Birgit E.P.J. Vriens

Accuracy of sentinel node biopsy after neoadjuvant chemotherapy in breast cancer patients: A systematic review

BACKGROUND As neoadjuvant chemotherapy (NAC) is increasingly used to downstage patients with breast cancer, the timing of the sentinel node (SN) biopsy has become an important issue. This review was conducted to determine the accuracy of SN biopsy following NAC. METHODS We searched Medline, Embase and Cochrane databases from 1993 to February 2009 for studies on patients with invasive breast cancer who underwent SN biopsy after NAC followed by an axillary lymph node dissection (ALND). RESULTS Of 574 eligible studies, 27 were included in this review with a total study population of 2148 patients. The pooled SN identification rate was 90.9% (95% confidence interval (CI)=88.0-93.1%) and the false-negative rate was 10.5% (95% CI=8.1-13.6%). Negative predictive value and accuracy after NAC were 89.0% (95% CI=85.1-92.1%) and 94.4% (95% CI=92.6-95.8%), respectively. The reported SN success rates were heterogeneous and several variables were reported to be associated with decreased SN accuracy, i.e. initially positive clinical nodal status. CONCLUSIONS There is a potential role for SN biopsy following NAC which could be considered on an individual basis. However, there is insufficient evidence to recommend this as a standard procedure. Further research with subgroup analysis using variables reported to be associated with decreased SN accuracy is required in order to clearly define its value in the subgroups of breast cancer patients.

Addition of zoledronic acid to neoadjuvant chemotherapy does not enhance tumor response in patients with HER2 negative stage II/III breast cancer: the NEOZOTAC trial (BOOG 2010-01)

BACKGROUND The role of zoledronic acid (ZA) when added to the neoadjuvant treatment of breast cancer (BC) in enhancing the clinical and pathological response of tumors is unclear. The effect of ZA on the antitumor effect of neoadjuvant chemotherapy has not prospectively been studied before. PATIENTS AND METHODS NEOZOTAC is a national, multicenter, randomized study comparing the efficacy of TAC (docetaxel, adriamycin and cyclophosphamide i.v.) followed by granulocyte colony-stimulating factor on day 2 with or without ZA 4 mg i.v. q 3 weeks inpatients withstage II/III, HER2-negative BC. We present data on the pathological complete response (pCR in breast and axilla), on clinical response using MRI, and toxicity. Post hoc subgroup analyses were undertaken to address the predictive value of menopausal status. RESULTS Addition of ZA to chemotherapy did not improve pCR rates (13.2% for TAC+ZA versus 13.3% for TAC). Postmenopausal women (N = 96) had a numerical benefit from ZA treatment (pCR 14.0% for TAC+ZA versus 8.7% for TAC, P = 0.42). Clinical objective response did not differ between treatment arms (72.9% versus 73.7%). There was no difference in grade III/IV toxicity between treatment arms. CONCLUSIONS Addition of ZA to neoadjuvant chemotherapy did not improve pathological or clinical response to chemotherapy. Further investigations are warranted in postmenopausal women with BC, since this subgroup might benefit from ZA treatment.

Taxane resistance in breast cancer: A closed HER2 circuit?

Microtubule inhibitors, such as the taxanes docetaxel and paclitaxel, are commonly used drugs for the treatment of breast cancer. Although highly active in a large fraction of individuals a considerable number of patients show poor response due to either intrinsic or acquired drug resistance. Extensive research in the past identified several taxane resistance-related mechanisms being activated by pathologically altered single gene function. To date, however, a clinically relevant predictive biomarker for taxanes has not been derived yet from this knowledge, most likely due to the manifold of resistance mechanisms that may combine in one tumor, thereby fostering escape from taxane cytotoxicity. Here, we aimed to comprehensively review the current literature on taxane resistance mechanisms in breast cancer. Interestingly, besides altered microtubule physiology we identified the HER2 signaling cascade as a major dominator influencing several routes of cytotoxicity escape, such as cell survival, apoptosis, drug efflux, and drug metabolism. Furthermore, the transcription factor YBX-1, activated by HER2, facilitates a sustaining HER2 signaling feedback loop contributing to the establishment of cellular survival detours. In conclusion, taxane resistance in breast cancer follows a multiplex establishment of drug cytotoxicity escape routes, which may be most efficiently therapeutically targeted by interference with their mutually governing signaling nodes.

