Eliminating the breast cancer surgery paradigm after neoadjuvant systemic therapy: current evidence and future challenges.

In patients with operable early breast cancer, neoadjuvant systemic treatment (NST) is a standard approach. Indications have expanded from downstaging of locally advanced breast cancer to facilitate breast conservation, to in vivo drug-sensitivity testing. The pattern of response to NST is used to tailor systemic and locoregional treatment, that is, to escalate treatment in nonresponders and de-escalate treatment in responders. Here we discuss four questions that guide our current thinking about 'response-adjusted' surgery of the breast after NST. (i) What critical diagnostic outcome measures should be used when analyzing diagnostic tools to identify patients with pathologic complete response (pCR) after NST? (ii) How can we assess response with the least morbidity and best accuracy possible? (iii) What oncological consequences may ensue if we rely on a nonsurgical-generated diagnosis of, for example, minimally invasive biopsy proven pCR, knowing that we may miss minimal residual disease in some cases? (iv) How should we design clinical trials on de-escalation of surgical treatment after NST?

Combined PET-CT and axillary lymph node marking with radioactive iodine seeds (MARI procedure) for tailored axillary treatment in node-positive breast cancer after neoadjuvant therapy.

BACKGROUND: The treatment of axillary lymph node metastases after neoadjuvant systemic therapy (NST) remains debatable and axillary lymph node dissection (ALND) is still the standard of care. Marking axillary lymph nodes with radioactive iodine seeds (MARI procedure) is accurate in restaging the axilla after NST (false-negative rate 7 per cent). Here, the potential of tailored axillary treatment, determined by combining the results of PET-CT before NST with those of the MARI procedure after NST, was analysed. METHODS: A cohort of axillary node-positive patients was used to construct a hypothetical treatment algorithm based on a combination of PET-CT and the MARI procedure. In the algorithm, the number of fluorodeoxyglucose (FDG)-avid axillary lymph nodes (1-3 versus 4 or more) before NST and the tumour status of the MARI node (positive versus negative) after NST were used to tailor axillary treatment. All patients in the cohort underwent ALND, allowing estimation of potential overtreatment and undertreatment. RESULTS: A total of 93 patients were included in the study. Between one and three FDG-avid axillary lymph nodes were observed in 59 patients, and four or more in 34 patients. The MARI node was tumour-negative in 32 patients and showed residual disease in 61. Treatment according to the constructed algorithm would have resulted in 74 per cent of patients avoiding an ALND, with potential undertreatment in three patients (3 per cent) and overtreatment in 16 (17 per cent). CONCLUSION: Tailored axillary treatment after NST in node-positive patients, by combining PET-CT before NST and the MARI procedure after NST, has the potential for ALND to be avoided in 74 per cent of patients.

PET/CT with 18F-FDG predicts short-term outcome in stage II/III breast cancer patients upstaged to N2/3 nodal disease.

INTRODUCTION: 18F-FDG PET/CT has high positive predictive value for the detection of avid lymph node metastases in breast cancer patients. We analysed the effect of upstaging lymph nodes by PET/CT on short-term outcome in stage II/III breast cancer patients. PATIENTS AND METHODS: A total of 278 stage II/III primary breast cancer patients (mean age 48.9 years, range 19-75 years) were re-staged with 18F-FDG PET/CT before start of pre-operative systemic treatment (PST). Patients were divided in three groups based on risk for local recurrence: a low - (T2N0), intermediate - (T0-2N1 and T3N0) and a high-risk group (T0-3N2-3, T3N1 and T4). Within these groups we looked at local recurrence-free survival (LRFS), recurrence-free survival (RFS) and overall survival (OS) within the first 3 years of follow-up. RESULTS: With a median follow-up (FU) of 50 months the RFS, LRFS and OS were 87%, 88% and 92% respectively for the whole group. PET/CT upstaged 43 patients from the low- and intermediate risk group to the high-risk group, based on detection of ≥4 avid axillary nodes or occult N2/3-disease. Patients upstaged with PET/CT had more events for all three analyses compared to the original risk groups, which resulted in a significantly worse RFS (69.8%; p = 0.03) a nearly significantly worse LRFS (p = 0.052) and no effect in OS (p = 0.433). DISCUSSION: Additional PET/CT staging allows breast cancer patients to be treated according to the true stage, still stage II/III breast cancer patients upstaged to N2/3 by PET/CT have worse short-term outcome, despite adjustment of treatment, than patients staged high-risk with conventional imaging.

