Stage wetenschap M3 Verslagscripties.umcg.eldoc.ub.rug.nl/FILES/root/geneeskunde/... ·...

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1 Stage wetenschap M3 Verslag Titel: Neoadjuvant chemotherapy adaptation and serial MRI response monitoring in ER-positive HER2-negative breast cancer Titel aanvraag: Responsmonitoring als prognostische parameter bij neoadjuvante chemotherapie voor mammacarcinoom Naam: Lisanne Rigter Studentnummer: 1641638 Locatie (instituut, afdeling): Antoni van Leeuwenhoek Ziekenhuis, Interne geneeskunde Facultair begeleider: Dr. Imholz Extern begeleider: Prof. dr. Rodenhuis

Transcript of Stage wetenschap M3 Verslagscripties.umcg.eldoc.ub.rug.nl/FILES/root/geneeskunde/... ·...

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Stage wetenschap M3 Verslag Titel: Neoadjuvant chemotherapy adaptation and serial MRI response monitoring in ER-positive HER2-negative breast cancer Titel aanvraag: Responsmonitoring als prognostische parameter bij neoadjuvante chemotherapie voor mammacarcinoom Naam: Lisanne Rigter Studentnummer: 1641638 Locatie (instituut, afdeling): Antoni van Leeuwenhoek Ziekenhuis, Interne geneeskunde Facultair begeleider: Dr. Imholz Extern begeleider: Prof. dr. Rodenhuis

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Abstract Introduction: Changing the neoadjuvant chemotherapy regimen in insufficiently responding breast cancer is not a standard policy. We analysed a consecutive series of patients in whom the second three courses of neoadjuvant chemotherapy were selected based on the response to the first three courses. Materials and methods: Estrogen receptor positive, human epidermal growth factor 2 receptor negative breast cancer patients received three courses of neoadjuvant dose dense Doxorubicin/Cyclophosphamide (ddAC). Serial contrast enhanced Magnetic Resonance Imaging (CE-MRI) studies before chemotherapy, after three and after six courses of chemotherapy were obtained. Three further courses of ddAC were administered in case of a favorable response on the second MRI and a switch to Docetaxel and Capecitabine was made in case of an unfavorable response. The efficacy of this approach was evaluated by pathological response, relapse free interval and by tumor size reductions on serial CE-MRI. Results: 309 patients were included. Early response was evaluated by MRI in 275 patients and in 180 patients all three serial MRI measurements were obtained. Pathological response was better in patients who had a favorable initial MRI response (p=0.067 for Neoadjuvant Response Index, p=0.022 for a pathological complete remission of the breast). The MRI response had no impact on the relapse free interval (p=0.296). Unfavorable initial responders had a median tumor size reduction of 8% after 3 courses of ddAC, while favorable responders had a 34% reduction. After switching to the alternative chemotherapy regimen, their tumor size reduction was 36% after three additional courses, while that of initially favorable responders who continued their successful first chemotherapy was 45%. A tumor diameter on MRI smaller than the median after six courses of neoadjuvant chemotherapy was a favorable prognostic factor for the recurrence free interval (hazard ratio 3.0 (95% confidence interval 1.0 – 9.3), p=0.045). Conclusions: The tumor size reduction of initially non-responsive tumors after treatment adaptation adds further evidence that a response-adapted strategy may enhance the efficacy of neoadjuvant chemotherapy. Prospective studies to optimally exploit this treatment strategy are warranted.

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Table of contents Page number Introduction 4 Problem definition 6 Material and method 7 Results 9 Discussion 18 Conclusion 21 Bibliography 22 Dutch abstract 26 Appendix 27

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Introduction Breast cancer is the most common type of cancer in women and is a major cause of death.(1) It is a very heterogeneous disease in which patient and tumor characteristics, therapeutic response and prognosis vary greatly among subtypes. The importance of adjuvant chemotherapy in terms of disease free and overall survival has been confirmed since the 1980’s.(2) Neoadjuvant chemotherapy Neoadjuvant chemotherapy is believed to be equally effective as adjuvant chemotherapy in reducing breast cancer mortality.(3) Other advantages include response monitoring and downstaging resulting in better possibilities for breast conserving therapy.(4) A single-institution project on neoadjuvant chemotherapy initiated in the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital in 1999, with main aims to develop methods for prediction and monitoring of response, to develop clinical methods and treatments and finally to improve the efficacy of neoadjuvant chemotherapy with the purpose of increasing the cure rate in high risk breast cancer. In this program, neoadjuvant chemotherapy is indicated in women younger than 70 years of age diagnosed with locally advanced breast cancer or early stage breast cancer with a tumor larger than 3 cm or lymph node involvement. After neoadjuvant chemotherapy, local therapeutic options are mastectomy or breast conserving surgery, commonly followed by locoregional radiotherapy. Adjuvant endocrine therapy is routinely given in hormone receptor positive tumors. Tumor characteristics and subtypes Clinical, histological and pathological characteristics provide information on the individual prediction of outcome and response to therapy, which are used for decision making regarding neoadjuvant, surgical and adjuvant treatment. Clinical and histological characteristics are T-stage, N-stage, tumor histology and histological grade. Positive nodal status results in a worse prognosis, though patients with both node-negative and node-positive disease benefit from chemotherapeutic treatment.(5) Lobular cancers have been reported to be less responsive to chemotherapy than the more common ductal breast cancers, even though conflicting data have been published on this topic.(6-8) Histological grade, a measure for the degree of tubule formation, nuclear pleomorphism and mitotic frequency, is associated with survival, a higher histological grade indicating a worse prognosis.(9) The most important molecular markers are the estrogen receptor (ER), the progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2). In estrogen receptor positive breast cancer, prognosis is improved by estrogen deprivation (for example through tamoxifen or aromatase inhibitors). Progesterone receptor status appears to have prognostic impact, but it has no predictive value.(10) Distinguishing incompletely and highly endocrine sensitive tumors, incompletely endocrine sensitive tumors showing less than 50% staining of either ER or PR, is important for treatment decisions, as low expression levels are associated with better response to chemotherapy and less benefit from endocrine therapy.(11) HER2 overexpression is associated with a worse prognosis and the tumor is susceptible to targeted therapy (lapatinib or trastuzumab, for example).(12)

