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NEO adjuvant chemotherapy in breast cancer: What have we learned so far?

CC BY-NC-ND 4.0 · Indian J Med Paediatr Oncol 2010; 31(01): 8-17

DOI: DOI: 10.4103/0971-5851.68846

Author : Nirmal V Raut,Nilesh Chordiya

Abstract

Neoadjuvant chemotherapy (NACT) in breast cancer has undergone continuous evolution over the last few decades to establish its role in the combined modality management of these tumors. The process of evolution is still far from over. Many questions are still lurking in the minds of oncologists treating breast cancer. This review analyzes the evidence from metaanlyses, major multiinstitutional prospective trials, retrospective institutional series and systematic reviews in breast cancer to determine the current standards and controversies in NACT. The most effective drugs, their advantages, issues and controversies in delivery as well as the criteria for response are reviewed. A summary of evidence-based consensus is presented and unresolved aspects are discussed.

Keywords

Breast cancer - neoadjuvant chemotherapy - review

Publication History

Article published online:
19 November 2021

© 2010. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

Abstract

Neoadjuvant chemotherapy (NACT) in breast cancer has undergone continuous evolution over the last few decades to establish its role in the combined modality management of these tumors. The process of evolution is still far from over. Many questions are still lurking in the minds of oncologists treating breast cancer. This review analyzes the evidence from metaanlyses, major multiinstitutional prospective trials, retrospective institutional series and systematic reviews in breast cancer to determine the current standards and controversies in NACT. The most effective drugs, their advantages, issues and controversies in delivery as well as the criteria for response are reviewed. A summary of evidence-based consensus is presented and unresolved aspects are discussed.

Keywords: Breast cancer, neoadjuvant chemotherapy, review

THE BIRTH OF NEOADJUVANT CHEMOTHERAPY (NACT): FROM HALSTEAD TO FISHER

The changing trends in management of locally advanced breast cancer actually reflect the paradigm shift in the understanding of the biology of the disease.

The Halsteadian concept of breast cancer, to begin with, as a localized disease prevailed at the end of the nineteenth century, the scene being dominated by the surgeons and the different radical surgical approaches with a hope of increasing survival.[,] However, contrary to their expectations, the 5-year overall survival continued to be 15–20%. A retrospective analysis of multiple case series concluded that the probability of cure was inversely proportional to initial stage of malignancy (i.e., T and N) without being influenced by the extent of radicality of thesurgery.[–] Studying the patterns of FAILURE lead to a better understanding of the biology of the disease and thus a multimodal approach came into vogue.

Preclinical studies being performed at the same time led to the recognition that metastatic deposits are established in patients months or years before diagnosis.[,]

The Fischer’s hypothesis that the disease was systemic from the very beginning ignited a holy grail search of cytotoxic agents. In various animal models, they demonstrated that removal of the primary tumor resulted in an increase in the labeling index in residual tumor cells and an increase in circulating growth-stimulating factors.[] Administration of NACT and endocrine treatment to these animals impaired the increase in cell growth observed in residual tumor cells in untreated animals.

Introduced in the early 1970s as part of an integrated therapeutic approach to treat inoperable locally advanced breast cancer, primary, anterior, induction or NACT resulted in high responses and sufficient down-staging to allow mastectomy in some patients. The small number of pathological complete responders, which was contrary to expectations, is now the prime focus of NACT trials.

Gradually, the idea of preoperative chemotherapy was extended to include patients with large but operable early-stage breast cancer. This approach allows the tumor to be used as a measure of treatment response in vivo. More recently, the possibility has opened up for NACT to provide information on the use of clinical, pathological and molecular endpoints, which can be used as surrogate markers to predict the long-term outcome in the adjuvant setting.

Perhaps the most dramatic conceptual change in the approach to breast cancer treatment is the realization that breast cancer is a conglomerate of several molecularly defined syndromes, with distinct prognoses, clinical courses and sensitivity profiles to existing therapeutics. The anatomical accessibility of the breast provides the potential for serial biopsies to investigate molecular changes during treatment.

