SYSTEMATIC REVIEW For reprint orders, please contact: [email protected]
Primary breast cancer in the elderly: a systematic literature review on histological type and clinical outcome Samuel O Ogunbiyi1, Sooyoung Lee1, John Mathew1 & Kwok Leung Cheung*,1
ABSTRACT The objective was to determine whether histological types of breast cancer in elderly women influence clinical outcome. Four major databases were searched. All relevant articles, from January 1990 to December 2013, were screened. After applying inclusion and exclusion criteria, 11 studies were included. Invasive ductal carcinoma was the commonest (68.5–87.1%) histological type, followed by lobular carcinoma (6.9–17.7%). Four studies reported on survival. However, none specifically looked at survival according to different histological types. There are very little data on the influence of histological type on clinical outcome in primary breast cancer in elderly patients. Further studies may elucidate any potential influence and its relationship with tumor biology. The incidence of breast cancer increases with age [1] . It is a heterogeneous disease, but can be classified according to histological types. The two most common histological types of invasive breast carcinoma are ductal and lobular cancer, comprising about 75 and 15%, respectively, of newly diagnosed cases [2] . In current clinical practice, less emphasis is placed on histological subtypes, with more attention on the traditional biomarkers (tumor grade, estrogen receptor [ER], progesterone receptor [PR] and HER2), due to the prognostic information they provide. However, the advent of the biomarker E-Cadherin, has enabled better distinction between invasive ductal carcinoma and lobular phenotypes [3,4] , as the majority of invasive lobular carcinomas (classified by traditional histological features) show a complete loss of E-Cadherin expression [3,5–6] . This does somewhat emphasize the importance of the different histological types of breast cancer. Breast cancer in the elderly is thought to have a good prognosis, compared with breast cancer in younger patients [7,8] . However, evidence for this is primarily based upon retrospective comparative studies of histological features in old and young patients [7–9] demonstrating a higher incidence of high grade cancers in younger women [10–12] . These studies do not appear to look specifically at survival outcome in the elderly, according to the histological type. The aim of this study was to evaluate the distribution of the different histological types of breast cancer in elderly patients and to look at their relationship with survival outcomes, by conducting a systematic review of the literature.
KEYWORDS
• elderly woman • histological type • outcome • primary breast
cancer
Methods ●●Search strategy
Medline, PubMed, EMBASE and Science Direct databases (from January 1990 to December 2013), were searched for titles in English, by combining the equation ([breast cancer or breast carcinoma] and [histological type]) and [breast cancer] and [elderly or older woman]). In some cases (Science Direct), equivalent free text search terms, such as ‘breast cancer histological types School of Medicine, University of Nottingham, Nottingham, UK *Author for correspondence: Tel.: +44 1332 724881; Fax: +44 1332 724880; [email protected] 1
10.2217/FON.14.210 © 2015 Future Medicine Ltd
Future Oncol. (2015) 11(2), 259–265
part of
ISSN 1479-6694
259
Systematic Review Ogunbiyi, Lee, Mathew & Cheung in elderly women’ were put into the all fields tab, and the search narrowed by limiting it with the topics ‘breast cancer’ and ‘elderly patient’. The titles were then screened for the presence of the key terms mentioned above, and relevant titles selected. All the abstracts for papers with relevant titles were retrieved. ●●Study selection
All abstracts deemed relevant were examined. The inclusion criteria for studies were that they included 500 or more patients with primary breast cancer and had a minimum of 20% of their patients over the age of 65 years. There is no agreed definition by age for elderly patients though the cut offs of 65 years, 70 years and 75 years have been used in various studies. For the purpose of the search, the lowest cut-off was used to attempt to capture studies which were most representative of this population. All abstracts that fulfilled these criteria had their full articles retrieved and reviewed. Multiple publications that involved the same series of patients (or same patient population) were identified; only the most recent or parent study was included for the purpose of this review. ●●Data extraction
The following data were extracted from the full articles selected: year of publication, number of patients with primary breast cancer in the study, number and percentage of patients over the age of 65 years, distribution of histological types in the cohort of elderly patients, details of any data on survival outcome. Results ●●Data retrieval from literature search