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Another frequently used molecular marker is Ki67, a marker of cell proliferation which can be determined through immunohistochemistry.(13) Immunohistochemistry is used for defining subtypes which approach the intrinsic subtypes that are defined based on gene expression as measured by mRNA microarrays.(14-17) For this purpose, the PAM50 classifier is the accepted standard. This classifier includes a reduced gene set for the determination of the major intrinsic biological subtypes, which determine the risk of relapse.(16) Biomarker assessment by immunohistochemistry uses specific antibodies for each marker. Results are given as an estimation of the number of positive staining cells. Estrogen receptor (ER) positive, human epidermal receptor 2 (HER2) negative breast cancer represents about two thirds of all breast cancer and is known for its relative chemotherapy resistance in the neoadjuvant setting, with a low pathologic complete remission (pCR) rate but nevertheless a favorable prognosis. This group is often subdivided into a luminal A subtype, with low cell proliferation markers, and a higher proliferative luminal B subtype.(18;19)

The 12th St Gallen International Breast Cancer Conference (2011) Expert Panel proposed a simplified immunohistochemical classification when mRNA expression microarray information is not available. Luminal A and luminal B (HER2 negative) subtypes include ER and/or PR positive and HER2 negative tumors which are distinguished by Ki67 level. When Ki67 level is not available, the histological grade can be used as an alternative estimate of proliferation.(20)

Predictive and prognostic assays The response to neoadjuvant chemotherapy is highly variable and this may lead to partial overtreatment. The previously mentioned characteristics are used to decide on the use of chemotherapy, based on their predictive or prognostic impact. Because of these multiple factors influencing the response to chemotherapy and prognosis, several models have been proposed to determine the indication for neoadjuvant chemotherapy. Adjuvant! is a widely used model that estimates the prediction of 10-year breast cancer outcome based on patient and tumor characteristics. It is used for the prediction of the benefit of adjuvant chemotherapy in stages I through III breast cancer.(21) Several multigene genetic assays have been proposed as a prognostic tool, for example the Oncotype Dx® and Mammaprint ®.(22;23) Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki67 provide prognostic information of similar value as that of Oncotype Dx.(24) Colleoni et al. developed a nomogram for the prediction of the propability of pathologic complete remission using ER, PR, Ki67 and the number of neoadjuvant chemotherapy cycles.(25) Response evaluation Response monitoring is essentially the serial measurement of the size of the primary tumor during chemotherapy. It can be achieved by means of physical examination, by sonographic measurement or by mammographic measurement. (26;27) Contrast enhanced MRI (CE-MRI) examination for the evaluation of neoadjuvant chemotherapy response is generally regarded as the most accurate imaging method.(28;29) CE-MRI is used for visualization of dynamical, kinetical and morphological characteristics of the tumor. A recommended criteria for a satisfactory

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CE-MRI response during chemotherapy is the change in late enhancement diameter as it has been shown to be the best predictor of pCR.(30) Late enhancement diameter is related to the size of the tumor but in fact estimates the size of the area of abnormal vascularity. It is assessed by the area of decreased signal intensity at 450 seconds after contrast injection. Less than 25% reduction is predictive for residual disease at pathological examination after neoadjuvant chemotherapy and surgery.(30) Recently, it has been shown that more than 25% reduction is strongly predictive for a pathologic complete remission (pCR) in triple-negative disease, but is less accurate in tumors that are estrogen receptor-positive and HER2-negative.(31) The latter group of patients frequently receives preoperative chemotherapy with the objective to decrease tumor size to facilitate breast conserving therapy. A pCR, however, is only rarely achieved. As a result, the pCR is not a sensitive measure of tumor response. For there is no standardized definition of pCR, in- or exclusion of remission of breast, axillary nodes and focal invasive cancer result in variable outcomes. Different subtypes have diverse pCR and survival rates, which makes it difficult to assign prognostic value.(32) The ‘neoadjuvant response index’ (NRI) was developed for obtaining a quantitative scale for the response to neoadjuvant chemotherapy. This is a simple scoring system reflecting the degree of downstaging in breast and axilla, resulting in a score between 0 and 1.(33) The use of the NRI is particularly beneficial for response assessment in tumor types with low pCR rates. Resistance to chemotherapy implies an indication for a different strategy. It is tempting to assume that neoadjuvant chemotherapy may be superior to adjuvant chemotherapy if the regimen is adapted to the response of the primary tumor. If the tumor fails to decrease in size, a switch could be made to a (presumably) non-cross resistant regimen that could be more effective than the first one. A recent report from the German Breast Group suggests that this concept is valid, and that patients who received Vinorelbine and Capecitabine after failure of a combination of Docetaxel, Doxorubicin and Cyclophosphamide (TAC) had a better survival than those who continued with TAC.(34) Problem definition Decision making concerning neoadjuvant chemotherapy in breast cancer is complex, with multiple characteristics holding predictive and prognostic impact, multiple theories on the effectiveness of different chemotherapy regimens (e.g. response adapted approach and to which chemotherapeutic treatment) and multiple methods for response monitoring. Even though neoadjuvant chemotherapy theoretically provides opportunity for response evaluation and treatment adaptation, these methods are still in development. ER-positive HER2-negative breast cancer is a difficult subtype to define the indication for chemotherapy because of low pathological remission rates and late relapses, hampering a timely evaluation. Potential optimization of neoadjuvant chemotherapy regimens can –in theory- be done through avoiding (all) chemotherapy for non-responsive tumors and through adaptation of chemotherapy to response. Non-responsive tumors are possibly surrogate intrinsic subtype ‘luminal A’s’ and/or highly endocrine responsive tumors, as proposed by the St. Gallen International Breast Cancer Conference (2011) Expert Panel.(20) The German Breast Group recently showed validating results for a response-adapted approach, but multiple questions remain; (i) how and when should

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response be monitored, (ii) when should a response be defined as favorable, (iii) how many courses of chemotherapy should be given, (iv) is there an MRI result that should be aimed at and (v) is Docetaxel and Capecitabine non-cross resistant in relation to Doxorubicine and Cyclophosphamide? It is impossible to answer all these questions in a single prospective study. This is a retrospective study on a series of consecutive patients with ER-positive HER2-negative breast cancer, who were started on neoadjuvant chemotherapy with dose-dense Doxorubicin-Cyclophosphamide (ddAC). The aim of this single centre study was to evaluate the factors that influence the outcome in this series of patients who received a response adapted approach and to define hypotheses and requirements for the further development of this strategy.