ADVANTAGES AND DISADVANTAGES OF NACT

Theoretically, they can be summed up as follows:[]

Advantages Disadvantages
Reduction in tumor volume Clinical/radiological staging imprecise
Tumor down-staging Overtreatment of small favorable tumors
In vivo assessment of tumor response Extent of surgery not confirmed
Less-extensive surgical resection Loss of prognostic significance of axillary nodal status
Postsurgical growth spurt abrogated Unknown relevance of surgical margins
Earlier introduction of a systemic therapy Large number of drugresistant cells present
Response to chemotherapy serves as a marker for long-term outcome Delays effective local therapy
Multiple sequential sampling of primary tumor allows evaluation of biologic changes during chemotherapy Response of primary tumor may not correlate with response of micrometastases

Table 1

<!--caption a7-->

Impact of NACT on overall survival

Study Overall survival rate Weight Hazard ratio
Neoadjuvant Adjuvant
Neoadjuvant
Danforth[] 3 of 26 6 of 27 0.37 0.18
Broet[] 55 of 200 60 of 190 9.55 0.79
Mauriac[] 48 of 134 51 of 139 7.64 0.99
Woolmark[] 221 of 742 218 of 751 40.20 1.02
Gianni[] 32 of 451 30 of 451 5.39 1.06
Van der Hage[] 111 of 350 104 of 348 18.57 1.09
Subtotal 470 of 1,903 469 of 1,905 31.73 1.00
Test of heterogeneity X2=5.16;
P=0.40
Test for overall effect Z=0.06;
P=0.95
Sandwich
Cleator[] 43 of 144 53 of 142 12.36 0.81
Semiglazov[] 20 of 137 30 of 134 2.61 0.88
Gazet[] 27 of 100 21 of 110 2.05 1.21
Enomoto[] 3 of 20 3 of 25 0.45 1.61
Subtotal 93 of 401 107 of 411 18.47 0.89
Test of heterogeneity X2=1.52;
P=0.68
Test for overall effect Z=0.87;
P=0.39
Total 563 of 2,304 576 of 2,316 100 0.98
Test of heterogeneity X2=7.26;
P=0.61
Test for overall effect Z=0.43;
P=0.67

Table 2

<!--caption a7-->

Impact of NACT on locoregional recurrence

Study Overall survival rate
Weight Hazard ratio
Neoadjuvant Adjuvant
Ostapenko[] 1 of 50 3 of 50 0.72 0.38
Gianni[] 8 of 438 22 of 875 5.43 0.75
Enomoto[] 2 of 20 3 of 25 0.90 0.93
Woolmark[] 108 of 742 96 of 751 36.90 1.15
Van der Hage[] 49 of 350 44 of 348 16.77 1.16
Gazet[] 24 of 100 104 of 348 18.57 1.09
20 of 110 5.19 1.21 31.73 1.00
Cleator[] 13 of 44 9 of 142 4.01 1.50
Danforth[] 3 of 26 2 of 27 0.90 1.58
Subtotal 208 of 1,870 199 of 2,328 70.82 1.12
Test for heterogeneity χ2=3.22, 7 d.f; 0.88
P=0.86
Test for overall effect Z=1.15;
P=0.25
Inadequate local treatment
Broet[] 17 of 95 17 of 86 6.15 0.90
Broet[] 49 of 200 37 of 190 15.25 1.31
Mauriac[] 31 of 134 12 of 138 7.78 2.57
Subtotal 97 of 429 66 of 414 29.18 1.45
Test for heterogeneity χ2=5.67, 2 d.f;
P=0.006
Test for overall effect Z=2.36;
P=0.02
Total 305 of 2,299 265 of 2,742 100 1.21
Test for heterogeneity χ2=10.76, 10 d.f;
P=0.38
Test for overall effect Z=2.24;
P=0.03