The literature search strategy and abstract selection are detailed in Figure 1. A total of 11 studies were available for full analysis of results. ●●Study characteristics
Basic characteristics such as sample size and percentage of elderly patients are summarized in Table 1. All were retrospective studies, eight of which were from single centers. Eight studies were from Europe [10–17] , two from North America [18–20] and one from Asia [20] . Most studies carried out their pathology reporting on surgical specimens [10–13,15–20] , with only one study using needle core biopsies from breast tumor tissue [14] . Three studies [10,18–19] retrieved pathology data from a pathology registry
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database, while in seven studies [11–12,14–17,20] the pathology reporting was done by a team of pathologists in the respective institutions. One study did not specify who did the pathology reporting [13] . ●●Histological types of breast cancer by age
All studies reported invasive ductal carcinoma as the commonest histological type of invasive breast carcinoma in elderly patients (range: 68.5–87.1%). The incidence of lobular carcinoma was reported as 6.9–17.7%. Five studies [10–12,16,18] reported a gradual increase in the incidence of lobular cancers with increasing age. Six studies reported on the incidence of mucinous carcinomas in the elderly [10,12,14,18–20] . Two studies [18,20] reported a higher incidence of mucinous breast cancers in elderly patients, compared with patients below the age of 65 years with primary breast cancer. ●●Survival outcome
Four out of 11 studies (Table 2) reported on survival outcome for elderly patients with primary breast cancer [11,15,17–18] that had surgery for loco-regional disease. Daidone et al. [11] reported a 6-year diseasefree survival of 84, 75 and 70% for tumors 2 cm in diameter, respectively, in elderly patients with primary breast cancer that underwent surgery. Diab et al. [18] reported on the 8-year survival for patients over the age of 65 years, that had surgery with or without adjuvant therapy for breast cancer, from the Surveillance, Epidemiology and End Results (SEER) registry database (Table 2) . Diab et al. also showed that the subgroup of older patients with lymph node negative breast cancer, had survival rates that were similar to that of age-matched controls in the general population. Similar comparisons on lymph node negative patients were not made in the other studies that reported on survival. Djordjevic et al. [15] reported a disease-free survival of 85% after a mean follow up period of 39.3 months [15] , for patients over 65 years, that had surgery, with or without adjuvant therapy for primary breast cancer. This survival outcome was similar to the outcome they reported (90%) for the cohort of patients less than 65 years in that study. Pierga et al. [17] reported a 10-year diseasefree survival rate of 64% in elderly patients (>70 years) that had curative surgery for breast
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Primary breast cancer in the elderly
Systematic Review
Potentially relevant titles from searching multiple databases n = 1388 Irrelevant titles n = 1258 Selected titles based on key terms within title n = 130 Failed to fulfil inclusion criteria n = 111 Selected studies based on inclusion criteria n = 19 Duplicate studies, n = 7 Study done on previous set of patients, n = 1 Total number of studies for analysis n = 11
Figure 1. Flow chart showing selection of articles for review.
cancer. The overall cancer related death rate was 49% and the local relapse rate was 14% [17] . ●●Relationship between survival outcome &
histological types
As mentioned above, four studies reported on both the survival outcome and the different histological types [11,15,17–18] . However, no correlation was made between the two parameters. Daidone et al. [11] , in addition to survival outcome and histological types, also looked at the expression of pathobiological variables-like tumor size, estrogen receptor (ER) status and proliferative rate. They reported a correlation between survival with ER status and tumor size. They demonstrated that for patients with tumors that were lymph node negative, those that were ER positive and less than 2 cm in diameter, had a better survival outcome than patients with a tumor diameter more than 2 cm or tumors that were ER negative. In summary, there were no studies identified which looked at correlation between histological types and survival outcome. On the other hand, survival outcome data were reported in a number of studies in association with major prognostic factors such as grade and stage.