Materials and methods Patients Patients between 18 and 70 years of age were included when invasive ER+ HER2- breast cancer was present, that was either greater than 3 cm or was associated with at least one tumor positive lymph node. When bilateral cancer was found, the larger tumor was used for this analysis. A previous diagnosis of invasive breast cancer was a reason for exclusion. Only patients who received initial chemotherapy consisting of dose-dense AC were included. All patients either took part in a single-institution clinical trial, which was approved by the ethical committee or were treated off study according to the standard arm. All patients gave informed consent. Chemotherapy All patients began neoadjuvant chemotherapy with three courses of dose dense Doxorubicine and Cyclophosphamide (ddAC, Doxorubicin 60 mg/m2 and Cyclophosphamide 600 mg/m2 on day 1, every 14 days, with PEG-filgrastim on day 2) between 2004 and 2012. Three courses of Docetaxel and Capecitabine (DC, Docetaxel 75 mg/m2 on day 1, every 21 days and Capecitabine 2 x 1000 mg/m2 on days 1-14) were administered when an ‘unfavorable response’ was detected by MRI evaluation. When a ‘favorable response’ was achieved, three further courses of ddAC were administered. MRI technique and assessment MRI monitoring was done as previously described (30;31). Briefly, both breasts were imaged with the patient in prone position. An unenhanced coronal three-dimensional fast field echo (thrive) sense T1-weighted sequence was acquired as the start of the standard dynamic protocol. A bolus (14 mL) of gadolinium containing contrast (0.1 mmol/kg) was administered intravenously at 3 mL/sec by using a power injector followed by a bolus of 30 mL of saline solution. Subsequently, dynamic imaging was performed in five consecutive series at 90-second intervals. Temporal and morphologic characteristics of contrast uptake were scored as previously described. (30;31).

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Response criteria The criteria for either a ‘favorable’ or an ‘unfavorable’ response were employed as published.(30) Contrast-enhanced Magnetic Resonance Imaging (CE-MRI) was performed before chemotherapy, after three courses of chemotherapy and after six courses of chemotherapy. Reduction of more than 25% in late enhancement diameter on the second MRI compared to the first MRI was regarded as a favorable response. All lesser responses were classified as ‘unfavorable’. To quantify the serial MRI-response, the percentage of reduction of the initial enhancement diameter was calculated by dividing the difference between the initial enhancements by the initial enhancement on a previous MRI. Three common definitions of pCR were used; no residual invasive tumor in the breast (ypT0/is ypN0/+); no residual invasive tumor in breast and lymph nodes (ypT0/is ypN0); and the absence of any tumor (invasive or non-invasive) in breast and lymph nodes (ypT0 ypN0). The Neoadjuvant Response Index (NRI) was calculated as published from the breast response score and the axillary response score.(33) Briefly, the breast response score was calculated by awarding 1 point for each decrease in T-stage, except for T1 to T0. An additional point was awarded for achieving a near pCR and 2 points for a pCR. The axillary response score was based on a simplified clinical staging system, resulting in 3 points for palpable and fine needle aspiration (FNA) positive nodes, 2 points for non-palpable nodes and positive ultrasound guided FNA, 1 point for clinical N0 when the sentinel node was tumor-positive (at least 0.2 mm in diameter), and zero points for a negative sentinel node. One point for each level of downstaging was awarded and this number was also divided by the maximum of achievable points. The sum of both response scores was divided by the maximum number of achievable points of breast and axilla. A result of 0 implies the breast and axilla are unresponsive and a result of 1 implies the achievement of the maximum awardable points, which represents a pCR (ypT0/is ypN0) of both breast and axilla. Relapse free interval (RFI) was also used as an endpoint and was defined as the length of time from the first treatment to local or distant relapse or breast cancer related death. Death from a non-breast cancer cause, ipsilateral DCIS, contralateral breast cancer and second primary invasive cancer were not taken into account. Staging As substantially more clinical lymph node staging information was available than is used for the clinical N-staging according to the UICC, we adapted the N-stage to match the NRI method. A negative sentinel node was assigned stage cNa; positive sentinel node stage cNb; non palpable and FNA-positive node stage cNc; axillary palpable and FNA positive stage cNd; and periclavicular and FNA positive stage cNe. Immunohistochemistry Pretreatment core biopsies of the primary tumor were taken under ultrasound guidance using a 14G core needle, after which they were snap-frozen in liquid nitrogen and stored at -80 degrees Celsius. Immunohistochemical assessment of paraffin-embedded sections was used for classification. Estrogen receptor and progesterone receptor were evaluated as positive when at least 10% of tumor cells