Ultrasound is at least as good as magnetic resonance imaging in predicting tumour size post-neoadjuvant chemotherapy in breast cancer

BACKGROUND The aim of this study was to evaluate the accuracy of clinical imaging of the primary breast tumour post-neoadjuvant chemotherapy (NAC) related to the post-neoadjuvant histological tumour size (gold standard) and whether this varies with breast cancer subtype. In this study, results of both magnetic resonance imaging (MRI) and ultrasound (US) were reported. METHODS Patients with invasive breast cancer were enrolled in the INTENS study between 2006 and 2009. We included 182 patients, of whom data were available for post-NAC MRI (n=155), US (n=123), and histopathological tumour size. RESULTS MRI estimated residual tumour size with <10-mm discordance in 54% of patients, overestimated size in 28% and underestimated size in 18% of patients. With US, this was 63%, 20% and 17%, respectively. The negative predictive value in hormone receptor-positive tumours for both MRI and US was low, 26% and 33%, respectively. The median deviation in clinical tumour size as percentage of pathological tumour was 63% (P25=26, P75=100) and 49% (P25=22, P75=100) for MRI and US, respectively (P=0.06). CONCLUSIONS In this study, US was at least as good as breast MRI in providing information on residual tumour size post-neoadjuvant chemotherapy. However, both modalities suffered from a substantial percentage of over- and underestimation of tumour size and in addition both showed a low negative predictive value of pathologic complete remission (Gov nr: NCT00314977).

Doxorubicin/cyclophosphamide with concurrent versus sequential docetaxel as neoadjuvant treatment in patients with breast cancer

BACKGROUND This study was designed to determine whether delivering neo-adjuvant chemotherapy at a higher dose in a shorter period of time improves outcome of breast cancer patients. PATIENTS AND METHODS Women with newly diagnosed breast cancer were randomly assigned to neoadjuvant chemotherapy of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC 60/600 - T 100 mg/m(2)) or six cycles of TAC (75/50/500 mg/m(2)) every 3 weeks. The primary endpoint was the pathologic complete response (pCR) rate, defined as no invasive tumour present in the breast. RESULTS In total, 201 patients were included. Baseline characteristics were well balanced. AC-T resulted in pCR in 21% and TAC in 16% of patients (odds ratio 1.44 (95% confidence interval (CI) 0.67-3.10). AC-T without primary granulocyte-colony stimulating factor (G-CSF) prophylaxis was associated with more febrile neutropenia compared to TAC with primary G-CSF prophylaxis (23% versus 9%), and with more grade 3/4 sensory neuropathy (5% versus 0%). CONCLUSIONS With a higher cumulative dose for the concurrent arm, no differences were observed between the two treatment arms with respect to pCR rate. The differential toxicity profile could partly be explained by different use of primary G-CSF prophylaxis.

If there is no overall survival benefit in metastatic breast cancer: Does it imply lack of efficacy? Taxanes as an example

In recent years, new drugs have shown activity in metastatic breast cancer, but not always resulting in an overall survival benefit. This has led to discussions if such drugs, mainly expensive drugs, should be reimbursed especially when also not leading to improvement in quality of life. For that reason, we decided to systematically review taxane-based chemotherapy studies in early and metastatic breast cancer, to assess which factors may have caused the differential outcome. Taxanes did not improve survival in metastatic breast cancer trials, whereas they did so in early breast cancer trials. We questioned if the differential outcome of taxanes in metastatic breast cancer might be caused by the chosen comparator and study design. We noticed that in the majority of metastatic breast cancer studies taxanes were used as a substitute for other active cytotoxic drugs, mainly cyclophosphamide, whereas in early breast cancer studies taxanes were generally delivered in addition to a standard regimen. We conclude from our analyses that use of taxanes instead of other active drugs explains the lack of overall survival benefit in metastatic breast cancer trials. Further, our results suggest that cyclophosphamide is an important drug in the treatment of breast cancer, being as effective as optimally dosed taxanes and anthracyclines. By studying the different study designs and comparators in both settings, we were able to demonstrate their impact on efficacy endpoints. We conclude, therefore, that re-assessment of studies of drugs both assessed in metastatic and early breast cancer provides a new tool for improved understanding.