Table 3

<!--caption a7-->

Metaanalysis of neoadjuvant chemotherapy

Study Overall survival rate
Weight Hazard ratio
Neoadjuvant Adjuvant
Cleator[] 16 of 149 31 of 144 2.39 0.50
Broet[] 22 of 95 31 of 96 2.47 0.64
Woolmark[] 239 of 743 302 of 752 22.77 0.80
Van der Hage[] 203 of 323 262 of 341 19.33 0.82
Jakesz[] 71 of 214 85 of 209 6.52 0.82
Danforth[] 15 of 26 16 of 27 1.19 0.97
Broet 73 of 200 66 of 190 5.13 1.05
Gazet[] 11 of 100 9 of 110 0.65 1.34
Subtotal 470 of 1,903 469 of 1,905 60.46 0.82
Test of heterogeneity χ2=9.43; 7 d.f.; P=0.22 199 of 2,328 70.82 1.12
Test for overall effect Z=5.10; 0.88
P<0>
Gianni[] 154 of 438 579 of 875 29.30 0.53
Mauriac[] 74 of 134 136 of 136 10.24 0.55
Subtotal 228 of 572 715 of 1,011 39.54 0.54
Test of heterogeneity χ2=0.16, 1 d.f.; P=0.69 37 of 190 15.25 1.31
Test for overall effect Z=11.32; 12 of 138 7.78 2.57
P<0>
Total 878 of 2,422 1,517 of 2,870 100 0.71
Test of heterogeneity χ2=53.66, 9 d.f.; P<0>
Test for overall effect Z=10.92;
P<0>
Total 305 of 2,299 265 of 2,742 100 1.21
Test for heterogeneity χ2=10.76, 10 d.f; P=0.38
Test for overall effect Z=2.24;
P=0.03

Table 4

<!--caption a7-->

NACT and response rates

Study Complete clinical response (%) Partial clinical response (%) Pathological response (%)
Avril, Mauriac[] 33 30 unknown
Semiglazov[] 12 57 29
Scholl[] 13 32 unknown
Scholl[] 24 42 unknown
Broet[]
Makris[] 22 61 7
Woolmark[] 36 43 13
Gazet[] 25 26 unknown
Van der hage[] 7 42 4
Danforth[] 65 12 20

Table 5

<!--caption a7-->

Addition of taxanes to anthracyclines in NACT

Study Stage of disease No. of patients Arms ORR pCR (%)
Malamos[] Operable 30/30 FEC 50 0
ED 81 28
Aberdeen[], II B and III 162/104 CVAP 64 15
Smith[] CVAP-D 85 31
Luprosi[] II and III 90/50 FEC 72 24
ED 84 24
NSABP-27[,] II 1605/1605 AC-D 85 14
AC 91 25
Evans[] II and III 365/363 AC 78 12
AT 88 8
Semiglazov[] III A and III B 103/103 FAC 73 10
AT 84 25
Dieras[] II A, II B and III A 247/200 AC 66 10
AT 83 16

Table 7

<!--caption a7-->

Dose dense NACT

Study No. Arms of the study pCR Rates of BCT
AGO Untch et al[] 1,069 pts Adria 150 mg/ m2 q2wkly for 3#‐>paclitaxel 250 mg/m2 q2wkly for 3# P=0.03 P=0.016
Adria 90 mg/ m2+docetaxel 175 mg/m2 q3wkly for 4#
GEPARDUO[] 931 pts Adria 50 mg/ m2+docetaxel 75 mg/ m2 q2wkly for 4# 14.3% 63.4%
Aria 60 mg/m2 and cyclophosphamide 600 mg/m2 q3wkly for 4# → docetaxel 10.6% 58.1%

Table 6

<!--caption a7-->

Results: Primary end points and sensitivity analysis (fixed effect model)

Patients (total no of pt’s) Relative risk (95% CI) P value Heterogeneity Absolute difference (%) Number need to treat
pCR
Overall 2455 1.22 0.11 0.05 - -
concomitant 746 1.04 0.77 0.06 - -
Sequential 1709 1.73 0.013 0.65 2.4 41
BCS
Overall 2425 1.11 0.012 0.43 3.4 29
Concomitant 716 1.22 0.027 0.78 5.3 19

Table 8

<!--caption a7-->

Should anthracyclines and taxanes be used concurrently or sequentially?

Effect name Citation Year N total P-value
Concomitant-pCR Malamos[] 1998 30 0.27
Concomitant-pCR Luprosi[] 2000 50 1.0
Concomitant-pCR Semiglazov[] 2002 103 0.006
Concomitant-pCR Dieras[] 2004 200 0.828
Concomitant-pCR Evans[] 2005 363 0.469
Fixed Concomitant-pCR 746 0.774
Random Concomitant-pCR 746 0.422
Sequential-pCR Heys[] 2002 104 0.063
Sequential-pCR Bear[] 2006 1,605 0.075
Fixed Sequential-pCR 1,709 0.013
Random Sequential-pCR 1,709 0.013
Fixed Combined 2,455 0.108
Random Combined 2,455 0.117

Table 9

<!--caption a7-->

Should all the cycles of chemotherapy be delivered preoperatively?