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Discussion ●●Study characteristics
The ratio of elderly patients in the 11 included studies varied considerably. This may be related to the different selection criteria for the study population in the respective studies (cohort studies focusing on the elderly population or registry-based studies), and the timing of the various studies. Because the incidence of breast cancer increases with age [1] , changing demographics of the western population over the last few decades may also account for the different proportions of elderly patients in the different studies. The demographics of all but one of the studies [20] are representative of a western population (Europe and USA). ●●Histological types of breast cancer by age
We have demonstrated a similar pattern of distribution of the different histological types of breast cancer in the elderly to that in younger patients. Of note though, all but one of the studies [14] , carried out histology on tissue from surgical specimens. However, we know that some patients, due to comorbidity or preference, undergo nonoperative management, notably
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Systematic Review Ogunbiyi, Lee, Mathew & Cheung Table 1. Patient characteristics and different histological types of breast cancer in 11 selected studies for systematic review. Study (year) Number of patients
Percentage of patients >65 years of age (n)
Distribution of histological Results types in elderly subgroup (%)
Fisher et al. (1997)
n = 1869 single center
20.4% (382)
Botos et al. (1998) Diab et al. (2000)
n = 560 single 38.6% (216) center n = 50,828†, n 45.4%† (23,053†) = 256,287‡
Daidone et al. (2002)
n = 14,007 single center
26% (3653)
Djordjevic et al. (2004)
n = 2196 single center
39.3% (862)
Ductal: 73 Lobular: 17 Mucinous: 3 Medullary: 0.8 Ductal: 75.3 Lobular: not stated Ductal: 81 Lobular: 9 Mucinous: 4 Tubular: 1 Medullary: 1 Ductal: 68.5 Lobular: 17.7 Mixed (ductal and lobular): 6.6 Ductal: 70.3 Lobular: not stated
Pierga et al. (2004) Li et al. (2005)
n = 1755 single center n = 135,157 (SEER database)
>70 years 100%
Not stated
> 70 years 30.0% (37,787)
Cheung et al. n = 1996 (2008) single center
>70 years 100% (1996)
Durbecq et al. (2008)
>61 years 37% (988)
Ductal: 73.5 Lobular: 10.7 Mucinous: 4 Medullary: 0.5 Ductal: 87.1 Lobular: 6.9 Mucinous: 3.1 Ductal: 69.3 Lobular: 14.9 Mixed: 10.6 Mucinous: 0.6 Ductal: 82.7 Lobular: 3.1 Mucinous: 3 Medullary: 0.6 Ductal: 74.2 Lobular: 9.5 Mucinous: 3.4 Tubular 1.9
n = 2723 single center
Chuan-Dong n = 866 (>60) et al. (2009) single center
>70 years 37.3% (323)
Albrektsen et al. (2010)
20.5% (60–74 years) 2.5% (70–74 years)
† ‡
n = 22,867 multiple centers
Ref.
Infiltrating lobular carcinomas showed a gradual increase in incidence with increasing age
[12]
Infiltrating ductal carcinoma most common in both age groups but better prognosis in elderly Advancing age is associated with more favorable tumor biology, older patients had more lobular and mucinous carcinomas
[13]
Advancing age is associated with favorable tumor biological features. Increasing incidence of lobular carcinomas in elderly patients Ductal carcinoma was the most frequently observed histological type. There is no significant difference in disease-specific survival by age Breast cancer in the elderly is more hormone dependent with a lower proliferation index Ductal carcinoma is the most common type. Elderly women more likely to be diagnosed with stage III or IV disease.
[11]
Greater preponderance of estrogen receptor positive cancers compared with cohort of younger patients Infiltrating ductal carcinoma was commonest type at any age. The incidence of lobular carcinomas increased with age
[18]
[15]
[17] [19]
[14]
[16]
Elderly women had larger tumors at diagnosis with more mucinous carcinomas
[20]
Ductal carcinoma was the most common type. The proportion of lobular tumors increased with age
[10]
San Antonio database. Surveillance, Epidemiology, and End results database.
primary endocrine therapy leading to a potential selection bias toward more patients with ERpositive disease in this case. As not all elderly patients have their primary breast cancer treated by surgery, pathological features obtained from needle core biopsies may provide a more accurate depiction of the distribution of the different histological types in this group of patients. On the other hand, whether we can reliably establish the histological type of an invasive carcinoma from the core biopsy sample remains debatable.
