multicenter trials are not only the basis for progress in medicine but also tools for quality control and quality improvement.