Preop AC alone Taxanes combination P-value
cCR 40% 63% <0>
pCR 13% 26% <0>
% of pts with negative nodes 50% 58% <0>

Table 10

<!--caption a7-->

Reported randomized phase III trials with neoadjuvant trastuzumab

Reference Number of patients Patient population Design HER2 assessment pCR rate, No H percentage with H (95% c.i.) p-value
Buzdar et al., 2005,[] 2007[] 42 65% T2 40% N0/57% N1 P → FEC vs. P+H → FEC+H IHC 3+ or FISH+ 26 (9–51) 65 (43–84) NS
Gianni et al., 2007[] 228 60% T4 85% N+ AP → P → CMF vs. AP+H → P+H → CMF+H IHC 3+ or FISH 23 (NR) 43 (NR) 0.002
Untch et al., 2008[] 453 NA EC → D or EC → DX or EC → D → X vs. EC → D+H or EC → DX+H or EC → D+H → X+H NA 20 (NR) 41 (NR) <0>

C, cyclophosphamide; CI, confidence interval; D, docetaxel; E, epirubicin; F, 5-fluoruracil; FISH, fluorescence in situ hybridization; H, trastuzumab; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; M, methotrexate; N, nodal status; NA, not applicable; NR, not reported; NS, not significant; P, paclitaxel; pCR, pathologic complete response; T, tumor size; X, capecitabine

The larger NeOAdjuvant Herceptin (NOAH) trial reported similar findings with trastuzumab added to doxorubicin-paclitaxel followed by paclitaxel followed by cyclophosphamide-methotrexate-5-fluoruracil (AP→P→CMF) chemotherapy.[] Both these studies administered anthracycline chemotherapy concurrently with trastuzumab and did not report a high rate of observed cardiac toxicity, contrary to the 16%-rate of clinical grade 3/4 congestive heart failure observed in the pivotal first-line metastatic trial with concurrent trastuzumab and doxorubicin cyclophosphamide (AC).[] The GeparQuattro study evaluating epirubicin, cyclophosphamide and docetaxel with or without capecitabine and/or trastuzumab before surgery reported a similar doubling in the observed pCR rate with the addition of trastuzumab. This study initiates trastuzumab after the completion of anthracycline therapy.

Two important ongoing neoadjuvant therapy trials are exploring the role of lapatinib in the neoadjuvant settings. Results are eagerly awaited. The schema of the study is shown in Figures ​Figures11 and ​and22.

|  Figure 1:GeparQuinto study schema

| Figure 2:Neo ALLTO study schema

GeparQuinto study (Ref Figure 1).

GeparQuinto study design for HER2-positive cohort. C, cyclophosphamide (600 mg/m2: day 1 q day 21 for four cycles); E, epirubicin (90 mg/m 2 : every 3 weeks for four cycles); H, trastuzumab (8 mg/kg: loading dose, 6 mg/kg: every 3 weeks); Her-2, human epidermal growth factor receptor 2; L, lapatinib (1,250 mg daily for 24 weeks: run-in phase cycles 1 and 5: 1,000 mg daily); R, randomization; T, docetaxel (100 mg/m2: every 3 weeks for four cycles).

DOES ADDITION OF BEVACIZUMAB HELP?

Greil et al,[] in a phase II study, studied the efficacy and safety of the combination of Bevacizumab, docetaxel and capecitabine for her2-negative breast cancer, and found a pCR of 22%.

WHAT IS THE BEST WAY OF ASSESSMENT OF RESPONSE TO NEOADJUVANT THERAPY?

A study of 189 breast cancer patients undergoing NACT assessed tumor response to treatment with physical examination, mammography or ultrasound and compared these approaches with the gold standard, pathologic examination. The study found that false-positive rates ranged from 20% to 65%-for all modalities; false-negative rates were 10-57%.[] The GeparTrio trial[] revealed a sonographic complete response in 50%-of the cases examined, whereas a pathologic complete response was seen in only 5–6%-of the patients.