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showed staining. HER2 status was scored negative when immunohistochemistry (IHC) showed no staining (1+) or colorimetric in situ hybridization (CISH) revealed no amplification after moderate membrane staining (2+) at IHC. Ki67 was used for assessment of proliferation status. As Ki67 status was not determined for all tumors, histological grade (when available) was also used for a second definition of ‘Surrogate Intrinsic Subtypes’. (20) The Mib-1 antibody was used for determination of Ki67 status, using the cut-off point of 14% of positive staining. This cut off point was determined as it yielded the best separation of Luminal A and Luminal B tumors, as defined by the PAM50 algorithm in the subgroup of tumors of which mRNA expression arrays were available. Ki67 cut off point was determined by preparing receiver operating characteristic (ROC) curves comparing results with PAM50 intrinsic subtypes. (16) Histological grade was determined using the Elston and Ellis method. (35) High endocrine responsiveness was defined as at least 50% of the tumor cell nuclei stained positive, for both ER and PR, in the absence of HER2 amplification. (36) Surrogate definitions of intrinsic subtypes were used, based on immunohistochemistry. ‘Luminal A’ tumors are ER and/or PR positive, HER2 negative and have less than 14% of the nuclei staining positive for Ki67 (or, when based on histological grade, grade 1 or 2). ‘Luminal B (HER2 negative)’ tumors are ER and/or PR positive, HER2 negative and Ki67 > 14% (or histological grade 3) (20) Statistics The software program SPSS version 10 was used for all analyses. For the assessment of associations between characteristics and MRI response or pCR, the Fisher’s exact test was used. Mann Whitney U tests were used for the comparison of NRI results and MRI measured tumor size reduction percentage and potential predictive markers. Relapse free interval analysis was performed using Kaplan Meier curves and Cox regression analysis. A ROC curve was used for the establishment of a cut-off point for the proliferation marker Ki67 that is used to define luminal A and luminal B subtypes, compared to the subtypes of the classifier PAM50. The Kappa’s coefficient was used for determination of the degree of concordance between the two definitions of surrogate luminal A and luminal B versus the PAM50 classifier. Results Patients A total of 309 patients with ER+ HER2- breast cancer began neoadjuvant chemotherapy with three courses of dose dense Doxorubicin-Cyclophosphamide between 19 October 2004 and 14 March 2012 (Table 1). Table 1. Patient and Tumor Characteristics (n=309) Number of patients 309

Median Age, (range) in years 48 (19-69)

Tumor stage

cT1 30

cT2 180

cT3 84

cT4 15

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N stage

cNa (negative) 64

cNb (FNA negative, sentinel node positive) 49

cNc (ultrasound-guided FNA positive) 64

cNd (palpable nodes, FNA positive) 118

cNe (FNA positive periclavicular node(s)) 11

Unknown (incomplete data) 3

Histological grade

1 24

2 163

3 43

n.d.* 79

Histology

ductal 226

lobular 54

ductal/lobular 6

other 23

ER%

10-49 10

50-100 291

positive 8

PR%

0-49 143

50-100 159

other (positive 5, unknown 2) 7

Surrogate intrinsic subtype: based on Ki67

Luminal A (ER/PR+; HER2-; Ki67 low) 174

Luminal B / HER2- (ER/PR+; HER2-; Ki67 high) 80

n.d. (No Ki67 available) 55

Surrogate intrinsic subtype: based on histological grade

Luminal A (ER/PR+; HER2-; grade 1 or 2) 187

Luminal B / HER2- (ER/PR+; HER2-; grade 3) 43

n.d. (No reliable grade available*) 79

Legend: * Reliable estimation of histological grade is frequently not possible in small core biopsies. Abbreviations: ER, estrogen receptor; HER2, human epidermal receptor 2; FNA, fine needle aspiration; n.d., not done; PR, progesterone receptor. Of these, 292 patients had a CE-MRI after the first three courses and were evaluable for response. 182 (62%) patients achieved a favorable response defined as a decrease of at least 25% of the largest diameter of the late enhancement area. The second chemotherapy regimen was selected according to protocol in 275 patients: 178 of the favorable responders were continued on ddAC, and 97 of the 110 non-favorable responders were switched to the DC regimen (Figure 1).

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ER+ HER2- patients

1st regimen 3 x ddAC n = 309

MRI

favorable response

n=182

2nd regimen

3 x ddAC

n=178

2nd regimen

other

n=4

MRI

unfavorable response

n=110

2nd regimen

3 x DC

n=97

2nd regimen

other

n=13

MRI not evaluable / not done

n=17

Figure 1. CONSORT diagram showing MRI results and chemotherapy

Legend: Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; ddAC, dose dense Doxorubicine-Cyclophosphamide; DC, Docetaxel-Capecitabine; For 180 patients, all three MRI measurements of the initial enhancement diameter were available (additional MRIs are awaiting revision by a radiologist). (Figure 2) Figure 2. CONSORT diagram showing MRI evaluations Legend: Abbreviations: ddAC, dose dense Doxorubicine-Cyclophosphamide; DC, Docetaxel-Capecitabine.

275 patients with evaluable MRI’s 1 and 2 (late enhancement)

178 favorable responders

2nd regimen; 3xddAC

3 MRI evaluations: n = 119

MRI 3 not done; n=3 MRI initial enhancement;

not evaluable n=2, incomplete measurements n=54

97 unfavorable responders

2nd regimen; 3xDC

3 MRI evaluations: n = 61

MRI 3 not done; n=5 MRI initial enhancement;

not evaluable n=10, incomplete measurements n=21

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A total of 4.2% of all 309 patients achieved a pCR (ypT0ypN0) after 6 courses and the median NRI (available for 85% of the patients) was 0.25. Additional (postoperative) adjuvant chemotherapy was administered in 59 out of 309 patients (22 unfavorable responders, 36 favorable responders and 1 not evaluated by MRI) and consisted mainly of taxane treatment. The median follow up was 29 months with a lead follow up of 88 months. The 5-year relapse free interval for all 309 patients was 87%, with an overall 5-year survival of 94%. Patient and tumor characteristics and initial MRI response MRI response monitoring results (a CE-MRI before NAC and a second one after the first three courses) were available for 292 patients. When the criteria for a ‘favorable response’ could not be applied because late enhancement was not present or not suitable for quantification, the response was classified according to other MRI characteristics (e.g. decrease in diameter of initial enhancement (23 patients) or a visual estimate or on clinical grounds (24 patients). In 17 cases, no MRI results were available and the evaluation was done by ultrasonography, mammography, physical examination or a combination of these. These patients, along with patients who received other treatment, were excluded from the analysis. (Figure 1) A favorable response as determined by MRI criteria (over 25% decrease in the largest diameter of late enhancement) was more often seen in patients with positive N-stage (p=0.044), but it was not more frequent in incompletely endocrine responsive tumors or in tumors of higher grade or higher Ki67. (Table 2) Table 2: Patient and Tumor Characteristics and MRI Response after 3 Courses of Neoadjuvant Chemotherapy (n=275) Characteristic MRI unfavorable

response (n=97) N (%)