Axillary staging in breast cancer patients treated with neoadjuvant chemotherapy in two Dutch phase III studies

Background Primary aim of our study was to assess the impact of timing of sentinel node procedure, pre- versus post-neoadjuvant chemotherapy, on final pathologic node-negative rate (pN0) in patients with clinically node-negative (cN0) breast cancer. Secondary endpoint was the usability of the sentinel node procedure in patients with clinically node-positive disease that converted to cN0 after neoadjuvant chemotherapy. Patients and Methods Patients were enrolled in two sequentially conducted Dutch phase III trials, studying the impact of two neoadjuvant chemotherapy schedules and use of zoledronic acid on complete pathologic response rate. For the present analyses, patients were excluded if they had not undergone surgical axillary staging. Results In total 439 patients were included, of whom 230 (52%) had pre-treatment cN0. In this group, pN0 status was seen in 58% (N = 23) of patients with a sentinel node biopsy post-neoadjuvant chemotherapy compared to 51% (N = 83) pre-neoadjuvant chemotherapy, including the axillary lymph node dissection whenever performed. In multivariable analysis, timing of sentinel node procedure (pre- versus post- neoadjuvant chemotherapy) was, however, not significantly associated with final pN0/pN0(i+) status, with an odds ratio of 1.18 (95% CI 0.64 - 2.18) after correction for age, clinical tumor status, histology, grade, hormone- and HER2 receptor. Of patients with clinically node-positive disease only 15% had a final pN0 status, with a false-negative rate of the sentinel node of 30%. Conclusion In breast cancer patients with cN0 disease, sentinel node procedure performed post-neoadjuvant chemotherapy led to nodal down staging, although not statistically significant after multivariate correction for patient and tumor characteristics.

Abstract PD07-06: NEO-ZOTAC: Toxicity data of a phase III randomized trial with NEOadjuvant chemotherapy (TAC) with or without ZOledronic acid (ZA) for patients with HER2-negative large resectable or locally advanced breast cancer (BC)

Background: The role of bisphosphonates (BP) when added to the (neo)adjuvant treatment of BC in enhancing the efficacy of therapy is still unknown. NEOZOTAC investigates the efficacy of ZA added to neoadjuvant chemotherapy in patients with HER2-negative BC. Trial design: NEOZOTAC is a Dutch multicenter study. Patients are 1:1 randomized to 3-weekly TAC (docetaxel 75mg/m 2 , adriamycin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 i.v., day 1) chemotherapy supported by pegfilgrastim (6 mg sc), day 2 with or without ZA (4 mg i.v. within 24 hr after chemotherapy) q3 weeks. Eligibility criteria: Main inclusion criteria: stage II or III, measurable, HER2-negative BC, age ≥18 years, WHO 0–2, adequate bone marrow-, renal-, and liver function, absence of prior BP usage and absence of active dental problems. Study endpoint: The primary endpoint is the pathologic complete response (pCR) rate. Secondary endpoints are toxicity, clinical response, tumor heterogeneity in core biopsy vs. operation specimen, and (disease free) survival. Optional side studies include fluorescent imaging (SoftScan®), changes in bone markers, single nucleotide polymorphisms and the insulin-like growth factor pathway, circulating tumor and endothelial cells and the false-negative rate of the sentinel node biopsy after neoadjuvant chemotherapy. Statistical Methods: Using a 5% significance level based on the two-sided Fishers exact test with a power of 80%, 250 patients (125/arm) are needed to show an improvement of the pCR-rate from 17% to 34% in the experimental arm. Randomization was done according to the Pococks minimisation technique stratified by cT, cN, and estrogen receptor status. Toxicity is analyzed using the Exact (2-sided) Chi-Square test. Results: From July 2010 to April 2012, 250 patients from 25 participating sites were randomized. Toxicity data of 173 patients are currently available and data of all 250 patients will be presented at SABCS. Patient characteristics are presented in table 1. Hematological and non-hematological toxicities were not significantly different between both treatment arms. Main grade 3/4 NCI-CTCv4 toxicities were neutropenia (8%), followed by febrile neutropenia (7%), fatigue (6%), diarrhea, hypertension, nausea (3%) and vomiting (1.2%). Bone pain, myalgia, and hypocalcemia occurred in one patient in the TAC-ZA arm (0.6%). Osteonecrosis of the jaw was not observed. Conclusions: Neoadjuvant TAC supported by pegfilgrastim plus ZA is feasible. No significant difference in toxicity are reported compared with the control arm. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD07-06.