The prognostic value of the neoadjuvant response index in triple-negative breast cancer: validation and comparison with pathological complete response as outcome measure.

The Neoadjuvant response index (NRI) has been proposed as a simple measure of downstaging by neoadjuvant treatment in breast cancer. It was previously found to predict recurrence-free survival (RFS) in triple-negative (TN) breast cancer. It was at least as accurate as the standard binary system, the absence or presence of a pathological complete remission (pCR), which is the commonly employed outcome measure. The NRI was evaluated in an independent consecutive series of patients to validate the previous findings. Univariable and multivariable analyses were done to assess the predictive value of clinical parameters and of the NRI for RFS. We combined the original and validation series of patients to build a multivariable predictive model for RFS after neoadjuvant chemotherapy in TN breast cancer. The validation set (N = 108) confirmed that patients with a higher-than-median NRI (>0.7) had excellent RFS (P = 0.002), similar to that of patients who had achieved a pCR. Multivariable analysis in 191 patients showed that the NRI was a strong independent predictor of RFS (P = 0.0002), with N-stage (P = 0.001) and T-stage (P = 0.014) ranking second and third, respectively. Importantly, among patients who did not achieve a pCR (NRI values below 1), higher NRI values were still associated with better RFS. The NRI is a simple method and a practical tool to predict RFS in TN breast cancer patients treated with neoadjuvant chemotherapy. It adds prognostic information to the presence or absence of pCR and could be useful to compare the efficacies of different chemotherapy regimens.

The use of radioactive iodine-125 seed localization in patients with non-palpable breast cancer: a comparison with the radioguided occult lesion localization with 99m technetium.

BACKGROUND: Radioactive Seed Localization with a radioactive iodine-125 seed (RSL) and Radioguided Occult Lesion Localization with 99mTechnetium colloid (ROLL) are both attractive alternatives to wire localization for guiding breast conserving surgery (BCS) of non-palpable breast cancer. The aim of this study was to evaluate and compare the efficacy of RSL and ROLL. METHODS: We retrospectively analyzed 387 patients with unifocal non-palpable ductal carcinoma in situ (DCIS) or invasive carcinoma treated with BCS at the Netherlands Cancer Institute. In total 403 non-palpable lesions were localized either by RSL (N = 128) or by ROLL (N = 275). Primary outcome measures were positive margins and re-excision rates; the secondary outcome measure was weight of the specimen. RESULTS: Pre-operative mammography or ultrasound showed similar sizes of DCIS and invasive tumours in both RSL and ROLL groups. In the RSL group, more lesions were DCIS (58%) than in the ROLL group, where 32% of the lesions were pure DCIS. The proportions of focally positive margins (11% vs. 10%) and more than focally positive margins (9% vs. 9%) were comparable between the RSL and the ROLL group, resulting in the same re-excision rate in both RSL and ROLL groups (9% vs. 10%). For DCIS lesions, the specimen weight was significantly lower in the RSL group than in the ROLL group after adjusting for tumour size on mammography (12 g; 95% CI 2.6-21). CONCLUSION: Margin status and re-excision rates were comparable for RSL and ROLL in patients with non-palpable breast lesions. Because of the significant lower weight of the resected specimen in DCIS, the feasibility of position verification of the I-125 seed and more convenient logistics, we favour RSL over ROLL to guide breast-conserving therapy.

Neoadjuvant chemotherapy adaptation and serial MRI response monitoring in ER-positive HER2-negative breast cancer.

BACKGROUND: Changing the neoadjuvant chemotherapy regimen in insufficiently responding breast cancer is not a standard policy. We analysed a series of patients with 'luminal'-type breast cancer in whom the second half of neoadjuvant chemotherapy was selected based on the response to the first half. METHODS: Patients with oestrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer received three courses of neoadjuvant dose-dense doxorubicin and cyclophosphamide (ddAC). Three further courses of ddAC were administered in case of a 'favourable response' on the interim magnetic resonance imaging (MRI) and a switch to docetaxel and capecitabine (DC) was made in case of an 'unfavourable response', using previously published response criteria. The efficacy of this approach was evaluated by tumour size reductions on serial contrast-enhanced MRI, pathologic response and relapse-free survival. RESULTS: Two hundred and forty-six patients received three courses of ddAC. One hundred and sixty-four patients (67%) had a favourable response at the interim MRI, with a mean tumour size reduction of 31% after the first three courses and 34% after the second three courses. Patients with unfavourable responsive tumours had a mean tumour size reduction of 12% after three courses and received three courses of DC rather than ddAC. This led to a mean shrinkage of 27%. CONCLUSION: The tumour size reduction of initially less responsive tumours after treatment adaptation adds further evidence that a response-adapted strategy may enhance the efficacy of neoadjuvant chemotherapy.

