Evaluation of Tumor Stiffness by Elastography Is Predictive for Pathologic Complete Response to Neoadjuvant Chemotherapy in Patients with Breast Cancer.
Hayashi M, Yamamoto Y, Ibusuki M, Fujiwara S, Yamamoto S, Tomita S, Nakano M, Murakami K, Iyama KI, Iwase H.
Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
BACKGROUND: Breast elastography (EG), which can objectively evaluate tumor stiffness, has been useful for differentiation of benign and malignant breast lesions. However, the value of EG for prediction of response to systemic therapy is poorly understood.
METHODS: The baseline evaluations of EG in 55 patients who received neoadjuvant chemotherapy were reviewed. We investigated the correlation between tumor stiffness and response to neoadjuvant chemotherapy. Tumor stiffness was evaluated by the Tsukuba elasticity scoring system.
RESULTS: The mean EG scores were significant lower for the clinical and pathologic complete response (pCR) groups than for the others. When we categorized patients into two groups according to tumor stiffness, 26 patients were assigned to the low EG group (soft, scores from 1 to 3) and 29 patients were assigned to the high EG group (hard, score 4 and 5). The low EG group had significantly higher clinical complete response and pCR rates than the high EG group (clinical complete response, low EG group 38 % vs. high EG group 10 %, P = 0.024; pCR, low EG group 50 % vs. high EG group 14 %, P = 0.003, respectively). Furthermore, multivariate analysis indicated that estrogen receptor, human epidermal growth factor receptor 2, and low EG (odds ratio 13.04, 95 % confidence interval 1.19-458.28, P = 0.035) were independent predictive factors of pCR.
CONCLUSIONS: Tumor stiffness evaluated by EG bears predictive potential for response to neoadjuvant chemotherapy. Stiffness evaluated by EG may be recognized as a clinically significant tumor characteristic, comparable to other data obtained by functional imaging techniques.
Definition and Impact of Pathologic Complete Response on Prognosis After Neoadjuvant Chemotherapy in Various Intrinsic Breast Cancer Subtypes.
von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J, Jackisch C,Kaufmann M, Konecny GE, Denkert C, Nekljudova V, Mehta K, Loibl S.
Gunter von Minckwitz, Valentina Nekljudova, Keyur Mehta, and Sibylle Loibl, German Breast Group, Neu-Isenburg; Michael Untch, Helios-Klinikum; Jens-Uwe Blohmer, St Gertrauden Krankenhaus; Carsten Denkert, Institute for Pathology, Charité, Berlin; Serban D. Costa, Universitäts-Frauenklinik, Magdeburg; Holger Eidtmann, Universitäts-Frauenklink, Kiel; Peter A. Fasching, Frauenklinik des Universitätsklinikums Erlangen, Erlangen; Bernd Gerber, Universitäts-Frauenklinik, Rostock; Wolfgang Eiermann, Klinikum zum Roten Kreuz, München; Jörn Hilfrich, Henrietten-Stiftung, Hannover; Christian Jackisch, Städtische Kliniken, Offenbach; Manfred Kaufmann, Universitäts-Frauenklinik, Frankfurt; Jens Huober, Kantonsspital, St Gallen, Switzerland; and Gottfried E. Konecny, University of California Los Angeles, Los Angeles, CA.
PURPOSE: The exact definition of pathologic complete response (pCR) and its prognostic impact on survival in intrinsic breast cancer subtypes is uncertain.
METHODS: Tumor response at surgery and its association with long-term outcome of 6,377 patients with primary breast cancer receiving neoadjuvant anthracycline-taxane-based chemotherapy in seven randomized trials were analyzed.ResultsDisease-free survival (DFS) was significantly superior in patients with no invasive and no in situ residuals in breast or nodes (n = 955) compared with patients with residual ductal carcinoma in situ only (n = 309), no invasive residuals in breast but involved nodes (n = 186), only focal-invasive disease in the breast (n = 478), and gross invasive residual disease (n = 4,449; P < .001). Hazard ratios for DFS comparing patients with or without pCR were lowest when defined as no invasive and no in situ residuals (0.446) and increased monotonously when in situ residuals (0.523), no invasive breast residuals but involved nodes (0.623), and focal-invasive disease (0.727) were included in the definition. pCR was associated with improved DFS in luminal B/human epidermal growth factor receptor 2 (HER2) -positive (P = .013), HER2-positive/nonluminal (P < .001), and triple-negative (P < .001) tumors but not in luminal A (P = .39) or luminal B/HER2-positive (P = .45) breast cancer. pCR in HER2-positive (nonluminal) and triple-negative tumors was associated with excellent prognosis.