Advantages of magnetic resonance imaging are that it provides evidence of response as early as 6 weeks of initiation of chemotherapy. Contrast enhancement is reduced even before actual reduction in the size of the tumor. However, the foible is that the accuracy varies with the degree of response to chemotherapy and with the chemotherapeutic agent, underestimating the response in well-responding tumors and taxane-based chemotherapy.[–] Several studies have shown the usefulness of Positron Emission Scan in the assessment of response.[–] A significant decline in the standardized uptake value occurs in responders early in the course of chemotherapy.

In a study of 22 patients, after an initial course of therapy, all responding (based on Standard Uptake Value changes) tumors were identified through a decrease in SUV of >55%-below baseline (sensitivity, 100%; specificity, 85%).[] Another study of 30 patients used PET at midtherapy assessments and reported a complete response, correlating with a 50—60%-reduction from baseline SUV.[]

However, outside a clinical trial, these approaches are not recommended for monitoring response of breast cancer to NACT.

The gold standard for assessing response to NACT for breast cancer is still pathologic evaluation.[] Despite the proven predictive value of pCR in this context, there is no consensus on the measurement of this important endpoint. Three of the most commonly used criteria in the literature are those of Sataloff et al.,[] Chevallier et al.[] and Feldman et al.[]

A study at M.D. Anderson[] analyzed postmastectomy pathology specimens from 241 patients treated with neoadjuvant sequential paclitaxel followed by FAC regimen and 141 patients treated with a neoadjuvant FAC regimen. The investigators then calculated the residual cancer burden (RCB), which consisted of a continuous index combining primary tumor size and cellularity as well as number and size of nodal metastases. Using multivariate analysis, they showed that RCB correlated with prognosis, independent of factors such as age, pretreatment clinical stage, hormone receptor status, hormone therapy and pathologic response (hazard ratio: 2.5; 95%-c.i. 1.7–3.69; P < 0>

NACT IN TRIPLE-NEGATIVE BREAST CANCER (TNBC)

TNBC is a heterogeneous, initially chemosensitive disease. Currently, there is no specific favored chemotherapy regimen for the treatment of TNBC. The use of taxane (paclitaxel or docetaxel) and anthracycline-based regimens, according to data for breast cancer patients in general, appear to provide higher pathological complete response rates. On the basis of the described similarities between sporadic triple-negative cancers and BRCA1-associated cancers, drugs with the ability to cause interstrand breaks, like platinum drugs, have been suggested to be used for the treatment of TNBC. This was supported by in vitro studies demonstrating the benefit of BRCA1-related tumors to these agents.[] Because the availability of HER 2 testing is only of late, there are no studies for TNBC specifically. One study by Garber et al.[] using preoperative single-agent cisplatin in T2/T3 TNBC reported a pCR of 23%.

A study by Carey et al.[] evaluated responses to NACT in 107 patients with stages II and III breast cancer. Patients received neoadjuvant doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) chemotherapy (AC) for four cycles, either alone or as the first component of a sequential AC-taxane neoadjuvant regimen. All patients received AC NACT at conventional doses for four cycles. Twenty-eight (26%) received AC on a dose-dense schedule (every 2 weeks), whereas the rest of the patients received AC on an every-3 weeks schedule. Most patients (80 of 107, 75%) received additional NACT following AC, which primarily involved either paclitaxel or docetaxel. PCR to chemotherapy (defined as postoperatively stage 0, no invasive cancer) was significantly better among basal-like subtype (27%), defined in this study as the immunohistochemical surrogates ER-, PR- and HER2/neu- and HER2/neu? /ER- (36%) subtypes vs. the combined luminal subtypes (7%; P=0.01). However, despite the initial chemosensitivity, patients with the basal-like and HER2/neu? /ER- subtypes had worse distant DFS (P=0.04) and OS (P=0.02) than those with the luminal subtypes This is known as the famous “Triple negative Paradox.” It has put to question all oncologists treating breast cancer who, until now, were using pCR as a surrogate for long-term survival.

Footnotes

Source of Support: Nil

Conflict of Interest: None declared.

