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Relapse profile of early breast cancer according to immunohistochemical subtypes: guidance for patient’s follow up?:

Relapse profile of early breast cancer according to immunohistochemical subtypes: guidance for... Purpose: To analyze the profile of annual recurrence rate (ARR) of patients with early breast cancer (BC) in Tunisia. Patients and methods: We classified 293 patients with histologically confirmed early BC relapsing after 1 year of follow up into three subgroups: hormone receptor (HR)+ ‘HR’ [estrogen receptor (ER)+ or progesterone receptor (PR)+ and human epidermal growth factor receptor 2 (HER2)–], triple negative ‘TN’ (ER–, PR– and HER2 score 0/1 or fluorescence in situ hybridization (FISH)/chromogenic in situ hybridization negative) and HER2 overexpression ‘HER2’ (HER2+). ARR was restricted to follow-up contribution of each specified time interval. The HR group was the reference group for comparison. Results: A higher proportion of patients who were up to 35 years old (18% versus 10%, p = 0.04), and patients with obesity (46% versus 26%, p = 0.045) was seen in the TN group. Median time to relapse (MTR) was shorter in TN and HER2 groups than in HR patients (20 and 29 months compared with 56 months, respectively, p < 0.001). In the HR group, the ARR was 22%, 16% and 10% at 3, 4 and 5 years respectively, becoming less than 3% at 7 years. In the TN group, 71% of patients relapsed during the first 2 years and the ARR declined rapidly to less than 1.5% after 4 years. In the HER2 group, the ARR peaked at 2 years (29%) and Correspondence to: decreased significantly to 7% and 3% at 5 and 7 years respectively. Adjuvant trastuzumab Nesrine Mejri, MD Department of Medical delayed the MTR from 24 to 34 months (p = 0.022). Oncology, Abderrahman Mami Hospital, Rue de Conclusion: The relapse risk in Tunisian patients is higher in young women and patients with l’Hopital, 2080, Ariana, HER2+ and TN tumors. A long and close follow up is recommended for patients with HR and Tunisia nesrinemejriturki@ HER2. Conversely, we suggest that follow up in patients with TN could be spaced after 4 years yahoo.fr (ARR being <1.5% after this period). Hamouda Boussen, Pr Department of Medical Oncology, Abderrahman Mami Hospital, Keywords: breast cancer, human epidermal growth factor receptor 2, hormonal receptors, and Association of immunohistochemical, relapse, triple negative Radiotherapy and Oncology of the Mediterranean (AROME), Ariana, Tunisia Soumaya Labidi, MD Introduction most important parameters to evaluate relapse Department of Medical Breast cancer (BC) is the most common female risk and to indicate adjuvant therapies according Oncology, Abderrahman Mami Hospital, Ariana, malignancy worldwide, as well in Tunisia, where to the international consensual guidelines for early Tunisia its incidence is still growing like in other Arab BC [Goldhirsch et al. 2013]. The available statisti- Ferouk Benna, Pr Countries. Most of occidental cases are detected cal models predict relapse risks varying from less Department of Radiation Therapy, Salah Azaiez at infraclinical and small-sized stage thanks to than 10% for N–/HR+/HER2– to over 30% for Institute, Tunis, Tunisia mammographic screening: in Tunisia and emerg- N+/HER2+ and triple negative (TN) tumors Mahdi Afrit, MD ing countries, BC remains diagnosed at the clini- [Cardoso et al. 2010]. Saphner and colleagues, in Department of Medical Oncology, Abderrahman cally palpable stage [Chouchane et  al. 2013]. their pivotal multicentric retrospective study con- Mami Hospital, Ariana, Clinical size greater than 2 cm and age up to 35 cerning early BC cases, treated in the 1990s by Tunisia years, as well as axillary node invasion, grade, hor- anthracycline-based chemotherapy and tamox- Khaled Rahal, Pr Department of Surgical mone receptors (HRs) and human epidermal ifen, reported the annual relapse profile of these Oncology, Salah Azaiez growth factor receptor 2 (HER2) status are the patients and their work may be considered as a Institute, Tunis, Tunisia 144 http://tam.sagepub.com N Mejri, H Boussen et al. good historical reference [Saphner et al. 1996]. In the standard of care. Trastuzumab has been used 2000, Perou and colleagues proposed a new in the adjuvant or neoadjuvant setting since 2010. molecular classification based on microarray gene Tamoxifen was the only available endocrine ther- expression of BC: basal like, HER2 enriched, nor- apy in the adjuvant setting. The aromatase inhibi- mal breast like and luminal divided subsequently tors letrozole, anastrozole and exemestane, in the into luminal A and luminal B [Perou et  al. 2000; frontline or in switch approach, were introduced Zepeda-Castilla et  al. 2008]. In 2011, the four in 2009. subtypes were included in treatment guidelines by the St Gallen International Expert Consensus After completion of the adjuvant chemotherapy group [Goldhirsch et  al. 2011]. The highest cor- and radiotherapy patients had regular visits every relation between gene expression patterns and 3–4 months in the first 2 years, every 6 months immunohistochemical (IHC) phenotype is from years 3 to 5 and annually thereafter. At each observed in HR and basal like BC (73–100%), visit patients had a physical examination and were and lower in HER2 BC (41–69%) [Guiu et  al. checked for symptoms. Mammography was per- 2012; Spitale et  al. 2009]. A strong relationship formed annually; chest X-ray and abdominal between IHC markers and responsiveness to sys- ultrasound were performed every 6 months for temic therapy has also been demonstrated, how- high-risk patients. A lipid blood test was per- ever only few studies investigated BC according to formed for patients on aromatase inhibitors and Perou subtypes and their relapse profile, particu- an annual gynecological examination was carried larly in North African and Arab patients. out for patients on tamoxifen. In the present study we aimed to report clinico- This study had ethical approval of the local com- pathological aspects of BC relapse according to mittee. At the moment of diagnosis, all patients IHC classification, to describe recurrence profile were informed about their disease, prognosis, risk and to suggest a personalized long-term follow up. of relapse and possible publication of their case. All the patients gave their consent. Patients and methods We analyzed a cohort of 1400 cases of histologi- Definition of breast cancer subtypes cally confirmed early BC treated with curative IHC analysis was performed on the primary intent in the period 1999–2010. All patients had tumor of 293 specimens