Neutrophil Recovery in Breast Cancer Patients Receiving Docetaxel-Containing Chemotherapy with and without Granulocyte Colony-Stimulating Factor Prophylaxis

Objective: The primary outcome of the current study is, whether there is a protective effect of prior chemotherapy or of prior granulocyte colony-stimulating factor (G-CSF) on the next cycle blood cell counts. Methods: Hematologic toxicity was evaluated, based on a randomized phase III study in breast cancer patients (n = 167) with >20% risk of febrile neutropenia. The primary endpoint was the nadir blood cell counts for patients treated with G-CSF given during all 6 chemotherapy cycles or limited to the first 2 chemotherapy cycles only. Results: For the present analyses, 47 patients were eligible. In the G-CSF 1-6 arm, the median white blood cell count (WBC) and absolute neutrophil count (ANC) nadir slowly decreased from 10.8 × 109/L in cycle 1 to 7.5 × 109/L in cycle 6 and from 7.1 × 109/L to 5.5 × 109/L, respectively. The median WBC nadir in the G-CSF 1-2 arm decreased from 1.2 × 109/L in cycle 3 to 0.9 × 109/L in cycle 6 and the ANC nadir showed a grade 4 neutropenia of 0.1 × 109/L in cycles 3-6. All patients had ANC recovery to normal levels (≥1.5 × 109/L) without delay on day 1 of the next cycle. Conclusion: We conclude that there is no protective effect of prior G-CSF or prior chemotherapy use on nadir blood cell counts in subsequent cycles.

Abstract PD6-03: Preserving fertility in young women undergoing chemotherapy for early breast cancer; the Maastricht experience

Purpose This study aimed to evaluate the uptake of fertility preservation, rate of pregnancy, pregnancy outcome and breast cancer outcome after diagnosis of early breast cancer in young women who were referred to Maastricht University Medical Center, from the regional hospitals in the Southeast part of the Netherlands. Patients and methods We prospectively registered the demographics of patients, who visited our university hospital for counseling on fertility preservation at diagnosis of stage I-III invasive breast cancer in the years 2008-2015. At baseline, tumor and treatment characteristics were registered. During follow-up information on fullfilled childwish and disease status was collected. To compare the fertility preservation group and the non-fertility preservation group independent samples Student t-tests and Chi-square tests were conducted. Results In total 128 women with a median age of 32 years (19 – 43) were referred for fertility preservation counseling before start of chemotherapy, with an increase in referral in the more recent years. Thirty-nine (30.5%) women chose for fertility preservation: in 26 patients embryos were frozen, in seven oocytes, and in one both embryos and oocytes. In four patients the procedure was not succesfull. Patients who had chosen for fertility preservation more often had a male partner (87.2% vs 70.8%, P = 0.05) and had a smaller tumor size (median 19 versus 23 mm, P = 0.04) at the time of diagnosis compared to those who did not chose for fertility preservation. During a median follow-up of 30.3 months (range 0 – 96.9), 27 (21.1%) patients had tried to conceive: 14 (35.9%) women in the fertility versus 13 (14.6%) in the non-fertility preservation group. All of these had recovery of ovarian function after chemotherapy-induced ovarian failure. Only two women used the cryopreserved embryos, both succesfully and combined with preimplantation genetic diagnosis of the embryos because of germline mutations in BRCA1-gene. Eight patients in the fertility preservation group and seven patients in the non-fertility preservation group became at least once pregnant. In the fertility preservation group, eight healthy babies were born, one baby had Morbus Hirschsprung, one women is pregnant at this moment and one woman had a miscarriage. Of the eleven pregnancies in the non-fertility preservation group, nine healthy babies were born and one woman had two miscarriages. Of the referred 128 women, nine (7.0%) had breast cancer recurrence, three in the fertility preservation group versus six in the non-fertility preservation group. Conclusion One third of referred patients choose for fertility preservation before start of chemotherapy. In all of these patients, the ovarian function recovered. However, two couples used their cryopreserved embryos for preimplantation genetic diagnosis and both became pregnant. Since the follow-up time is relatively short, more data are mandatory to make a statement on the effectiveness of fertility preservation techniques in young breast cancers patients. Citation Format: Vriens IJ, Butalid EM, Schepers-van der Sterren EE, van der Poel MH, Jansen-Engelen SL, van Riel A-MM, van de Wouw YJ, Vriens BE, van Haaren ER, Lemaire BM, Dercksen WW, Luiten EJ, de Boer M, de Die-Smulders CE, Derhaag JG, van Golde RJ, Tjan-Heijnen VC. Preserving fertility in young women undergoing chemotherapy for early breast cancer; the Maastricht experience [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD6-03.