MRI favorable response (n=178)

N (%)

p-value

T-stage 1.000

cT1 / cT2 65 (67) 119 (67)

cT3 / cT4 32 (33) 59 (33)

N-stage 0.044

cN negative 28 (29) 30 (18)

cN positive 68 (71) 138 (82)

unknown 1 10

Histology 0.227

lobular 12 (13) 32 (20)

ductal 79 (87) 127 (80)

other 6 19

Age 0.125

< 50 50 (52) 110 (62)

≥ 50 47 (49) 68 (38)

Highly endocrine responsive

0.798

Non HER 44 (46) 82 (48)

HER 51 (54) 88 (52)

n.d. 2 8

Surrogate intrinsic subtype (Ki67)

0.757

Luminal A (<14) 52 (70) 91 (68)

Luminal B (≥14) 22 (30) 43 (32)

n.d. 23 44

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Surrogate intrinsic subtype (grade)

0.835

Luminal A (1/2) 40 (78) 79 (80)

Luminal B (3) 11 (22) 20 (20)

n.d. 46 79

Legend: A reduction of over 25% of the late enhancement diameter on the second contrast-enhanced MRI was regarded as a favorable response. Abbreviations: HER, highly endocrine responsive; IHC, immunohistochemistry, n.d., not done. Initial MRI response and outcome The MRI response criteria were originally developed with the objective to recognize patients who would not be likely to achieve a pCR or near-pCR of the breast.(30) It was later recognized that pCR is not a practical endpoint for ER-positive, HER2-negative tumors, and the Neoadjuvant Response Index (NRI) was proposed to quantify the degree of downstaging. NRI results were available for 232 patients with measurable MRI’s one and two and the correlation between a favorable response and the NRI approached statistical significance (p=0.067). (Figure 3, Table 3) Figure 3. Waterfall Plots of Neoadjuvant Response Index by Initial MRI Response to Neoadjuvant Chemotherapy.

Legend: Each bar represents one patient with the NRI result shown on the y-axis. Panel A: NRI of 78 unfavorable responders; Panel B: NRI of 154 unfavorable responders. (p=0.067) Abbreviations: NRI, Neoadjuvant Response Index; The NRI is a measure of downstaging. An NRI of 1 is equal to a pCR of breast and axilla (ypT0 ypN0), an NRI of 0 signifies no downstaging at all, or even progression. Table 3. MRI Response after 3 Courses of Neoadjuvant Chemotherapy and Outcome Measures (n=275) MRI Response Category

n NRI median

(n**)

% pCR ypT0/is ypN0/+

% pCR ypT0/is ypN0

% pCR ypT0 ypN0

RFI hazard ratio (95% CI)

Unfavorable 97 0.25 (78) 3 2 2 1.6 (0.7 – 3.6)

Favorable 178 0.29 (154) 11 5 3 1.0

p-value * 0.067 0.022 0.338 0.717 0.296

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Legend: * NRI, Mann Whitney U test; pCR, Fisher’s exact test; RFI, Cox regression analysis ** Different patient numbers because NRI results are not available for all patients. Abbreviations: NRI, neoadjuvant response index; pCR, pathological complete remission; ypT0/is ypN0/+, no residual invasive tumor in the breast; ypT0/is ypN0, no residual invasive tumor in breast and lymph nodes; ypT0 ypN0, the absence of any tumor (invasive or non-invasive) in breast and lymph nodes; RFI, relapse free interval; CI, confidence interval. The pCR rate was low and different pCR definitions resulted in decreasing pCR percentage as stricter definitions were employed. 23 complete remissions of the breast were observed in 275 patients, 11 complete remissions of both breast and axilla and 8 complete remissions breast and axilla in the absence of residual carcinoma in situ. A favorable MRI response was associated with a higher pCR rate than an unfavorable response (p=0.022 for invasive breast only), but the numbers were very low. Ten relapse events occurred in the 97 unfavorably responding patients and 12 relapses in the 178 favorably responding ones (p=0.296). (Figure 4) Figure 4. Initial MRI Response Category and Relapse Free Interval (n=275)

Legend: p=0.296 Abbreviations: UN, unfavorable responders to neoadjuvant chemotherapy; FAV, favorable responders to neoadjuvant chemotherapy. Initial MRI response and serial MRI evaluation Serial MRI measurements of initial enhancement diameters were done in 180 patients, of whom 119 achieved a favorable response on the second MRI, which was then followed by three more courses of ddAC. In 61 patients a switch to the DC regimen was made because of an ‘unfavorable’ MRI response. The overall radiological tumor size reduction percentage after six courses of chemotherapy was higher in patients who had achieved a favorable response on the second MRI. The fractional reduction in tumor size as measured by MRI over the

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second set of three courses, however, was similar for both the initially favorable and the initially unfavorable responders. (Table 4, Figure 5) Table 4: Mean MRI Tumor Size Reductions by Chemotherapy Regimen Adaptation (n=180) MRI Response Category

n Tumor Size Reduction (%)

Courses 1, 2 and 3 MRI 1 vs 2

Tumor Size Reduction (%)

Courses 4, 5 and 6 MRI 2 vs 3

Overall Tumor Size Reduction (%)

MRI 1 vs 3

Unfavorable (3xddAC, 3xDC)

61 8 36 41

Favorable (6xddAC)

119 34 45* 62

Legend: 180 patients were evaluated by three MRI’s; MRI 1: prior to neoadjuvant chemotherapy, MRI 2: after 3 courses of ddAC, MRI 3: after 3 courses of ddAC or after 3 courses of DC. * n=111 for the reduction percentage on MRI 2 vs 3 of favorable responders, because 8 patients had achieved a complete remission on MRI 2 and were not used for the calculation of this percentage. Abbreviations: ddAC, dose dense Doxorubicine-Cyclophosphamide; DC, Docetaxel-Capecitabine. Figure 5: Waterfall Plots of the MRI Tumor Size Reductions before and after MRI Response Evaluation First 3 courses Second 3 courses