of primary BC (biopsy or complete workup, including chest X-ray, abdomi- surgical resection). We individualized three sub- nal ultrasound and bone scan. We identified 324 groups: TN defined as estrogen receptor (ER)–, patients who relapsed during follow up (between progesterone receptor (PR)– and HER2–, hor- 2001 and 2012); both locoregional and distant monal receptor (HR)+ defined as ER+ or PR+ relapses were considered. Diagnosis of distant and HER2–, and HER2 overexpressed (HER2) and local/regional relapses was based on clinical, defined as HER2+. radiological and histological findings. Data con- cerning age, menopausal status, obesity, TNM Annual recurrence rate (ARR) and median time stage, histological findings (grade, pN) were col- to relapse (MTR) were studied in the following lected. Three BC subtypes were defined accord- subgroups: age (⩽35 years, >65 years), meno- ing to IHC profile collected from pathology pausal status, obesity (body mass index < 30 ver- reports. We excluded patients relapsing during the sus ⩾ 30), histological nodal involvement (positive first 12 months after diagnosis, secondary can- versus negative), grade (I versus II/III) and trastu- cers, controlateral BCs, lobular carcinomas and zumab administration. HER2 antibody type male sex. Novocastra NCL-HER clone NCL-N-CB11 was used. Only membrane staining was scored accord- Management of BC in Tunisia follows interna- ing to standard criteria. HER2 positivity was tional (French/European Society for Medical assessed using the following scoring system: 0, no Oncology/National Comprehensive Cancer membrane staining or less than 10% of cells; 1, Network) guidelines adapted to the available partial membrane staining in more than 10% of drugs in the country. Patients received anthracy- cells; 2, weak, circumferential membrane staining cline-based chemotherapy in the adjuvant or neo- in more than 10% of cells or intense membrane adjuvant settings until 2004, then sequential staining in less than 30% of cases; 3, intense anthracycline and taxane chemotherapy became membrane staining in more than 30% of cells. http://tam.sagepub.com 145 Therapeutic Advances in Medical Oncology 7(3) Protein overexpression was considered present if years. A total of 60% (193) were menopausal. IHC score was 3. Specimens with a score of 2 Obesity (BMI ⩾ 30) was seen in 44% (142) with were selected for chromogenic in situ hybridiza- 15% (49) having morbid obesity (BMI > 40). tion (CISH) analysis. HER2+ tumors were either Among patients with obesity 11% were under the scored 3 by IHC or HER2 amplified on the basis age of 35 years. Mean age was not statistically dif- of CISH. HR status was evaluated using ferent between patients who were obese and non- Novocastra NCL-ER-6F11 and NCL-PR-312. obese (44 versus 48 years, p = 0.9). Mean clinical HR was considered positive if greater than 10% of tumor size was 34 mm (range 10–150 mm). T1 IHC staining was observed. and T2 tumors represented 14% and 54% of cases, T3 and T4 represented 17% and 14% of cases, 8% had an inflammatory BC. All patients had systemic Statistical analysis therapy (chemotherapy or hormonal therapy). MTR was defined as the interval between the First treatment was neoadjuvant chemotherapy in date of first therapeutic action and relapse occur- 27% (88 patients) and surgery in 73% (236). In rence. ARR was defined as the fraction of fol- HR patients, 12.4% received only tamoxifen adju- lowed patients that had recurring disease in a vant therapy. The first anatomic site of relapse was 1-year period restricted to follow-up contribution visceral in 48% (149), bone in 28% (91) and local of each specified time interval. ARR was calcu- in 18% (59) of cases (Figure 1). lated for each IHC BC subtype. Log-rank test was used to compare subgroups with statistical signifi- cance if p was less than 0.05. We compared differ- Results ent variables between groups considering HR as Within the 324 relapses, IHC was performed in the reference group. 293 cases. We observed 41% HR (119), 33% HER2 (96) and 26% TN patients (78). Median tumor size, percentage of inflammatory BC, type Population of surgery, grade and nodal status were compara- With a median follow up of 67 months (5.7 years) ble in the three groups. HER2 patients were during the period 1999–2012 for a cohort of 1400 younger but without statistical significance (p = early BC cases, 324 patients (23%) relapsed. 0.51). The proportion of very young patients (⩽35 Median age was 48 years (range 23–85). We years) was higher in the TN group (18% versus observed 12% were up to 35 years old, 82% were 10%, p = 0.04). We observed fewer older patients between 35 and 70 years old and 6% were over 70 (>65 years) in the HER2 group (8% versus 19%, Figure 1. Flow diagram of the screened population. HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IHC, immunohistochemical; TN, triple negative. 146 http://tam.sagepub.com N Mejri, H Boussen et al. p = 0.02). T4 tumors were more frequent in the HER2 (30%), with p < 0.05. No difference was TN (24%) and HER2 groups (20%) compared seen in terms of visceral and local recurrences with the HR group (7%, p < 0.05). More patients within the three groups. We observed more brain with obesity were observed in the TN (46%) and relapses in the TN and HER2 groups (10% versus HER2 (39%) groups compared with the HR 2%, p < 0.05) (Table 1). group (26%, p < 0.05). The first anatomic site of recurrence was more frequently bone in HR Median follow up was 76 months in the HR patients (46%) compared with TN (14%) and group, 49 months in the TN group and 56 months Table 1. Patient’s characteristics according to immunohistochemistry subgroups: HR, TN, HER2. Variable HR (N = 119) TN (N = 78) HER2 (N = 96) p log-rank TN/HER2 Age Median 47 47 40 0.51/0.56 Range 29–75 23–85 27–72 Young age (⩽ 35) 11 (9%) 14 (18%) 10 (10%) 0.04/0.09 Elderly (>65) 22 (19%) 17 (21%) 17 (8%) 0.07/0.02 Menopausal 41 (30%) 32 (41%) 45 (47%) 0.081/0.078 BMI ⩾30 31 (26%) 36 (46%) 37 (39%) 0.045/0.042 Tumor size (mm) 32 39 34 0.42/0.31 T stage T1 12 (10%) 9 (11%) 17 (18%) 0.12/0.09 T2 83 (70%) 34 (34%) 45 (49%) 0.048/0.051 T3 16 (13%) 16 (21%) 13 (13%) 0.045/0.09 T4 8 (7%) 19 (24%) 19 (20%) 0.032/0.043 Inflammatory BC 6 (5%) 6 (8%) 13 (14%) 0.051/0.049 Chemotherapy 105 (87.6%) 78 (100%) 96 (100%) Anthracycline 85 (72%) 30 (39%) 43 (45%) 0.003/0.031 Anthracycline+ 33 (28%) 47 (61%) 53 (56%) 0.06/0.078 taxanes Surgery 76 Lumpectomy 32 (27%) 24 (32%) 24 (25%) 0.089/0.12 Mastectomy 87 (73%) 51 (68%) 72 (75%) 0.34/0.23 Grade 108 59 85 SBR I 21 (17%) 6 (10%) 14 (15%) 0.98/0.78 SBR II 53 (46%) 24 (35%) 31 (32%) 0.34/0.47 