First clinical experience with a dedicated PET for hanging breast molecular imaging.

AIM: Recently, a high-resolution dedicated PET system for hanging breast imaging (MAMMI PET) has been developed to improve primary tumor detection and characterization. The aim of this pilot study was to assess its feasibility for tumor detection and FDG uptake measurements in patients with stage II and III breast cancer. METHODS: Thirty-two patients with invasive breast cancer (26 ductal, 4 lobular, 2 other), prior to and/or during neoadjuvant chemotherapy, underwent both conventional PET/CT and MAMMI PET in prone position with hanging breasts. Conventional PET/CT and MAMMI PET were performed 60±10 min and 110±10 min after injection of 180-240 MBq of FDG, respectively. Primary tumor detection was assessed and FDG uptake, expressed as maximum standardized uptake value (SUVmax), was calculated. RESULTS: Both MAMMI PET and conventional PET/CT visualized the primary tumor in 31 patients (97%). The mean distance from the tumor to the pectoral muscle was 26.4mm (smallest distance 3.3mm). Agreement in FDG uptake between PET/CT and MAMMI PET was high (r=0.86, 95% CI 0.69-0.94). However, SUVmax as assessed with MAMMI PET was consistently higher than with PET/CT in all patients with an average ratio of 2.7. CONCLUSION: The dedicated high-resolution breast PET with hanging breast technique is able to visualize approximately all breast tumors in stage II and III breast cancer patients, including tumors in the vicinity of the thoracic wall. This may enable its sequential use in the assessment of response in breast cancer patients receiving neoadjuvant systemic therapy, although SUVmax values are not directly comparable to standard PET/CT.

Radioguided occult lesion localisation (ROLL) in breast-conserving surgery after neoadjuvant chemotherapy.

BACKGROUND: An important benefit of neoadjuvant chemotherapy, as compared to adjuvant chemotherapy, in breast cancer patients is down staging of the primary tumour, which allows for more breast-conserving surgery. When a tumour becomes non-palpable after this down staging, precise localisation of the original tumour bed is crucial to be able to perform breast-conserving surgery. Radioguided Occult Lesion Localisation with (99m)Technetium (ROLL-(99m)Tc) is commonly used to perform breast-conserving surgery in patients with non-palpable breast tumours. We modified this technique to use it in the neoadjuvant setting. The present analysis was performed to assess its feasibility and analyse the number of patients in which a mastectomy was correctly withheld using this technique. METHODS: A retrospective analysis was performed for all patients who were treated with neoadjuvant chemotherapy between 2007 and 2010 in our institute and underwent breast-conserving surgery with the ROLL-(99m)Tc technique afterwards. The status of the margins and the weight of the resected specimen were assessed. RESULTS: The median weight of the resected specimen in these 83 patients was 53 g (range: 11-204 g). Eleven of the 58 patients with residual disease revealed positive margins at pathological examination. However, in only 5 of those 11 patients a secondary mastectomy was indicated. This means that in 94% of all included patients a mastectomy was correctly withheld. CONCLUSION: The ROLL-(99m)Tc technique is a feasible technique that can be used to perform breast-conserving surgery after neoadjuvant chemotherapy in a carefully selected group of patients.

Molecular Imaging in Breast Cancer: From Whole-Body PET/CT to Dedicated Breast PET.

Positron emission tomography (PET), with or without integrated computed tomography (CT), using 18F-fluorodeoxyglucose (FDG) is based on the principle of elevated glucose metabolism in malignant tumors, and its use in breast cancer patients is frequently being investigated. It has been shown useful for classification, staging, and response monitoring, both in primary and recurrent disease. However, because of the partial volume effect and limited resolution of most whole-body PET scanners, sensitivity for the visualization of small tumors is generally low. To improve the detection and quantification of primary breast tumors with FDG PET, several dedicated breast PET devices have been developed. In this nonsystematic review, we shortly summarize the value of whole-body PET/CT in breast cancer and provide an overview of currently available dedicated breast PETs.