Legend: Each bar represents one of the 180 patients who had three MRI measurements of initial enhancement diameter. Panels A & B: tumor size reduction in 61 unfavorable responders to the first three courses of ddAC (Panel A); or three courses of DC

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(Panel B). Panel C & D: tumor size reduction of 119 favorable responders; to the first three courses of ddAC (Panel C); or to second three courses of ddAC (Panel D). 8 tumors that had achieved a radiological complete remission after the first three courses were inevaluable for the second three courses and were excluded. The tumor size reductions after the first 3 courses are significantly smaller for the ‘unfavorable responders’ than for the ‘favorable responders’ (p<0.001). Over courses 4 through 6, after regimen adaptation in case of unfavorable response, the tumor size reductions are similar for the two response categories (p=0.519) Abbreviations: ddAC, dose dense Doxorubicine-Cyclophosphamide; DC, Docetaxel-Capecitabine. Eight favourably responding patients had a radiological CR on their second MRI, which resulted in a tumor size reduction of zero percent after the second course of ddAC. A better relapse free interval was observed in patients whose tumor size on the third (and final) MRI was smaller than median (≤ 15 mm). Only 4 events occurred in 94 patients with smaller residual tumors, versus 12 events in 86 patients with larger residual tumors (HR 3.0 (95% CI 1.0 – 9.3), p=0.045). (Figure 6) Figure 6: Residual Tumor Size on MRI and Relapse Free Interval (n=180)

Legend: Tumor size after chemotherapy was defined as the largest diameter of the initial enhancement on contrast enhanced MRI. Patients with larger than median tumors (15 mm) had more recurrences than those with smaller ones (p=0.045, log rank test). Patient and tumor characteristics and outcome The predictive and prognostic impact of tumor characteristics was analyzed for 275 initial response evaluated patients with NRI, pCR and RFI as endpoints. (Table 5)

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Table 5. Patient and Tumor Characteristics and Outcome Measures (n=275)

Legend: * Different numbers because NRI results are not available for all patients. Abbreviations: NRI, Neoadjuvant Response Index; pCR, pathological complete remission; ypT0/is, no residual invasive tumor in the breast; ypT0/is ypN0, no residual invasive tumor in breast and lymph nodes; ypT0 ypN0, the absence of any tumor (invasive or non-invasive) in breast and lymph nodes; RFI, relapse free

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interval; CI, confidence interval; HER, highly endocrine responsive; SIS, surrogate intrinsic subtype; IHC, immunohistochemistry. The NRI was significantly influenced by ‘high endocrine responsiveness (lower NRI, p=0.006) and by age (higher age, lower NRI, p=0.017). Lower age was associated with a higher pCR rate (ypT0). The effect of age persisted when the endpoint was ypT0/is ypN0 but was no longer significant when the strictest pCR definition was employed (ypT0 ypN0). The relapse free interval was only affected by age, resulting in a better prognosis when diagnosed at a younger age (p=0.005). Surrogate intrinsic subtypes We also studied the predictive value of the ‘surrogate intrinsic subtypes’. Since tumors were classified as either surrogate luminal A or surrogate luminal B, the distinguishing feature between these was the Ki67 staining percentage or, alternatively, histological grade (I/II versus III). Defining the best Ki67 cut off point for differentiating the Luminal A and Luminal B surrogate intrinsic subtypes was done in 65 samples of which both the Ki67 percentage and the PAM50 intrinsic subtype definition (determined by mRNA expression microarray analysis) was known. A ROC curve resulted in an area under the curve (AUC) of 0.81 with 95% confidence interval for a cut-off point of 10-15%. (See appendix) We therefore employed the usual cut-off value of 14% for Ki67-low or Ki67-high. The Kappa’s coefficient was calculated to establish the degree of concordance between the two definitions of Surrogate Luminal A and Luminal B versus the PAM50 classifier. For Ki67% and histological grade, the kappa values were 0.45 and 0.15, respectively. Discussion Neoadjuvant chemotherapy in ER+ HER2- breast cancer Despite the low pathological complete remission rates and the relative good prognosis in ER+ HER2- breast cancer, chemotherapy has been proven to substantially improve recurrence-free survival.(37) A potential advantage of neoadjuvant chemotherapy over standard postoperative chemotherapy is the opportunity to monitoring the response. Consequently, a change in chemotherapy can be made when the response to the initial chemotherapy is unsatisfactory. Adaptation of the chemotherapy regimen, e.g. switching the chemotherapy to a (presumably) non-cross resistant one that has different targets in the cell is assumed to have a better treatment effect than continuing the initial, non-effective regimen. A relatively large proportion of ER+ HER2- tumors is ‘nonresponsive’ to chemotherapy. Therefore, a response-adapted strategy as described above, could improve the response to neoadjuvant chemotherapy and the survival rates particularly in this subgroup. Such a strategy has recently been shown effective in terms of both disease free and overall survival.(34) Study design This is a retrospective study on a series of patients that received neoadjuvant chemotherapy for ER+ HER2- breast cancer. The choice of chemotherapy was