SBR III 34 (29%) 29 (49%) 40 (43%) 0.44/0.78 Nodal status p N0 40 (34%) 25 (33%) 34 (35%) 0.45/0.57 p N+ 79 (66%) 52 (66%) 62 (65%) 0.23/0.38 Median time to 56 20 29 0.0001/0.002 relapse Median follow up 76 49 56 <0.001 First relapse site Local 21 (18%) 14 (17%) 19 (20%) 0.9/0.8 Bone 55 (46%) 11 (14%) 29 (30%) 0.04/<0.001 Visceral 40 (34%) 45 (57%) 39 (40%) 0.07/0.08 Brain 3 (2%) 8 (10%) 10 (10%) <0.001 Peak of relapse 2–3 1–2 1–2 interval BC, breast cancer; BMI, body mass index; HER2, human epidermal growth factor receptor 2; SBR, Scarff-Bloom-Rich- ardson HR, hormone receptor; R, reference group for comparison; TN, triple negative. Bold figures in the last column are the statistically significant results. The second R is given in the last line of the table is the reference group for comparison. http://tam.sagepub.com 147 Therapeutic Advances in Medical Oncology 7(3) in the HER2 group. MTR for the overall popula- of mammographic screening, BC is frequently tion was 47 months. Compared with HR patients, ‘bulky’ with palpable tumors and a mean clinical MTR was statistically significant earlier in the TN tumor size greater than 4 cm [Mook et al. 2010]. and HER2 groups, 20 and 29 months versus 56 Most of the patients in Tunisia are within the months (p < 0.001). intermediate and high relapse risk categories of St Gallen [Goldhirsch et al. 2011]. These unfavora- ARR of the overall population and among IHC ble parameters explain the high relapse rate of subgroups is represented in Figure 1. In the HR 23% (324/1400) observed in our series. Our rate BC group, 20% relapsed within the first 2 years, is higher than that reported in the historical series ARR peaked at 3 years (22%), remaining high of Saphner in the 1990s concerning first relapse with 16.8% and 10.8% at 4 and 5 years respec- profile of early BC treated during the period of tively. It became less than 3% after 7 years. In the adjuvant anthracyclines based chemotherapy and TN group, 71% of patients relapsed within the tamoxifen [Saphner et al. 1996]. This is explained first 2 years, ARR peaked at the first second year by the young age at diagnosis (48 years, 10–15% interval (42%), ARR declined rapidly thereafter being ⩽35 years), 10 years younger than in becoming less than 1.5% after 4 years. In the Europe and the USA [Chouchane et  al. 2013]. HER2 group, 44% relapsed within the first 2 Age is reported by some authors as an independ- years, ARR peaked at 2 years (29.2%); however, it ent prognostic and predictive factor of early decreased significantly to 7% and 3% at 5 years recurrence [Najjar and Easson, 2010]. In addi- and 7 years (Figure 1). tion, 7% of our patients presented with inflamma- tory BC, which is known to be more aggressive In a subgroup analysis, MTR was statistically sig- than ‘classical’ BC with a high risk of locoregional nificantly shorter in patients who were node posi- and high distant relapse rate with poor survival. tive compared with those who were node negative Tunisian data reported by Boussen and colleagues (41 versus 59 months, p = 0.04). At 2 years, 38% showed a 5-year survival of 8.5% in the anthracy- of patients who were node positive relapsed. clines era before taxanes and trastuzumab Compared with patients who were HR+, those [Boussen et al. 2010]. We also observed that obe- who were HR– had an earlier and a higher ARR; sity was associated with an earlier median relapse 41% relapsed between the first and the second time. As reported in the literature, this parameter year. MTR was also shorter in patients who were is a risk factor but also a survival indicator in HR– (28 versus 59 months, p = 0.003). MTR was women diagnosed with BC. These data were con- longer in patients without obesity (39 versus 50 firmed by a meta-analysis published in 2010 months, p = 0.001). We observed 30% ARR at 2 [Protani et  al. 2010; Goodwin et  al. 2002]. The years. We did not observe a difference in MTR high mean tumor size (34 mm) and N+ (60%) between menopausal and nonmenopausal women observed in our population are also known major (49 versus 44, p = 0.3) and also between grade I negative predictive factors. Local or regional tumors and grade II/III tumors (51 versus 46, p = recurrence for early BC occurs in approximately 0.051). We did not observe a statistical difference 5% of cases at 5 years [Eikhuizen et  al. 1998], in MTR in patients who received neoadjuvant higher in HER2 and basal subtypes compared therapy (78) compared with those who received with luminal A BC [Wallgren et  al. 2003]. adjuvant therapy (215) (45 versus 47 months, p = However, in our series, we noted a relatively high 0.7). In the HER2 group, only 43% (42 patients) proportion (18%) of local recurrence but without received trastuzumab. Mean age (41 versus 39, p = statistical difference. This fact could be attributed 0.6), tumor size (32 versus 34, p = 0.7) and grade to the high proportion of T4 stage [Carreño et al. were comparable between patients who received 2007] as well as young age. trastuzumab and those who did not respectively. Patients who received trastuzumab were more Our series is a mixture of ‘Saphner-like’ patients and likely to receive taxanes (67% versus 33%, p = anthracycline–taxanes–trastuzumab pati ents. As 0.04). Trastuzumab delayed MTR by 10 months noted in Figure 2, the introduction of trastuzumab (24 versus 34 months, p = 0.022) (Figure 3). modified the relapse profile by decreasing and delay- ing the peak intensity by more than 10 months. In the pivotal HERA trial, adjuvant trastuzumab clearly Discussion improved overall and disease-free survivals [Untch Our early BC relapsing series is representative of et al. 2008]. The pattern of recurrence in the HER2 BC presentation in Tunisia, where in the absence population was that of a peak hazard of recurrence of 148 http://tam.sagepub.com N Mejri, H Boussen et al. Figure 2. Annual recurrence rate per year interval of the entire population and immunohistochemical subgroups. HER2, human epidermal growth factor receptor 2; HR, hormone receptor; TN, triple negative. 