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  39. Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, et al. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2003;21:4165-74.
  40. Bear HD, Anderson S, Smith RE, Geyer CE Jr, Mamounas EP, Fisher B, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 2006;24:2019-27.
  41. Evans TR, Yellowlees A, Foster E, Earl H, Cameron DA, Hutcheon AW, et al. Phase III randomized trial of doxorubicin and docetaxel versus doxorubicin and cyclophosphamide as primary medical therapy in women with breast cancer: An anglo-celtic cooperative oncology group study. J Clin Oncol 2005;23:2988-95.
  42. Diιras V, Fumoleau P, Romieu G, Tubiana-Hulin M, Namer M, Mauriac L, et al. Randomized parallel study of doxorubicin plus paclitaxel and doxorubicin plus cyclophosphamide as neoadjuvant treatment of patients with breast cancer. J Clin Oncol 2004;22:4958-65.
  43. Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003;21:1431-9.
  44. Untch M, Konecy G, Ditsch N. Dose dense sequential Epirubicin-Paclitaxel as preoperative treatment of Breast cancer: Results of a randomized AGO study. Pro Am Soc Clin Onco 2002;21:133a.
  45. Von Minkwitz G, Raab G, Scheuette M. Dose dense versus sequential adriamycin /docetaxel combination as preoperative chemotherapy in operable breast cancer-primary endpoint analysis of GEPARDUO study. Pro Am Soc Clin Onco 2002;21:168a.
  46. Jones S, Holmes FA, O′Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, et al. Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. J Clin Oncol 2009;27:1177-83.
  47. Slamon D, Eiermann W, Robert N. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC;T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC;TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Breast Cancer Res Treat 2005;94:S5.
  48. Von Minckwitz G, Kόmmel S, Vogel P, Hanusch C, Eidtmann H, Hilfrich J, et al. Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: Phase III randomized GeparTrio trial. J Natl Cancer Inst 2008;100:542-51.
  49. Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: Results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 2005;23:3676-85.
  50. Buzdar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, et al. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: An update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res 2007;13:228-33.
  51. Gianni L, Semiglazov V, Manikhas GM, Eiermann W, Lluch A, Tjulandin S, et al. Neoadjuvant trastuzumab in locally advanced breast cancer (NOAH): Antitumour and safety analysis. 2007 ASCO Annual Meeting Proceedings 43rd American Society of Clinical Oncology Annual Meeting; 1-5 June 2007; Chicago, IL. Abstract 532.
  52. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783-92.
  53. Untch M, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, et al. Neoadjuvant treatment of HER2 overexpressing primary breast cancer with trastuzumab given concomitantly to epirubicin/cyclophosphamide followed by docetaxel ΁ capecitabine. First analysis of efficacy and safety of the GBG/AGO multicenter intergroup-study ′GeparQuattro′. Presented at: 6th European Breast Cancer Conference; 15-19 April 2008; Berlin, Germany. Abstract 1LB.
  54. Greil R, Moik M, Reitsamer R, Ressler S, Stoll M, Namberger K, et al. Neoadjuvant bevacizumab, docetaxel and capecitabine combination therapy for HER2/neu-negative invasive breast cancer: Efficacy and safety in a phase II pilot study. Eur J Surg Oncol 2009;35:1048-54.
  55. ;Chagpar AB, Middleton LP, Sahin AA, Dempsey P, Buzdar AU, Mirza AN, et al. Accuracy of physical examination, ultrasonography, and mammography in predicting residual pathologic tumor size in patients treated with neoadjuvant chemotherapy. Ann Surg 2006;243:257-64.
  56. Partridge SC, Gibbs JE, Lu Y, Esserman LJ, Sudilovsky D, Hylton NM. Accuracy of MR imaging for revealing residual breast cancer in patients who have undergone neoadjuvant chemotherapy. AJR Am J Roentgenol 2002;179:1193-9.