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based on a response adapted approach. This analysis had the objective to evaluate associations of patient and tumor characteristics with outcome, and to develop hypothesies that could be tested in future prospective studies of neoadjuvant chemotherapy. A total of 309 patients was started on the approach and 275 patients were included in the evaluation of patient and tumor characteristics, radiological and pathological outcome and survival analysis. To study the responses to a switch in chemotherapy, three complete MRI measurements were available in 180 of these 275 patients. (Figure 1, Figure 2) In this group of patients, the serial MRIs were performed before the initiation of chemotherapy, after three courses of chemotherapy and after three subsequent courses of chemotherapy (before surgery), so that the effects of each set of three courses could be compared. Initial chemotherapy response on MRI The majority of patients achieved a favorable response after the first three courses of chemotherapy and continued the initial treatment. A minority (about one-third) did not achieve an initial favorable response and the chemotherapy was adapted to the non-cross resistant treatment. The final pathological outcome was worse in these initially unfavorable response patients compared to the favorable response patients. This could be the result of having received only three effective courses of chemotherapy (after adaptation of the treatment). An alternative explanation could, of course, be that all chemotherapy is less effective in initial non responders. Despite the smaller effect of chemotherapy on the unfavorably responding tumors, there was no difference in relapse free survival between favorable and unfavorable response patients. It is important to note that median follow up was only 29 months and the ER+ HER2- tumors are known for relapsing after a long period of time. Thus, a longer follow up is needed. Response adaptive strategy The efficacy of a response adaptive strategy for neoadjuvant chemotherapy cannot be proven through this non randomized study, but independent support for the concept has been presented in a recent analysis of the German Breast Group.(34) Because of the serial MRI measurements in this study, conclusions can be drawn on the effect of chemotherapy on tumor shrinkage. As the late enhancement diameter was used for the evaluation of the early response, a similar effect of the first three courses on the strongly correlated parameter ‘initial enhancement’ could be expected. This parameter was used for the serial MRI evaluations of tumor size. A tumor shrinkage of 8% after the first three courses of chemotherapy (dose-dense Doxorubicin/Cyclophosphamide) was observed in initially unfavorable response patients, as opposed to 34% in favorable response patients. The second set of three courses of a non-cross resistant chemotherapy (Docetaxel/Capecitabine), however, led to 36% shrinkage in the previously unfavorably responding patients. This is almost identical with the initial shrinkage in favorable responders (34%) and this is similar to the effect of the second set of three courses in the initially favorable responders (45%) who had continued the initial chemotherapy. Apparently, Docetaxel/Capecitabine was able to induce a satisfactory response, when dose-dense AC was not.(Figure 5)

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The increased response to the second three courses of ddAC in favorably responding patients could be due to a continuing late effect of chemotherapy on the tumor vascularization. It is generally believed that the first courses of chemotherapy are the most effective ones, at least in terms of tumor cell kill. The MRI tumor measurement, however, does not measure the mass of tumor cells, but rather the size of the region containing abnormal (‘leaky’) tumor vessels. As it takes time to replace these abnormal vasculature by normal vessels, the MRI image may lag behind the tumor cell kill. One explanation for an ‘unfavorable’ response could conceivably be that perhaps slowly proliferating tumors show a late response to treatment. However, no association was found between these characteristics (low Ki-67, grade I/II) and a late response. A late effect of ddAC cannot be excluded completely as a part of the improved response to the second three courses of chemotherapy (DC) in the unfavorably responding patients. Because of the on-going response to ddAC in the favorably responding tumors, one may conclude that continuing ddAC is an effective approach. To determine whether or not a switch in regimen has benefit for all patients, including the initially favourably responding ones, a prospective study is needed. The average total percentage of tumor shrinkage remained lower in the initially unfavorable responders (41%) than in the favorable responders (62%), despite the efficacy of the alternative chemotherapy. This could very well be the result of having received only three effective courses of chemotherapy, whereas the initially favorable responders had received six effective courses, and showed a similar (or even better) percentage of tumor shrinkage during the second set of three courses (45%) to that of courses 1 through 3 (34%). If this explanation is correct, one might consider extending the Docetaxel/Capecitabine therapy in initially unfavorable responders to six rather than three courses, in order to obtain a similar total reduction in tumor size and a smaller tumor on the final MRI. Because the size of the initial enhancement on the final MRI is significantly associated with relapse free survival, this outcome could be a potential endpoint that might be aimed at during neoadjuvant treatment and further individualization of chemotherapy. Patient and tumor characteristics and outcome The evaluation of patient and tumor characteristics did not result in the observation of any non-responsive subgroups. This analysis is complicated by the fact that the use of multiple definitions for the pathological outcome leads to inconsistent results. The use of stricter definitions of pCR results in a very low complete remission rate in this breast cancer subtype. Despite the proposal to use the so-called ‘surrogate intrinsic subtype’ definitions by the St. Gallen Expert Panel,(20) both Ki-67 and grade did not have predictive or prognostic value. Remarkably, patients older than fifty years had a worse pathological response and prognosis. The higher pCR rate in younger patients could be explained by a larger proportion of highly proliferative tumors in younger patients and a better response to chemotherapy of these tumors. However, no relation between age and proliferative characteristics could be confirmed. Also, patients with highly proliferative tumors present with early relapses, which would lead to a worse relapse free survival in younger patients. On the contrary, this analysis showed a better relapse free survival in younger patients.

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Future development of the neoadjuvant chemotherapy regimen Complete non-responsiveness to chemotherapy in ER+ HER2- breast cancer seems relatively rare, because an improved response after the switch to a non-cross resistant treatment was observed. The patients with early non responsive tumors did not have a worse relapse free survival, which supports the theory that a response adapted regimen is indeed effective. First of all, these results indicate the requirement for a phase III study that compares individualized treatment to standard treatment for the determination of the efficacy of a response adapted approach. Secondly, additional studies are needed to develop more accurate response monitoring techniques. The criteria for response evaluation by MRI have shown not to be predictive for a pCR in ER+ HER2- breast cancer.(31) The use of or combination with PET/CT could improve the accuracy of the response evaluation.(38) In addition, more appropriate outcome measures than pCR should be defined for the response of ER+ HER2- tumors, which are applicable in general practice and have prognostic value. Perhaps the recently proposed Neoadjuvant Response Index (NRI) (9) could be used in this manner, but its prognostic value is still awaiting longer follow up and/or independent confirmation. Other breast cancer subtypes also need to be examined for the usefulness of response adapted strategies in neoadjuvant chemotherapy. Survival analysis of a response adapted regimen suggested no prognostic value of a response adapted regimen in ER-negative tumors.(34) Therefore, separate analyses are needed for other subtypes. Conclusion The observation of tumor size reduction after treatment adaptation, despite the absence of a response to initial neoadjuvant chemotherapy, strongly suggests that different chemotherapy regimens in breast cancer may be “non-cross resistant”. These results, combined with the recently established evidence of a survival advantage of a response adapted regime in ER+ HER2- breast cancer,(34) emphasize the need for prospective studies to determine the role of an individualized response adapted approach in the neoadjuvant chemotherapy of breast cancer.