CONCLUSION: pCR defined as no invasive and no in situ residuals in breast and nodes can best discriminate between patients with favorable and unfavorable outcomes. Patients with noninvasive or focal-invasive residues or involved lymph nodes should not be considered as having achieved pCR. pCR is a suitable surrogate end point for patients with luminal B/HER2-negative, HER2-positive (nonluminal), and triple-negative disease but not for those with luminal B/HER2-positive or luminal A tumors.
Preoperative Chemotherapy Plus Trastuzumab, Lapatinib, or Both in Human Epidermal Growth Factor Receptor 2-Positive Operable Breast Cancer: Results of the Randomized Phase II CHER-LOB Study.
Guarneri V, Frassoldati A, Bottini A, Cagossi K, Bisagni G, Sarti S, Ravaioli A, Cavanna L, Giardina G, Musolino A, Untch M, Orlando L,Artioli F, Boni C, Generali DG, Serra P, Bagnalasta M, Marini L, Piacentini F, D’Amico R, Conte P.
Valentina Guarneri, Antonio Frassoldati, Federico Piacentini, Roberto D’Amico, and PierFranco, Modena University Hospital, Modena; Alberto Bottini and Daniele Giulio Generali, AO Istituti Ospitalieri di Cremona, Cremona; Katia Cagossi and Fabrizio Artioli, Ramazzini Hospital, Carpi; Giancarlo Bisagni and Corrado Boni, Arcispedale Santa Maria Nuova, Reggio Emilia; Samanta Sarti and Patrizia Serra, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola; Alberto Ravaioli, Ospedale Infermi, Rimini; Luigi Cavanna, Hospital of Piacenza, Piacenza; Giovanni Giardina, Ospedale di Circolo e Fondazione Macchi, Varese; Antonino Musolino, University Hospital of Parma, Parma; Laura Orlando, Antonio Perrino Hospital, Brindisi; Michela Bagnalasta and Luca Marini, GlaxoSmithKline, Verona, Italy; and Michael Untch, Helios Klinikum Berlin-Buch, Berlin, Germany.
PURPOSE: This is a noncomparative, randomized, phase II trial of preoperative taxane-anthracycline in combination with trastuzumab, lapatinib, or combined trastuzumab plus lapatinib in patients with human epidermal growth factor receptor 2 (HER2) -positive, stage II to IIIA operable breast cancer. The primary aim was to estimate the percentage of pathologic complete response (pCR; no invasive tumor in breast and axillary nodes).
PATIENTS AND METHODS: In the three arms, chemotherapy consisted of weekly paclitaxel (80 mg/m(2)) for 12 weeks followed by fluorouracil, epirubicin, and cyclophosphamide for four courses every 3 weeks. The patients randomly assigned to arm A received a 4-mg loading dose of trastuzumab followed by 2 mg weekly; in arm B patients received lapatinib 1,500 mg orally (PO) daily; and in arm C, patients received trastuzumab and lapatinib 1,000 mg PO daily.ResultsA total of 121 patients were randomly assigned. Diarrhea and dermatologic and hepatic toxicities were observed more frequently in patients receiving lapatinib. No episodes of congestive heart failure were observed. The rates of breast-conserving surgery were 66.7%, 57.9%, and 68.9% in arms A, B and C, respectively. The pCR rates were 25% (90% CI, 13.1% to 36.9%) in arm A, 26.3% (90% CI, 14.5% to 38.1%) in arm B, and 46.7% (90% CI, 34.4% to 58.9%) in arm C (exploratory P = .019).
CONCLUSION: The primary end point of the study was met, with a relative increase of 80% in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared with chemotherapy plus either trastuzumab or lapatinib. These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of HER2-positive breast cancer.