29.2% during the second year of follow up, followed colleagues reported a higher hazard of recurrence by a steady decrease in the annual hazard of recur- in patients who were ER– during the first years of rence until year 6. Beyond that time, the hazard of follow up. However, beyond 5 years the hazard was recurrence slowly declined and averaged 3%. higher for patients who were ER+. They suggested that the hazard of recurrence for patients who were Thanks to the introduction of new drugs into ER+ was relatively constant, while the hazard of the continuum of care of BC, the relapse profile recurrence for patients who were ER– decreased modification was similarly reported by Jatoi and significantly with time [Saphner et al. 1996]. colleagues, showing hazard curves for BC death that peaked between 2 and 3 years after initial In Tunisia, the available initial workup for metas- diagnosis and declined sharply afterwards [Jatoi tases detection is based on conventional chest et  al. 2011]. In their study, the annual hazard X-ray, abdominal ultrasound and bone scan, rate for all cases peaks near 3% per year between revealing more than 10% of patients who are met- the second and third years after diagnosis and astatic at diagnosis. Infraclinical metastatic dis- decreased to 1–2% per year by the sixth through ease is better detected with fluoro-2-deoxyglucose eighth years. The hazard rates for ER– and ER+ positron emission tomography (FDG-PET) (not tumors peak at approximately 6.5% and 2% per yet available in Tunisia). It has been clearly proved year respectively between the first and third as more sensitive than conventional imaging pro- years. Notably, ER– to ER+ hazard rates cross cedures for detection of distant BC metastases between the seventh and eighth years, after and particularly in our intermediate to high risk which women with ER– tumors have a lower population with 60% of node-positive cases rate of BC death than those with ER+ tumors. [Heusner et al. 2010; Maalej et al. 2008]. Our graphs showed that TN BC has the highest In patients with HER2 and HR BC we suggest and earliest risk of recurrence, less than two-thirds long and close follow up, beyond 5 years; how- of patients relapsing during the 4 years of follow up. ever, we suggest that follow up for patients with Dent and colleagues also reported a recurrence TN BC could be spaced after 4 years since, in our peak at 12 months, remaining high for the first 4 series ARR was less than 1.5% after that period. years and decreasing rapidly thereafter. We believe that women with TN BC who do not relapse in the Many models of risk prediction have been devel- first 4 years are at low relapse risk [Dent et al. 2007]. oped and are available online to help oncologists in the selection of patients who could benefit HR patients had the latest ARR peak with a from adjuvant chemotherapy and hormone remaining risk beyond year 6. Saphner and therapy. Initial tools such as adjuvant online http://tam.sagepub.com 149 Therapeutic Advances in Medical Oncology 7(3) Figure 3. Annual recurrence rate per year interval of subgroup analysis. SBR, Scarff-Bloom-Richardson; N, nodal status. were based on traditional clinicopathological biomolecular/genomic parameters like Oncotype factors and the more recently used DX or MammaPrint, but they remain 150 http://tam.sagepub.com N Mejri, H Boussen et al. Inflammatory breast cancer in Tunisia. Cancer 116(11 suboptimal for patients under 40 or over 65 Suppl.): 2730–2735. years old [Mook et  al. 2010; Dowsett et  al. 2013]. Adjuvant online evaluation risks an over- Cardoso, F., Senkus-Konefka, E., Fallowfield, estimation of overall survival by 20% and the L., Costa, A. and Castiglione, M. (2010) Locally use of Mammaprint classified 20% more recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and patients in the high-risk group. Most of the vali- follow-up. Ann Oncol 21(Suppl 5): v15–v19. dation studies are retrospective and performed in heterogeneous populations, making the Carreño, G., del Casar, J., Corte, M., González, assumption that currently available risk predic- L., Bongera, M., Merino, A. et al. (2007) Local tion models are clinically valid too weak. recurrence after mastectomy for breast cancer: analysis Moreover, ethnic variations between occidental of clinicopathological, biological and prognostic characteristics. Breast Cancer Res Treat 102: 61–73. and Asian populations have been reported for the different prediction models, maybe explained Chouchane, L., Boussen, H. and Sastry, K. (2013) by gene disparities [Engelhardt et  al. 2014]. Breast cancer in Arab populations: molecular There are no available data concerning those characteristics and disease management implications. risk prediction models considering Arab or Lancet Oncol 14: e417–e424. African populations. Dent, R., Trudeau, M., Pritchard, K., Hanna, W., Kahn, H., Sawka, C. et al. (2007) Triple-negative breast cancer: clinical features and patterns of Conclusion recurrence. Clin Cancer Res 13: 4429–4434. This is the first study about the early BC relapse Dowsett, M., Sestak, I., Lopez-Knowles, E., Sidhu, profile in North African and Arab patients when K., Dubien, K., Cowers, J. et al. (2013) Comparison considering an intermediate to high risk St Gallen of PAM50 risk of recurrence score with oncotype DX population. As expected, the cohort is in line with and IHC4 for predicting risk of distant recurrence the specific Tunisian BC anatomoclinical charac- after endocrine therapy. J Clin Oncol 31: 2783–2790. teristics in terms of young median age, high clini- Elkhuizen, P., van de Vijver, M., Hermans, J., cal/histological tumor volume and poor histological Zonderland, H., van de Velde, C. and Leer, J. (1998) features impacting negatively and explaining the Local recurrence after breast-conserving therapy high rate of relapses. However, we noted that for invasive breast cancer: high incidence in young modifications of treatment protocols during the patients and association with poor survival. Int J study period induced a transition in relapse profile Radiat Oncol Biol Phys 40: 859–867. within recently treated patients by sequential Engelhardt, E., Garvelink, M., de Haes, J., Van anthracycline, taxanes and trastuzumab that pre- Der Hoeven, J., Smets, E., Pieterse, A. et al. (2014) sented a delayed and decreased relapse peak. Predicting and communicating the risk of recurrence Relapse risk of early BC in Tunisian patients seems and death in women with early-stage breast cancer: to be higher in young women with a high propor- a systematic review of risk prediction models. J Clin tion of HER2 tumors. Long and close follow up is Oncol 32: 238–350. recommended in patients with HR (6 years) and Goldhirsch, A, Winer, E., Coates, A., Gelber, HER2 (7 years) BC, after which the recurrence R., Piccart-Gebhart, M., Thürlimann, B. et al. rate becomes less than 3%. Adjuvant trastuzumab (2013) Personalizing the treatment of women with delayed recurrence time in this group. We suggest early breast cancer: highlights of the St Gallen that follow up for patients with TN BC could be International Expert Consensus on the Primary spaced after 4 years (ARR becoming <1.5%). Therapy of Early Breast Cancer 2013. Ann Oncol 24: 2206–2223. Conflict of interest statement Goldhirsch, A., Wood, W., Coates, A., Gelber, R., The authors declare that there is no conflict of Thürlimann, B. and Senn, H. (2011) Strategies for interest. subtypes – dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Funding Consensus on the Primary Therapy of Early Breast Cancer 2011. 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Relapse profile of early breast cancer according to immunohistochemical subtypes: guidance for patient’s follow up?:

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Abstract

Purpose: To analyze the profile of annual recurrence rate (ARR) of patients with early breast cancer (BC) in Tunisia. Patients and methods: We classified 293 patients with histologically confirmed early BC relapsing after 1 year of follow up into three subgroups: hormone receptor (HR)+ ‘HR’ [estrogen receptor (ER)+ or progesterone receptor (PR)+ and human epidermal growth factor receptor 2 (HER2)–], triple negative ‘TN’ (ER–, PR– and HER2 score 0/1 or fluorescence in situ hybridization (FISH)/chromogenic in situ hybridization negative) and HER2 overexpression ‘HER2’ (HER2+). ARR was restricted to follow-up contribution of each specified time interval. The HR group was the reference group for comparison. Results: A higher proportion of patients who were up to 35 years old (18% versus 10%, p = 0.04), and patients with obesity (46% versus 26%, p = 0.045) was seen in the TN group. Median time to relapse (MTR) was shorter in TN and HER2 groups than in HR patients (20 and 29 months compared with 56 months, respectively, p < 0.001). In the HR group, the ARR was 22%, 16% and 10% at 3, 4 and 5 years respectively, becoming less than 3% at 7 years. In the TN group, 71% of patients relapsed during the first 2 years and the ARR declined rapidly to less than 1.5% after 4 years. In the HER2 group, the ARR peaked at 2 years (29%) and Correspondence to: decreased significantly to 7% and 3% at 5 and 7 years respectively. Adjuvant trastuzumab Nesrine Mejri, MD Department of Medical delayed the MTR from 24 to 34 months (p = 0.022). Oncology, Abderrahman Mami Hospital, Rue de Conclusion: The relapse risk in Tunisian patients is higher in young women and patients with l’Hopital, 2080, Ariana, HER2+ and TN tumors. A long and close follow up is recommended for patients with HR and Tunisia nesrinemejriturki@ HER2. Conversely, we suggest that follow up in patients with TN could be spaced after 4 years yahoo.fr (ARR being <1.5% after this period). Hamouda Boussen, Pr Department of Medical Oncology, Abderrahman Mami Hospital, Keywords: breast cancer, human epidermal growth factor receptor 2, hormonal receptors, and Association of immunohistochemical, relapse, triple negative Radiotherapy and Oncology of the Mediterranean (AROME), Ariana, Tunisia Soumaya Labidi, MD Introduction most important parameters to evaluate relapse Department of Medical Breast cancer (BC) is the most common female risk and to indicate adjuvant therapies according Oncology, Abderrahman Mami Hospital, Ariana, malignancy worldwide, as well in Tunisia, where to the international consensual guidelines for early Tunisia its incidence is still growing like in other Arab BC [Goldhirsch et al. 2013]. The available statisti- Ferouk Benna, Pr Countries. Most of occidental cases are detected cal models predict relapse risks varying from less Department of Radiation Therapy, Salah Azaiez at infraclinical and small-sized stage thanks to than 10% for N–/HR+/HER2– to over 30% for Institute, Tunis, Tunisia mammographic screening: in Tunisia and emerg- N+/HER2+ and triple negative (TN) tumors Mahdi Afrit, MD ing countries, BC remains diagnosed at the clini- [Cardoso et al. 2010]. Saphner and colleagues, in Department of Medical Oncology, Abderrahman cally palpable stage [Chouchane et  al. 2013]. their pivotal multicentric retrospective study con- Mami Hospital, Ariana, Clinical size greater than 2 cm and age up to 35 cerning early BC cases, treated in the 1990s by Tunisia years, as well as axillary node invasion, grade, hor- anthracycline-based chemotherapy and tamox- Khaled Rahal, Pr Department of Surgical mone receptors (HRs) and human epidermal ifen, reported the annual relapse profile of these Oncology, Salah Azaiez growth factor receptor 2 (HER2) status are the patients and their work may be considered as a Institute, Tunis, Tunisia 144 http://tam.sagepub.com N Mejri, H Boussen et al. good historical reference [Saphner et al. 1996]. In the standard of care. Trastuzumab has been used 2000, Perou and colleagues proposed a new in the adjuvant or neoadjuvant setting since 2010. molecular classification based on microarray gene Tamoxifen was the only available endocrine ther- expression of BC: basal like, HER2 enriched, nor- apy in the adjuvant setting. The aromatase inhibi- mal breast like and luminal divided subsequently tors letrozole, anastrozole and exemestane, in the into luminal A and luminal B [Perou et  al. 2000; frontline or in switch approach, were introduced Zepeda-Castilla et  al. 2008]. In 2011, the four in 2009. subtypes were included in treatment guidelines by the St Gallen International Expert Consensus After completion of the adjuvant chemotherapy group [Goldhirsch et  al. 2011]. The highest cor- and radiotherapy patients had regular visits every relation between gene expression patterns and 3–4 months in the first 2 years, every 6 months immunohistochemical (IHC) phenotype is from years 3 to 5 and annually thereafter. At each observed in HR and basal like BC (73–100%), visit patients had a physical examination and were and lower in HER2 BC (41–69%) [Guiu et  al. checked for symptoms. Mammography was per- 2012; Spitale et  al. 2009]. A strong relationship formed annually; chest X-ray and abdominal between IHC markers and responsiveness to sys- ultrasound were performed every 6 months for temic therapy has also been demonstrated, how- high-risk patients. A lipid blood test was per- ever only few studies investigated BC according to formed for patients on aromatase inhibitors and Perou subtypes and their relapse profile, particu- an annual gynecological examination was carried larly in North African and Arab patients. out for patients on tamoxifen. In the present study we aimed to report clinico- This study had ethical approval of the local com- pathological aspects of BC relapse according to mittee. At the moment of diagnosis, all patients IHC classification, to describe recurrence profile were informed about their disease, prognosis, risk and to suggest a personalized long-term follow up. of relapse and possible publication