  57. Rieber A, Brambs HJ, Gabelmann A, Heilmann V, Kreienberg R, Kόhn T. Breast MRI for monitoring response of primary breast cancer to neo-adjuvant chemotherapy. Eur Radiol 2002;12: 1711-9.
  58. Cheung YC, Chen SC, Su MY, See LC, Hsueh S, Chang HK, et al. Monitoring the size and response of locally advanced breast cancers to neoadjuvant chemotherapy (weekly paclitaxel and epirubicin) with serial enhanced MRI. Breast Cancer Res Treat 2003;78:51-8.
  59. Belli P, Romani M, Costantini M, Magistrelli A, Terribile D, Nardone L, et al. Role of magnetic resonance imaging in the pre and postchemotherapy evaluation in locally advanced breast carcinoma. Rays 2002;27:279-90.
  60. Bollet MA, Thibault F, Bouillon K, Meunier M, Sigal-Zafrani B, Savignoni A, et al. Role of dynamic magnetic resonance imaging in the evaluation of tumor response to preoperative concurrent radiochemotherapy for large breast cancers: A prospective phase II study. Int J Radiat Oncol Bio Phys 2007;69:13-8.
  61. Segara D, Krop IE, Garber JE, Winer E, Harris L, Bellon JR, et al. Does MRI predict pathologic tumor response in women with breast cancer undergoing preoperative chemotherapy? J Surg Oncol 2007;96:474-80.
  62. Wasser K, Sinn HP, Fink C, Klein SK, Junkermann H, Lόdemann HP, et al. Accuracy of tumor size measurement in breast cancer using MRI is influenced by histological regression induced by neoadjuvant chemotherapy. Eur Radiol 2003;13:1213-23.
  63. Denis F, Desbiez-Bourcier AV, Chapiron C, Arbion F, Body G, Brunereau L. Contrast enhanced magnetic resonance imaging underestimates residual disease following neoadjuvant docetaxel based chemotherapy for breast cancer. Eur J Surg Oncol 2004;30:1069-76.
  64. Kwong MS, Chung GG, Horvath LJ, Ward BA, Hsu AD, Carter D, et al. Postchemotherapy MRI overestimates residual disease compared with histopathology in responders to neoadjuvant therapy for locally advanced breast cancer. Cancer J 2006;12:212-21.
  65. Wahl RL, Zasadny K, Helvie M, Hutchins GD, Weber B, Cody R. Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography: Initial evaluation. J Clin Oncol 1993;11:2101-11.
  66. Jansson T, Westlin JE, Ahlstrφm H, Lilja A, Lεngstrφm B, Bergh J. Positron emission tomography studies in patients with locally advanced and/or metastatic breast cancer: A method for early therapy evaluation? J Clin Oncol 1995;13:1470-7.
  67. Bassa P, Kim EE, Inoue T, Wong FC, Korkmaz M, Yang DJ, et al. Evaluation of preoperative chemotherapy using PET with fluorine-18-fluorodeoxyglucose in breast cancer. J Nucl Med 1996;37:931-8.
  68. Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Lieber CP, Baloch Z. J Am Coll Surg. 1995 Mar;180(3):297-306.
  69. Smith IC, Welch AE, Hutcheon AW, Miller ID, Payne S, Chilcott F, et al. Positron emission tomography using [(18)F]-fluorodeoxy-D-glucose to predict the pathologic response of breast cancer to primary chemotherapy. J Clin Oncol 2000;18:1676-88.
  70. Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Lieber CP, Baloch Z. Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome. J Am Coll Surg 1995;180:297-306.
  71. Chevallier B, Roche H, Olivier JP, Chollet P, Hurteloup P. Inflammatory breast cancer. Pilot study of intensive induction chemotherapy (FEC-HD) results in a high histologic response rate. Am J Clin Oncol 1993;16:223-8.
  72. Feldman LD, Hortobagyi GN, Buzdar AU, Ames FC, Blumenschein GR. Pathological assessment of response to induction chemotherapy in breast cancer. Cancer Res 1986;46:2578-81.
  73. Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 2007;25:4414-22.
  74. Bhattacharyya A, Ear US, Koller BH, Weichselbaum RR, Bishop DK. The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA crosslinking agent cisplatin. J Biol Chem 2000;275:23899-903.
  75. Garber JE, Richardson A, Harris LN. Neo-adjuvant cisplatin (CDDP) in triple-negative breast cancer (BC). Proceedings San Antonio Breast Cancer Symposium, 2006.
  76. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 2007;13:2329-34.