Association of primary tumour FDG uptake with clinical, histopathological and molecular characteristics in breast cancer patients scheduled for neoadjuvant chemotherapy.

PURPOSE: The aim of this study was to evaluate the association of primary tumour (18)F-fluorodeoxyglucose (FDG) uptake with clinical, histopathological and molecular characteristics of breast cancer patients scheduled for neoadjuvant chemotherapy. Second, we wished to establish for which patients pretreatment positron emission tomography (PET)/CT could safely be omitted because of low FDG uptake. METHODS: PET/CT was performed in 214 primary stage II or III breast cancer patients in the prone position with hanging breasts. Tumour FDG uptake was qualitatively evaluated to determine the possibility of response monitoring with PET/CT and was quantitatively assessed using maximum standardized uptake values (SUV(max)). FDG uptake was compared with age, TNM stage, histology, hormone and human epidermal growth factor receptor 2 status, grade, Ki-67 and molecular subtype in univariable and multivariable analyses. RESULTS: In 203 tumours (95 %) FDG uptake was considered sufficient for response monitoring. No subgroup of patients with consistently low tumour FDG uptake could be identified. In a univariable analysis, SUV(max) was significantly higher in patients with distant metastases at staging examination, non-lobular carcinomas, tumours with negative hormone receptors, triple negative tumours, grade 3 tumours, and in tumours with a high proliferation index (Ki-67 expression). After multiple linear regression analysis, triple negative and grade 3 tumours were significantly associated with a higher SUV(max). CONCLUSION: Primary tumour FDG uptake in breast cancer patients scheduled for neoadjuvant chemotherapy is significantly higher in tumours with prognostically unfavourable characteristics. Based on tumour characteristics associated with low tumour FDG uptake, this study was unable to identify a subgroup of patients unlikely to benefit from pretreatment PET/CT.

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.

A trial of consent procedures for future research with clinically derived biological samples.

BACKGROUND: The aims of this study were to determine which consent procedure patients prefer for use of stored tissue for research purposes and what the effects of consent procedures on actual consenting behaviour are. METHODS: We offered 264 cancer patients three different consent procedures: 'one-time general consent' (asked written informed consent), 'opt-out plus' (had the opportunity to opt out by a form), or the standard hospital procedure (control group). The two intervention groups received a specific leaflet about research with residual tissue and verbal information. The control group only received a general hospital leaflet including opt-out information, which is the procedure currently in use. Subsequently, all patients received a questionnaire to examine their preferences for consent procedures. RESULTS: In all, 99% of patients consented to research with their residual tissue. In the 'one-time consent' group 85% sent back their consent form. Patients preferred 'opt-out plus' (43%) above 'one-time consent' (34%) or 'opt-out' (16%), whereas 8% indicated that they did not need to receive information about research with residual tissues or be given the opportunity to make a choice. CONCLUSIONS: The 'opt-out plus' procedure, which places fewer demands on administrative resources than 'one-time consent', can also address the information needs of patients.

Volume-controlled vs no/short-term drainage after axillary lymph node dissection in breast cancer surgery: a meta-analysis.

It is unknown whether there are any clinically relevant differences between volume-controlled (<30-50 ml/24h across trials) vs no/short-term drainage after axillary lymph node dissection in breast cancer surgery on outcomes such as seroma formation, wound infection or length of hospital stay. Randomised controlled trials comparing volume-controlled drainage vs no or short-term drainage after axillary lymph node dissection in breast cancer surgery were identified systematically using Pubmed, EMBASE and The Cochrane library. Trial data were reviewed and extracted independently by two reviewers in a standardised unblinded manner. Six randomised controlled trials which included a total of 561 patients fulfilled our inclusion criteria. Patients randomised to volume-controlled drainage were less likely to develop clinically relevant seromas compared to patients randomised to no/short-term drainage. There was, however, no difference in wound infections between patients treated with volume-controlled drainage and patients with no or short-term drainage. Patients randomised to volume-controlled drainage stayed significantly longer in hospital than patients randomised to no/short-term drainage. Based on available evidence, clinically relevant seromas occur more frequently in patients treated with no/short-term drainage. However, no/short-term drainage after axillary lymph node dissection does not lead to an increase in wound infections and is associated with shorter hospital stay.