of their case. All the patients gave their consent. Patients and methods We analyzed a cohort of 1400 cases of histologi- Definition of breast cancer subtypes cally confirmed early BC treated with curative IHC analysis was performed on the primary intent in the period 1999–2010. All patients had tumor of 293 specimens of primary BC (biopsy or complete workup, including chest X-ray, abdomi- surgical resection). We individualized three sub- nal ultrasound and bone scan. We identified 324 groups: TN defined as estrogen receptor (ER)–, patients who relapsed during follow up (between progesterone receptor (PR)– and HER2–, hor- 2001 and 2012); both locoregional and distant monal receptor (HR)+ defined as ER+ or PR+ relapses were considered. Diagnosis of distant and HER2–, and HER2 overexpressed (HER2) and local/regional relapses was based on clinical, defined as HER2+. radiological and histological findings. Data con- cerning age, menopausal status, obesity, TNM Annual recurrence rate (ARR) and median time stage, histological findings (grade, pN) were col- to relapse (MTR) were studied in the following lected. Three BC subtypes were defined accord- subgroups: age (⩽35 years, >65 years), meno- ing to IHC profile collected from pathology pausal status, obesity (body mass index < 30 ver- reports. We excluded patients relapsing during the sus ⩾ 30), histological nodal involvement (positive first 12 months after diagnosis, secondary can- versus negative), grade (I versus II/III) and trastu- cers, controlateral BCs, lobular carcinomas and zumab administration. HER2 antibody type male sex. Novocastra NCL-HER clone NCL-N-CB11 was used. Only membrane staining was scored accord- Management of BC in Tunisia follows interna- ing to standard criteria. HER2 positivity was tional (French/European Society for Medical assessed using the following scoring system: 0, no Oncology/National Comprehensive Cancer membrane staining or less than 10% of cells; 1, Network) guidelines adapted to the available partial membrane staining in more than 10% of drugs in the country. Patients received anthracy- cells; 2, weak, circumferential membrane staining cline-based chemotherapy in the adjuvant or neo- in more than 10% of cells or intense membrane adjuvant settings until 2004, then sequential staining in less than 30% of cases; 3, intense anthracycline and taxane chemotherapy became membrane staining in more than 30% of cells. http://tam.sagepub.com 145 Therapeutic Advances in Medical Oncology 7(3) Protein overexpression was considered present if years. A total of 60% (193) were menopausal. IHC score was 3. Specimens with a score of 2 Obesity (BMI ⩾ 30) was seen in 44% (142) with were selected for chromogenic in situ hybridiza- 15% (49) having morbid obesity (BMI > 40). tion (CISH) analysis. HER2+ tumors were either Among patients with obesity 11% were under the scored 3 by IHC or HER2 amplified on the basis age of 35 years. Mean age was not statistically dif- of CISH. HR status was evaluated using ferent between patients who were obese and non- Novocastra NCL-ER-6F11 and NCL-PR-312. obese (44 versus 48 years, p = 0.9). Mean clinical HR was considered positive if greater than 10% of tumor size was 34 mm (range 10–150 mm). T1 IHC staining was observed. and T2 tumors represented 14% and 54% of cases, T3 and T4 represented 17% and 14% of cases, 8% had an inflammatory BC. All patients had systemic Statistical analysis therapy (chemotherapy or hormonal therapy). MTR was defined as the interval between the First treatment was neoadjuvant chemotherapy in date of first therapeutic action and relapse occur- 27% (88 patients) and surgery in 73% (236). In rence. ARR was defined as the fraction of fol- HR patients, 12.4% received only tamoxifen adju- lowed patients that had recurring disease in a vant therapy. The first anatomic site of relapse was 1-year period restricted to follow-up contribution visceral in 48% (149), bone in 28% (91) and local of each specified time interval. ARR was calcu- in 18% (59) of cases (Figure 1). lated for each IHC BC subtype. Log-rank test was used to compare subgroups with statistical signifi- cance if p was less than 0.05. We compared differ- Results ent variables between groups considering HR as Within the 324 relapses, IHC was performed in the reference group. 293 cases. We observed 41% HR (119), 33% HER2 (96) and 26% TN patients (78). Median tumor size, percentage of inflammatory BC, type Population of surgery, grade and nodal status were compara- With a median follow up of 67 months (5.7 years) ble in the three groups. HER2 patients were during the period 1999–2012 for a cohort of 1400 younger but without statistical significance (p = early BC cases, 324 patients (23%) relapsed. 0.51). The proportion of very young patients (⩽35 Median age was 48 years (range 23–85). We years) was higher in the TN group (18% versus observed 12% were up to 35 years old, 82% were 10%, p = 0.04). We observed fewer older patients between 35 and 70 years old and 6% were over 70 (>65 years) in the HER2 group (8% versus 19%, Figure 1. Flow diagram of the screened population. HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IHC, immunohistochemical; TN, triple negative. 146 http://tam.sagepub.com N Mejri, H Boussen et al. p = 0.02). T4 tumors were more frequent in the HER2 (30%), with p < 0.05. No difference was TN (24%) and HER2 groups (20%) compared seen in terms of visceral and local recurrences with the HR group (7%, p < 0.05). More patients within the three groups. We observed more brain with obesity were observed in the TN (46%) and relapses in the TN and HER2 groups (10% versus HER2 (39%) groups compared with the HR 2%, p < 0.05) (Table 1). group (26%, p < 0.05). The first anatomic site of recurrence was more frequently bone in HR Median follow up was 76 months in the HR patients (46%) compared with TN (14%) and group, 49 months in the TN group and 56 months Table 1. Patient’s characteristics according to immunohistochemistry subgroups: HR, TN, HER2. Variable HR (N = 119) TN (N = 78) HER2 (N = 96) p log-rank TN/HER2 Age Median 47 47 40 0.51/0.56 Range 29–75 23–85 27–72 Young age (⩽ 35) 11 (9%) 14 (18%) 10 (10%) 0.04/0.09 Elderly (>65) 22 (19%) 17 (21%) 17 (8%) 0.07/0.02 Menopausal 41 (30%) 32 (41%) 45 (47%) 0.081/0.078 BMI ⩾30 31 (26%) 36 (46%) 37 (39%) 0.045/0.042 Tumor size (mm) 32 39 34 0.42/0.31 T stage T1 12 (10%) 9 (11%) 17 (18%) 0.12/0.09 T2 83 (70%) 34 (34%) 45 (49%) 0.048/0.051 T3 16 (13%) 16 (21%) 13 (13%) 0.045/0.09 T4 8 (7%) 19 (24%) 19 (20%) 0.032/0.043 Inflammatory BC 6 (5%) 6 (8%) 13 (14%) 0.051/0.049 Chemotherapy 105 (87.6%) 78 (100%) 96 (100%) Anthracycline 85 (72%) 30 (39%) 43 (45%) 0.003/0.031 Anthracycline+ 33 (28%) 47 (61%) 53 (56%) 0.06/0.078 taxanes Surgery 76 Lumpectomy 32 (27%) 24 (32%) 24 (25%) 0.089/0.12 Mastectomy 87 (73%) 51 (68%) 72 (75%) 0.34/0.23 Grade 108 59 85 SBR I 21 (17%) 6 (10%) 14 (15%) 0.98/0.78 SBR II 53 (46%) 24 (35%) 31 (32%) 0.34/0.47 SBR III 34 (29%) 29 (49%) 40 (43%) 0.44/0.78 Nodal status p N0 40 (34%) 25 (33%) 34 (35%) 0.45/0.57 p N+ 79 (66%) 52 (66%) 62 (65%) 0.23/0.38 Median time to 56 20 29 0.0001/0.002 relapse Median follow up 76 49 56 <0.001 First relapse site Local 21 (18%) 14 (17%) 19 (20%) 0.9/0.8 Bone 55 (46%) 11 (14%) 29 (30%) 0.04/<0.001 Visceral 40 (34%) 45 (57%) 39 (40%) 0.07/0.08 Brain 3 (2%) 8 (10%) 10 (10%) <0.001 Peak of relapse 2–3 1–2 1–2 interval BC, breast cancer; BMI, body mass index; HER2, human epidermal growth factor receptor 2; SBR, Scarff-Bloom-Rich- ardson HR, hormone receptor; R, reference group for comparison; TN, triple negative. Bold figures in the last column are the statistically significant results. The second R is given in the last line of the table is the reference group for comparison. http://tam.sagepub.com 147 Therapeutic Advances in Medical Oncology 7(3) in the HER2 group. MTR for the overall popula- of mammographic screening, BC is frequently tion was 47 months. Compared with HR patients, ‘bulky’ with palpable tumors and a mean clinical MTR was statistically significant earlier in the TN tumor size greater than 4 cm [Mook et al. 2010]. and HER2 groups, 20 and 29 months versus 56 Most of the patients in Tunisia are within the months (p < 0.001). intermediate and high relapse risk categories of St Gallen [Goldhirsch et al. 2011]. These unfavora- ARR of the overall population and among IHC ble parameters explain the high relapse rate of subgroups is represented in Figure 1. In the HR 23% (324/1400) observed in our series. Our rate BC group, 20% relapsed within the first 2 years, is higher than that reported in the historical series ARR peaked at 3 years (22%), remaining high of Saphner in the 1990s concerning first relapse with 16.8% and 10.8% at 4 and 5 years respec- profile of early BC treated during the period of tively. It became less than 3% after 7 years. In the adjuvant anthracyclines based chemotherapy and TN group, 71% of patients relapsed within the tamoxifen [Saphner et al. 1996]. This is explained first 2 years, ARR peaked at the first second year by the young age at diagnosis (48 years, 10–15% interval (42%), ARR declined rapidly thereafter being ⩽35 years), 10 years younger than in becoming less than 1.5% after 4 years. In the Europe and the USA [Chouchane et  al. 2013]. HER2 group, 44% relapsed within the first 2 Age is reported by some authors as an independ- years, ARR peaked at 2 years (29.2%); however, it ent prognostic and predictive factor of early decreased significantly to 7% and 3% at 5 years recurrence [Najjar and Easson, 2010]. In addi- and 7 years (Figure 1). tion, 7% of our patients presented with inflamma- tory BC, which is known to be more aggressive In a subgroup analysis, MTR was statistically sig- than ‘classical’ BC with a high risk of locoregional nificantly shorter in patients who were node posi- and high distant relapse rate with poor survival. tive compared with those who were node negative Tunisian data reported by Boussen and colleagues (41 versus 59 months, p = 0.04). At 2 years, 38% showed a 5-year survival of 8.5% in the anthracy- of patients who were node positive relapsed. clines era before taxanes and trastuzumab Compared with patients who were HR+, those [Boussen et al. 2010]. We also observed that obe- who were HR– had an earlier and a higher ARR; sity was associated with an earlier median relapse 41% relapsed between the first and the second time. As reported in the literature, this parameter year. MTR was also shorter in patients who were is a risk factor but also a survival indicator in HR– (28 versus 59 months, p = 0.003). MTR was women diagnosed with BC. These data were con- longer in patients without obesity (39 versus 50 firmed by a meta-analysis published in 2010 months, p = 0.001). We observed 30% ARR at 2 [Protani et  al. 2010; Goodwin et  al. 2002]. The years. We did not observe a difference in MTR high mean tumor size (34 mm) and N+ (60%) between menopausal and nonmenopausal women observed in our population are also known major (49 versus 44, p = 0.3) and also between grade I negative predictive factors. Local or regional tumors and grade II/III tumors (51 versus 46, p = recurrence for early BC occurs in approximately 0.051). We did not observe a statistical difference 5% of cases at 5 years [Eikhuizen et  al. 1998], in MTR in patients who received neoadjuvant higher in HER2 and basal subtypes compared therapy (78) compared with those who received with luminal A BC [Wallgren et  al. 2003]. adjuvant therapy (215) (45 versus 47 months, p = However, in our series, we noted a relatively high 0.7). In the HER2 group, only 43% (42 patients) proportion (18%) of local recurrence but without received trastuzumab. Mean age (41 versus 39, p = statistical difference. This fact could be attributed 0.6), tumor size (32 versus 34, p = 0.7) and grade to the high proportion of T4 stage [Carreño et al. were comparable between patients who received 2007] as well as young age. trastuzumab and those who did not respectively. Patients who received trastuzumab were more Our series is a mixture of ‘Saphner-like’ patients and likely to receive taxanes (67% versus 33%, p = anthracycline–taxanes–trastuzumab pati ents. As 0.04). Trastuzumab delayed MTR by 10 months noted in Figure 2, the introduction of trastuzumab (24 versus 34 months, p = 0.022) (Figure 3). modified the relapse profile by decreasing and delay- ing the peak intensity by more than 10 months. In the pivotal HERA trial, adjuvant trastuzumab clearly Discussion improved overall and disease-free survivals [Untch Our early BC relapsing series is representative of et al. 2008]. The pattern of recurrence in the HER2 BC presentation in Tunisia, where in the absence population was that of a peak hazard of recurrence of 148 http://tam.sagepub.com N Mejri, H Boussen et al. Figure 2. Annual recurrence rate per year interval of the entire population and immunohistochemical subgroups. HER2, human epidermal growth factor receptor 2; HR, hormone receptor; TN, triple negative. 