Locoregional recurrence after breast-conserving therapy remains an independent prognostic factor even after an event free interval of 10years in early stage breast cancer.
Tanis E, van de Velde CJ, Bartelink H, van de Vijver MJ, Putter H, van der Hage JA.
Department of Surgery, The Netherlands Cancer Institute, The Netherlands.
INTRODUCTION: Locoregional recurrence (LRR) after breast-conserving therapy is a well-known independent risk factor associated with unfavourable long-term outcome. Controversy exists concerning the prognostic impact of a LRR after a very long event-free interval.
METHOD: Patients who underwent breast-conserving therapy for early stage breast cancer were pooled from four European Organisation for Research and Treatment of Cancer (EORTC) Breast Group trials. Only LRR as a first event was taken into account. Risk factors such as tumour size, nodal status, young age and chemotherapy were assessed in multivariate Cox regression analysis. LRR was used as a time-dependent variable in the landmark analysis for distant disease-free survival (DFS) and overall survival (OS). Patients were categorised as having at least 0, 5 or 10years event-free survival.
RESULTS: In total, 7751 early stage breast cancer patients were included with a median follow-up of 10.9years. Tumour size, nodal status, young age and chemotherapy are strong independent prognostic factors with a significant impact on long-term outcome, but lose their power and significance over time. Including all patients, LRR was the strongest prognostic factor for OS and distant DFS (resp. HR 5.01 and HR 5.31, p<0.001). In the subgroup of patients developing a LRR after at least 5 or 10years, LRR remained the strongest independent prognostic factor for OS (resp. HR 3.98, HR 4.96, p⩽0.001) and distant DFS (HR 4.42, HR 7.57 p<0.001).
CONCLUSION: This is the first study which shows LRR after breast-conserving therapy is a very strong, time-independent prognostic factor for long term outcome in early stage breast cancer patients. These findings suggest that a LRR after a long event-free interval seems to be an indicator rather than an instigator of subsequent distant disease.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Mastectomy trends for early-stage breast cancer: A report from the EUSOMA multi-institutional European database.
Garcia-Etienne CA, Tomatis M, Heil J, Friedrichs K, Kreienberg R, Denk A, Kiechle M, Lorenz-Salehi F, Kimmig R, Emons G, Danaei M,Heyl V, Heindrichs U, Rageth CJ, Janni W, Marotti L, Turco MR, Ponti A.
Breast Unit, Humanitas Cancer Center, Milan, Rozzano, Italy; EUSOMA Data Centre, Turin, Italy.
INTRODUCTION: Recent single-institution reports have shown increased mastectomy rates during the last decade. Further studies aiming to determine if these reports could be reflecting a national trend in the United States of America (US) have shown conflicting results. We report these trends from a multi-institutional European database.
PATIENTS AND METHODS: Our source of data was the eusomaDB, a central data warehouse of prospectively collected information of the European Society of Breast Cancer Specialists (EUSOMA). We identified patients with newly diagnosed unilateral early-stage breast cancer (stages 0, I or II) to examine rates and trends in surgical treatment.
RESULTS: A total of 15,369 early-stage breast cancer cases underwent surgery in 13 Breast Units from 2003 to 2010. Breast conservation was successful in 11,263 cases (73.3%). Adjusted trend by year showed a statistically significant decrease in mastectomy rates from 2005 to 2010 (p=0.003) with a progressive reduction of 4.24% per year. A multivariate model showed a statistically significant association of the following factors with mastectomy: age <40 or ⩾70years, pTis, pT1mi, positive axillary nodes, lobular histology, tumour grade II and III, negative progesterone receptors and multiple lesions.
CONCLUSION: Our study demonstrates that a high proportion of patients with newly diagnosed unilateral early-stage breast cancer from the eusomaDB underwent breast-conserving surgery. It also shows a significant trend of decreasing mastectomy rates from 2005 to 2010. Moreover, our study suggests mastectomy rates in the population from the eusomaDB are lower than those reported in the US.
Long-term cosmetic changes after breast-conserving treatment of patients with stage I-II breast cancer and included in the EORTC ‘boost versus no boost’ trial.
Immink JM, Putter H, Bartelink H, Cardoso JS, Cardoso MJ, van der Hulst-Vijgen MH, Noordijk EM, Poortmans PM, Rodenhuis CC,Struikmans H.