|  Figure 1:GeparQuinto study schema

| Figure 2:Neo ALLTO study schema

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  47. Slamon D, Eiermann W, Robert N. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC;T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC;TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Breast Cancer Res Treat 2005;94:S5.
  48. Von Minckwitz G, Kόmmel S, Vogel P, Hanusch C, Eidtmann H, Hilfrich J, et al. Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: Phase III randomized GeparTrio trial. J Natl Cancer Inst 2008;100:542-51.
  49. Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: Results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol 2005;23:3676-85.
  50. Buzdar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, et al. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: An update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res 2007;13:228-33.
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  53. Untch M, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, et al. Neoadjuvant treatment of HER2 overexpressing primary breast cancer with trastuzumab given concomitantly to epirubicin/cyclophosphamide followed by docetaxel ΁ capecitabine. First analysis of efficacy and safety of the GBG/AGO multicenter intergroup-study ′GeparQuattro′. Presented at: 6th European Breast Cancer Conference; 15-19 April 2008; Berlin, Germany. Abstract 1LB.
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  55. ;Chagpar AB, Middleton LP, Sahin AA, Dempsey P, Buzdar AU, Mirza AN, et al. Accuracy of physical examination, ultrasonography, and mammography in predicting residual pathologic tumor size in patients treated with neoadjuvant chemotherapy. Ann Surg 2006;243:257-64.
  56. Partridge SC, Gibbs JE, Lu Y, Esserman LJ, Sudilovsky D, Hylton NM. Accuracy of MR imaging for revealing residual breast cancer in patients who have undergone neoadjuvant chemotherapy. AJR Am J Roentgenol 2002;179:1193-9.
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  59. Belli P, Romani M, Costantini M, Magistrelli A, Terribile D, Nardone L, et al. Role of magnetic resonance imaging in the pre and postchemotherapy evaluation in locally advanced breast carcinoma. Rays 2002;27:279-90.
  60. Bollet MA, Thibault F, Bouillon K, Meunier M, Sigal-Zafrani B, Savignoni A, et al. Role of dynamic magnetic resonance imaging in the evaluation of tumor response to preoperative concurrent radiochemotherapy for large breast cancers: A prospective phase II study. Int J Radiat Oncol Bio Phys 2007;69:13-8.
  61. Segara D, Krop IE, Garber JE, Winer E, Harris L, Bellon JR, et al. Does MRI predict pathologic tumor response in women with breast cancer undergoing preoperative chemotherapy? J Surg Oncol 2007;96:474-80.
  62. Wasser K, Sinn HP, Fink C, Klein SK, Junkermann H, Lόdemann HP, et al. Accuracy of tumor size measurement in breast cancer using MRI is influenced by histological regression induced by neoadjuvant chemotherapy. Eur Radiol 2003;13:1213-23.
  63. Denis F, Desbiez-Bourcier AV, Chapiron C, Arbion F, Body G, Brunereau L. Contrast enhanced magnetic resonance imaging underestimates residual disease following neoadjuvant docetaxel based chemotherapy for breast cancer. Eur J Surg Oncol 2004;30:1069-76.
  64. Kwong MS, Chung GG, Horvath LJ, Ward BA, Hsu AD, Carter D, et al. Postchemotherapy MRI overestimates residual disease compared with histopathology in responders to neoadjuvant therapy for locally advanced breast cancer. Cancer J 2006;12:212-21.
  65. Wahl RL, Zasadny K, Helvie M, Hutchins GD, Weber B, Cody R. Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography: Initial evaluation. J Clin Oncol 1993;11:2101-11.
  66. Jansson T, Westlin JE, Ahlstrφm H, Lilja A, Lεngstrφm B, Bergh J. Positron emission tomography studies in patients with locally advanced and/or metastatic breast cancer: A method for early therapy evaluation? J Clin Oncol 1995;13:1470-7.
  67. Bassa P, Kim EE, Inoue T, Wong FC, Korkmaz M, Yang DJ, et al. Evaluation of preoperative chemotherapy using PET with fluorine-18-fluorodeoxyglucose in breast cancer. J Nucl Med 1996;37:931-8.
  68. Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Lieber CP, Baloch Z. J Am Coll Surg. 1995 Mar;180(3):297-306.
  69. Smith IC, Welch AE, Hutcheon AW, Miller ID, Payne S, Chilcott F, et al. Positron emission tomography using [(18)F]-fluorodeoxy-D-glucose to predict the pathologic response of breast cancer to primary chemotherapy. J Clin Oncol 2000;18:1676-88.
  70. Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Lieber CP, Baloch Z. Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome. J Am Coll Surg 1995;180:297-306.
  71. Chevallier B, Roche H, Olivier JP, Chollet P, Hurteloup P. Inflammatory breast cancer. Pilot study of intensive induction chemotherapy (FEC-HD) results in a high histologic response rate. Am J Clin Oncol 1993;16:223-8.
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