29.2% during the second year of follow up, followed colleagues reported a higher hazard of recurrence by a steady decrease in the annual hazard of recur- in patients who were ER– during the first years of rence until year 6. Beyond that time, the hazard of follow up. However, beyond 5 years the hazard was recurrence slowly declined and averaged 3%. higher for patients who were ER+. They suggested that the hazard of recurrence for patients who were Thanks to the introduction of new drugs into ER+ was relatively constant, while the hazard of the continuum of care of BC, the relapse profile recurrence for patients who were ER– decreased modification was similarly reported by Jatoi and significantly with time [Saphner et al. 1996]. colleagues, showing hazard curves for BC death that peaked between 2 and 3 years after initial In Tunisia, the available initial workup for metas- diagnosis and declined sharply afterwards [Jatoi tases detection is based on conventional chest et  al. 2011]. In their study, the annual hazard X-ray, abdominal ultrasound and bone scan, rate for all cases peaks near 3% per year between revealing more than 10% of patients who are met- the second and third years after diagnosis and astatic at diagnosis. Infraclinical metastatic dis- decreased to 1–2% per year by the sixth through ease is better detected with fluoro-2-deoxyglucose eighth years. The hazard rates for ER– and ER+ positron emission tomography (FDG-PET) (not tumors peak at approximately 6.5% and 2% per yet available in Tunisia). It has been clearly proved year respectively between the first and third as more sensitive than conventional imaging pro- years. Notably, ER– to ER+ hazard rates cross cedures for detection of distant BC metastases between the seventh and eighth years, after and particularly in our intermediate to high risk which women with ER– tumors have a lower population with 60% of node-positive cases rate of BC death than those with ER+ tumors. [Heusner et al. 2010; Maalej et al. 2008]. Our graphs showed that TN BC has the highest In patients with HER2 and HR BC we suggest and earliest risk of recurrence, less than two-thirds long and close follow up, beyond 5 years; how- of patients relapsing during the 4 years of follow up. ever, we suggest that follow up for patients with Dent and colleagues also reported a recurrence TN BC could be spaced after 4 years since, in our peak at 12 months, remaining high for the first 4 series ARR was less than 1.5% after that period. years and decreasing rapidly thereafter. We believe that women with TN BC who do not relapse in the Many models of risk prediction have been devel- first 4 years are at low relapse risk [Dent et al. 2007]. oped and are available online to help oncologists in the selection of patients who could benefit HR patients had the latest ARR peak with a from adjuvant chemotherapy and hormone remaining risk beyond year 6. Saphner and therapy. Initial tools such as adjuvant online http://tam.sagepub.com 149 Therapeutic Advances in Medical Oncology 7(3) Figure 3. Annual recurrence rate per year interval of subgroup analysis. SBR, Scarff-Bloom-Richardson; N, nodal status. were based on traditional clinicopathological biomolecular/genomic parameters like Oncotype factors and the more recently used DX or MammaPrint, but they remain 150 http://tam.sagepub.com N Mejri, H Boussen et al. Inflammatory breast cancer in Tunisia. Cancer 116(11 suboptimal for patients under 40 or over 65 Suppl.): 2730–2735. years old [Mook et  al. 2010; Dowsett et  al. 2013]. Adjuvant online evaluation risks an over- Cardoso, F., Senkus-Konefka, E., Fallowfield, estimation of overall survival by 20% and the L., Costa, A. and Castiglione, M. (2010) Locally use of Mammaprint classified 20% more recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and patients in the high-risk group. Most of the vali- follow-up. Ann Oncol 21(Suppl 5): v15–v19. dation studies are retrospective and performed in heterogeneous populations, making the Carreño, G., del Casar, J., Corte, M., González, assumption that currently available risk predic- L., Bongera, M., Merino, A. et al. (2007) Local tion models are clinically valid too weak. recurrence after mastectomy for breast cancer: analysis Moreover, ethnic variations between occidental of clinicopathological, biological and prognostic characteristics. Breast Cancer Res Treat 102: 61–73. and Asian populations have been reported for the different prediction models, maybe explained Chouchane, L., Boussen, H. and Sastry, K. (2013) by gene disparities [Engelhardt et  al. 2014]. Breast cancer in Arab populations: molecular There are no available data concerning those characteristics and disease management implications. risk prediction models considering Arab or Lancet Oncol 14: e417–e424. African populations. Dent, R., Trudeau, M., Pritchard, K., Hanna, W., Kahn, H., Sawka, C. et al. (2007) Triple-negative breast cancer: clinical features and patterns of Conclusion recurrence. Clin Cancer Res 13: 4429–4434. This is the first study about the early BC relapse Dowsett, M., Sestak, I., Lopez-Knowles, E., Sidhu, profile in North African and Arab patients when K., Dubien, K., Cowers, J. et al. (2013) Comparison considering an intermediate to high risk St Gallen of PAM50 risk of recurrence score with oncotype DX population. As expected, the cohort is in line with and IHC4 for predicting risk of distant recurrence the specific Tunisian BC anatomoclinical charac- after endocrine therapy. J Clin Oncol 31: 2783–2790. teristics in terms of young median age, high clini- Elkhuizen, P., van de Vijver, M., Hermans, J., cal/histological tumor volume and poor histological Zonderland, H., van de Velde, C. and Leer, J. (1998) features impacting negatively and explaining the Local recurrence after breast-conserving therapy high rate of relapses. However, we noted that for invasive breast cancer: high incidence in young modifications of treatment protocols during the patients and association with poor survival. Int J study period induced a transition in relapse profile Radiat Oncol Biol Phys 40: 859–867. within recently treated patients by sequential Engelhardt, E., Garvelink, M., de Haes, J., Van anthracycline, taxanes and trastuzumab that pre- Der Hoeven, J., Smets, E., Pieterse, A. et al. (2014) sented a delayed and decreased relapse peak. Predicting and communicating the risk of recurrence Relapse risk of early BC in Tunisian patients seems and death in women with early-stage breast cancer: to be higher in young women with a high propor- a systematic review of risk prediction models. J Clin tion of HER2 tumors. 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Journal

Therapeutic Advances in Medical OncologySAGE

Published: Mar 15, 2015

Keywords: breast cancer; human epidermal growth factor receptor 2; hormonal receptors; immunohistochemical; relapse; triple negative

References