Department of Radiotherapy, Medical Center, Reinier de Graaf Groep, Delft.
BACKGROUND: In breast cancer treated with breast-conserving radiotherapy, the influence of the boost dose on cosmetic outcome after long-term follow-up is unknown.
PATIENTS AND METHODS: We included 348 patients participating in the EORTC ‘boost versus no boost’ mega trial with a minimum follow-up of 6 years. Digitalised pictures were analysed using specific software, enabling quantification of seven relative asymmetry features associated with different aspects of fibrosis.
RESULTS: After 3 years, we noted a statistically significantly poorer outcome for the boost patients for six features compared with those of the no boost patients. Up to 9 years of follow-up, results continued to worsen in the same magnitude for the both patient groups. We noted the following determinants for poorer outcome: (i) boost treatment, (ii) larger excision volumes, (iii) younger age, (iv) tumours located in the central lower quadrants of the breast and (v) a boost dose administered with photons.
CONCLUSIONS: A boost dose worsens the change in breast appearance in the first 3 years. Moreover, the development of fibrosis associated with whole-breast irradiation, as estimated with the relative asymmetry features, is an ongoing process until (at least) 9 years after irradiation.
Final results of a multicenter phase II clinical trial evaluating the activity of single-agent lapatinib in patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells. A proof-of-concept study.
Pestrin M, Bessi S, Puglisi F, Minisini AM, Masci G, Battelli N, Ravaioli A, Gianni L, Di Marsico R, Tondini C, Gori S, Coombes CR,Stebbing J, Biganzoli L, Buyse M, Di Leo A.
Medical Oncology Unit, Hospital of Prato, Prato, Italy.
This multicenter phase II trial was designed to evaluate the activity of lapatinib in metastatic breast cancer patients with HER2-negative primary tumors and HER2-positive circulating tumor cells (CTCs). In this study MBC patients with HER2-negative primary tumors and HER2-positive CTCs previously treated with at least a first-line therapy for metastatic disease received lapatinib 1500 mg/day. The CellSearch System(®) was used for CTCs isolation and bio-characterization. HER2 status was assessed on CTCs by immunofluorescence. A case was defined as CTCs positive if ≥2 CTC/7.5 ml of blood were isolated and HER2-positive if ≥50 % of CTCs were HER2-positive. 139 HER2-negative patients were screened, 96 patients were positive for CTCs (mean number of CTCs: 85; median number of CTCs: 19; range 2-1637). Seven of the 96 patients (7 %) had ≥50 % HER2-positive CTCs and were eligible for treatment with lapatinib. No objective tumor responses occurred in this population. In one patient, disease stabilization lasting 254 days (8.5 months) was observed. From the findings of this study, we concluded that a subset of patients with a HER2-negative primary tumor presents HER2-positive CTCs during disease progression, although the HER2 shift rate seems to be lower than previously reported. Despite the lack of objective response, the durable disease stabilization observed in one patient cannot rule out the hypothesis that lapatinib may have some activity in this patient population. However, considering that only 1/139 screened patients may potentially have derived benefit from this approach, future trials designed according to the presented strategy cannot be recommended.
Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk.
Berg WA, Zhang Z, Lehrer D, Jong RA, Pisano ED, Barr RG, Böhm-Vélez M, Mahoney MC, Evans WP 3rd, Larsen LH, Morton MJ,Mendelson EB, Farria DM, Cormack JB, Marques HS, Adams A, Yeh NM, Gabrielli G; ACRIN 6666 Investigators.
American College of Radiology Imaging Network, Philadelphia, Pennsylvania, USA. firstname.lastname@example.org
CONTEXT: Annual ultrasound screening may detect small, node-negative breast cancers that are not seen on mammography. Magnetic resonance imaging (MRI) may reveal additional breast cancers missed by both mammography and ultrasound screening.
OBJECTIVE: To determine supplemental cancer detection yield of ultrasound and MRI in women at elevated risk for breast cancer.