Expansion of donor hepatocytes after recombinant adenovirus-induced liver regeneration in mice.

Hepatocyte transplantation is a potential form of therapy for patients with genetic hepatodeficiency disorders. Unfortunately, hepatocellular transplantation has been limited because of the relatively low numbers of donor cells that can ultimately take up residence in the host liver. To give the donor cells a proliferative stimulus, a recombinant adenovirus vector that expresses a nonsecreted urokinase (urokinase-type plasminogen activator) was transduced into the livers of recipient animals before transplantation. Because urokinase production in hepatocytes causes the slow turnover of hepatocytes, 2 days after adenovirus-mediated gene transfer into the livers of recipient mice, 2 x 10(6) congenic donor cells tagged with beta-galactosidase (beta-Gal) reporter were implanted via the portal vein. As a result, on average, 8.6% of the recipient hepatocytes in the livers were derived from donor cells--a 20-fold increase compared with control animals in which no proliferative stimulus was present.

Method for multiple portal vein infusions in mice: quantitation of adenovirus-mediated hepatic gene transfer.

For many preclinical studies, the mouse has been an invaluable model. For hepatic studies, including gene therapy, the use of the mouse has been limited because of the inability to obtain long-term portal vein access. In this study, we have developed a surgical cannula model that allows for repeat portal vein infusion in a noninvasive manner. We have used this model to establish that the tissue distribution of recombinant adenoviral vectors is similar after portal vein or peripheral vein infusion. The majority of the vector was present in the liver, ranging from 14 to 28 copies per hepatocyte. The second most prevalent tissues were the spleen and lung with 1/10 less adenoviral DNA. The brain and ovaries had the least DNA, 1/1000 less than the liver. Additional studies were performed to study the effects of secondary adenovirus infusion through the portal vein cannula. Permanent portal vein access in a mouse model will be invaluable for a large number of medical studies, including the development of new technologies for hepatic gene transfer.

Adenovirus-mediated urokinase gene transfer induces liver regeneration and allows for efficient retrovirus transduction of hepatocytes in vivo.

Retrovirus-mediated gene transfer into hepatocytes in vivo results in long-term gene expression. Limitations include the need to remove two-thirds of the liver and the relatively low frequency of gene transfer. To increase gene transfer without surgical hepatectomy, mouse hepatocytes were transduced in vivo with a recombinant adenovirus that transiently expressed urokinase, resulting in high rates of asynchronous liver regeneration. During the regenerative phase, in vivo retroviral-mediated gene transfer in hepatocytes resulted in 5- to 10-fold greater transduction efficiencies than that obtained by conventional partial hepatectomy. In 3-4 weeks, the architecture and microscopic structure of the recipient livers were normal. The two-viral system of achieving permanent transgene expression from hepatocytes in vivo offers an alternative approach to current ex vivo and in vivo gene-transfer models.

Adenovirus-mediated transfer of the amphotropic retrovirus receptor cDNA increases retroviral transduction in cultured cells.

The presence of functional amphotropic receptors on the cell surface is necessary for amphotropic retrovirus-mediated gene transfer. A recombinant adenoviral vector that expresses the receptor for amphotropic retrovirus (RAM) was constructed and used to express the receptor cDNA in different cell types in culture. Transfer of the RAM cDNA increased amphotropic retroviral-mediated transfer from 0 to 60% in Chinese hamster ovary cells. RAM expression increased retroviral transduction four- to eight-fold from 2-4% to 18%-35% in HeLa, Namalva, and X63 cells, but had no effect on 208F and HepG2 cells which have high baseline retroviral transduction rates of about 50%. For the purpose of application to ex vivo gene therapy, primary mouse hepatocytes were studied in a similar manner. Hepatocytes had a baseline transduction efficiency of about 40% and did not have increased rates of retroviral-mediated gene transfer with expression of recombinant RAM. This recombinant adenoviral vector conferred infection of amphotropic retrovirus into cells that were relatively resistant to infection, thus offering a rapid and easy method to stably introduce genes into these cell lines.