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(12) Harris CA, Ward RL, Dobbins TA, Drew AK, Pearson S. The efficacy of HER2-targeted agents in metastatic breast cancer: a meta-analysis. Ann Oncol 2011 Jun;22(6):1308-17.

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(17) Blows FM, Driver KE, Schmidt MK, Broeks A, van Leeuwen FE, Wesseling J, et al. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med 2010 May;7(5):e1000279.

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(24) Cuzick J, Dowsett M, Pineda S, Wale C, Salter J, Quinn E, et al. Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer. J Clin Oncol 2011 Nov 10;29(32):4273-8.

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(26) Rosen EL, Blackwell KL, Baker JA, Soo MS, Bentley RC, Yu D, et al. Accuracy of MRI in the detection of residual breast cancer after neoadjuvant chemotherapy. AJR Am J Roentgenol 2003 Nov;181(5):1275-82.

(27) Prati R, Minami CA, Gornbein JA, Debruhl N, Chung D, Chang HR. Accuracy of clinical evaluation of locally advanced breast cancer in patients receiving neoadjuvant chemotherapy. Cancer 2009 Mar 15;115(6):1194-202.

(28) Yeh E, Slanetz P, Kopans DB, Rafferty E, Georgian-Smith D, Moy L, et al. Prospective comparison of mammography, sonography, and MRI in patients undergoing neoadjuvant chemotherapy for palpable breast cancer. AJR Am J Roentgenol 2005 Mar;184(3):868-77.

(29) Shin HJ, Kim HH, Ahn JH, Kim SB, Jung KH, Gong G, et al. Comparison of mammography, sonography, MRI and clinical examination in patients with locally advanced or inflammatory breast cancer who underwent neoadjuvant chemotherapy. Br J Radiol 2011 Jul;84(1003):612-20.

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(31) Loo CE, Straver ME, Rodenhuis S, Muller SH, Wesseling J, Vrancken Peeters MJ, et al. Magnetic resonance imaging response monitoring of breast cancer during neoadjuvant chemotherapy: relevance of breast cancer subtype. J Clin Oncol 2011 Feb 20;29(6):660-6.

(32) von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 2012 May 20;30(15):1796-804.

(33) Rodenhuis S, Mandjes IA, Wesseling J, van de Vijver MJ, Peeters MJ, Sonke GS, et al. A simple system for grading the response of breast cancer to neoadjuvant chemotherapy. Ann Oncol 2010 Mar;21(3):481-7.

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Trial. San Antonio Breast Cancer Symposium 2011 . 8-12-2011. Ref Type: Abstract

(35) Ellis IO, Galea M, Broughton N, Locker A, Blamey RW, Elston CW. Pathological prognostic factors in breast cancer. II. Histological type. Relationship with survival in a large study with long-term follow-up. Histopathology 1992 Jun;20(6):479-89.

(36) Colleoni M, Bagnardi V, Rotmensz N, Gelber RD, Viale G, Pruneri G, et al. Increasing steroid hormone receptors expression defines breast cancer subtypes non responsive to preoperative chemotherapy. Breast Cancer Res Treat 2009 Jul;116(2):359-69.

(37) Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 2012 Feb 4;379(9814):432-44.

(38) Tateishi U, Miyake M, Nagaoka T, Terauchi T, Kubota K, Kinoshita T, et al. Neoadjuvant chemotherapy in breast cancer: prediction of pathologic response with PET/CT and dynamic contrast-enhanced MR imaging--prospective assessment. Radiology 2012 Apr;263(1):53-63.

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Abstract (Nederlands) Introductie: Aanpassing van het neoadjuvante chemotherapie regime bij onvoldoende responderend mammacarcinoom is geen standaard beleid. Een opeenvolgende serie patiënten is geanalyseerd waarbij de tweede helft van de neoadjuvante chemotherapie werd geselecteerd op basis van de respons op de eerste helft van de chemotherapie. Materiaal en methode: Oestrogeenreceptor positief, humaan epidermaal groeifactor receptor 2 negatief mammacarcinoom patiënten ondergingen drie kuren neoadjuvant dose dense doxorubicine en cyclofosfamide (ddAC). Contrastversterkte MRI onderzoeken werden in serie verricht; voor de aanvang van chemotherapie, na drie en na zes kuren. Drie opeenvolgende kuren ddAC werden toegediend in het geval van een ongunstig resultaat op de tweede MRI en een switch naar Docetaxel en Capecitabine werd gemaakt in het geval van een gunstig resultaat. De effectiviteit van dit regime werd geëvalueerd d.m.v. de pathologische respons, de ziektespecifieke overleving en de afname van tumorgrootte op MRI. Resultaten: 309 patiënten werden geïncludeerd. Vroege respons werd geëvalueerd m.b.v. MRI bij 275 patiënten en voor 180 patiënten werden drie MRI metingen verkregen. Pathologische respons was beter voor patiënten die een initiële gunstige respons hadden behaald op MRI (p=0.067 voor Neoadjuvante Response Index, p=0.022 voor een pathologische complete remissie van de mamma). De MRI respons had geen invloed op de ziektespecifieke overleving (p=0.296). Ongunstige vroege responders hadden een mediane afname van tumorgrootte van 8% na 3 kuren ddAC, in tegenstelling tot 34% bij gunstige responders. Na de switch naar het alternatieve chemotherapie regime, was de afname van tumorgrootte 36% na drie kuren, terwijl dit voor de vroege gunstige responders, die hun eerste chemotherapie nog 3 kuren vervolgden, toenam tot 45%. Een tumordiameter kleiner dan de mediaan op de MRI na zes kuren neoadjuvante chemotherapie was een gunstige prognostische factor voor ziektespecifieke overleving (hazard ratio 3.0 (95% confidence interval 1.0 – 9.3), p=0.045). Conclusie: De afname van tumorgrootte na aanpassing van chemotherapie bij initiële niet responderende tumoren voegt toe aan het bestaande bewijs dat adaptatie van chemotherapie op de respons de effectiviteit van neoadjuvante chemotherapie kan vergroten. Prospectieve studies moeten worden opgezet om deze behandelstrategie te ontwikkelen.

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Appendix: ROC curve Ki67 and PAM 50