DESIGN, SETTING, AND PARTICIPANTS: From April 2004-February 2006, 2809 women at 21 sites with elevated cancer risk and dense breasts consented to 3 annual independent screens with mammography and ultrasound in randomized order. After 3 rounds of both screenings, 612 of 703 women who chose to undergo an MRI had complete data. The reference standard was defined as a combination of pathology (biopsy results that showed in situ or infiltrating ductal carcinoma or infiltrating lobular carcinoma in the breast or axillary lymph nodes) and 12-month follow-up.
MAIN OUTCOME MEASURES: Cancer detection rate (yield), sensitivity, specificity, positive predictive value (PPV3) of biopsies performed and interval cancer rate.
RESULTS: A total of 2662 women underwent 7473 mammogram and ultrasound screenings, 110 of whom had 111 breast cancer events: 33 detected by mammography only, 32 by ultrasound only, 26 by both, and 9 by MRI after mammography plus ultrasound; 11 were not detected by any imaging screen. Among 4814 incidence screens in the second and third years combined, 75 women were diagnosed with cancer. Supplemental incidence-screening ultrasound identified 3.7 cancers per 1000 screens (95% CI, 2.1-5.8; P < .001). Sensitivity for mammography plus ultrasound was 0.76 (95% CI, 0.65-0.85); specificity, 0.84 (95% CI, 0.83-0.85); and PPV3, 0.16 (95% CI, 0.12-0.21). For mammography alone, sensitivity was 0.52 (95% CI, 0.40-0.64); specificity, 0.91 (95% CI, 0.90-0.92); and PPV3, 0.38 (95% CI, 0.28-0.49; P < .001 all comparisons). Of the MRI participants, 16 women (2.6%) had breast cancer diagnosed. The supplemental yield of MRI was 14.7 per 1000 (95% CI, 3.5-25.9; P = .004). Sensitivity for MRI and mammography plus ultrasound was 1.00 (95% CI, 0.79-1.00); specificity, 0.65 (95% CI, 0.61-0.69); and PPV3, 0.19 (95% CI, 0.11-0.29). For mammography and ultrasound, sensitivity was 0.44 (95% CI, 0.20-0.70, P = .004); specificity 0.84 (95% CI, 0.81-0.87; P < .001); and PPV3, 0.18 (95% CI, 0.08 to 0.34; P = .98). The number of screens needed to detect 1 cancer was 127 (95% CI, 99-167) for mammography; 234 (95% CI, 173-345) for supplemental ultrasound; and 68 (95% CI, 39-286) for MRI after negative mammography and ultrasound results.
CONCLUSION: The addition of screening ultrasound or MRI to mammography in women at increased risk of breast cancer resulted in not only a higher cancer detection yield but also an increase in false-positive findings.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00072501.
Correlation of treatment-emergent adverse events and clinical response to endocrine therapy in early breast cancer: a retrospective analysis of the German cohort of TEAM.
Hadji P, Kieback DG, Tams J, Hasenburg A, Ziller M.
Departments of Gynaecological Endocrinology, Reproductive Medicine and Osteoporosis, University Hospital of Giessen and Marburg, Marburg.
BACKGROUND: Previous studies have suggested a correlation between the occurrence of vasomotor or joint symptoms during tamoxifen or aromatase inhibitor treatment and improved clinical response.
PATIENTS AND METHODS: A retrospective analysis of the German cohort of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial was carried out to assess disease-free survival (DFS) and overall survival (OS) in patients with and without arthralgia/myalgia and/or menopausal symptoms during adjuvant endocrine treatment.
RESULTS: A total of 1502 patients were included; 739 patients received tamoxifen followed by exemestane and 763 received exemestane. Patients reporting arthralgia/myalgia and patients reporting menopausal symptoms during endocrine treatment had significantly longer OS and DFS than those not reporting these events. The effect on OS was irrespective of treatment. DFS was significantly improved in exemestane-treated patients reporting arthralgia/myalgia or those reporting menopausal symptoms versus those not reporting these events. This effect on DFS was not observed in patients receiving sequential treatment. A combined analysis of patients reporting either menopausal symptoms or arthralgia/myalgia showed that OS and DFS were significantly improved in patients reporting one of these symptoms versus those not reporting either symptom.
CONCLUSION: The occurrence of arthralgia/myalgia or menopausal symptoms during endocrine treatment is associated with significantly improved OS.