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The results also suggest that the incidence of lobular carcinomas [11–12,16,18] and mucinous carcinomas [18,20] increases with age. Though high heterogeneity exists among different types of breast cancer, the fact that these studies were based both in single centers and large registries would imply that this finding is less likely to be due to heterogeneous methodology. Studies by others [21] have shown that patients with invasive lobular cancers tend to be older, and have low-grade tumors that are estrogen receptor
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Primary breast cancer in the elderly
Systematic Review
Table 2. Survival outcome data from the four studies that reported on survival. Study (year)
Elderly patients in study (n)
Mean follow-up (months)
Relative survival (All patients)
Disease-free survival (%) Ref.
Daidone et al. (2003)
3653
72
–
39.3
–
84 (tumors ≤1 cm)† 75 (tumors 1–2 cm)† 70 (tumors ≥2 cm)† 85‡
[15]
96 (median)
–
64§
[17]
96
0.80 (65–69 years) 0.81 (70–74 years) 0.82 (75–79 years) 0.82 (80–84 years) 0.78 (≥85 years)
–
[18]
Djordjevic et al. 2196 (2004) Pierga et al. 1755 (2004) Diab et al. 23,053 (2000)
[11]
All patients were elderly patients with primary breast cancer that had surgery (with or without adjuvant treatment). † 6 years; ‡3.3 years; §10 years.
positive compared with patients with invasive ductal carcinoma. This may contribute to the ‘favorable tumor biology’ that is reported in studies on breast cancer in the elderly [11,14,17–18] . Li et al. correlated the histological types of breast cancer directly with favorable and unfavorable biological features. They demonstrated that lobular, ductal, mucinous, tubular and papillary carcinomas were less likely to be steroid receptor negative and high grade, than medullary and inflammatory cancers [19] . A study based on the SEER database demonstrated similar findings, notably grade and steroid receptor status in the very elderly (over 80 years), compared with their younger counterparts (65–79 years) [22] . ●●Clinical outcome & correlation to histology
All the four studies with data on outcome, reported a good survival outcome for elderly patients that had surgery for primary breast cancer. Survival outcome was either similar to age-matched controls in the general population [18] or similar to survival in cohorts of younger patients treated for breast cancer [15] . This systematic review did not find any data linking the different histological types of breast cancer to survival outcome. The lack of evidence on this topic is suggested by the small number of articles written on both histological types of breast cancer and survival outcome. Furthermore, the correlation between outcome and biology of breast cancer in older women is important as there is emerging data showing differing biology due to age. Our group has recently demonstrated a distinct biological type (low ER luminal type) in the elderly population
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using partitional clustering of tissue microarrays from surgical specimen [23] . It is therefore paramount to tease out detailed biological information from the tumor in order to personalize treatment. Otherwise patients might be at risk of being ‘over’ or ‘under’ treated. Future work could include an integral approach taking into account both molecular and histological subtypes in characterizing the biology of breast cancer. Conclusion & future perspective There is very little data on the influence of histological type on clinical outcome in primary breast cancer in elderly patients. In the current era of molecular medicine, the traditional biomarkers (ER, PR and HER2) drive patient care, and there is evidence linking these biomarkers (ER, PR and HER2) to clinical outcome. Future research would be aimed at identifying biomarkers specifically linked to histological subtypes of breast cancer. This has the potential to complement the current use of histological subtype and traditional biomarkers (ER, PR and HER2) in clinical practice, and move us a step closer to personalizing patient treatment for breast cancer Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
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Systematic Review Ogunbiyi, Lee, Mathew & Cheung EXECUTIVE SUMMARY ●●
Ductal and lobular breast cancer comprise 75 and 15%, respectively, of newly diagnosed cases of invasive breast cancer.
●●
The aim of the study was to see whether the different histological types of breast cancer in elderly women influences clinical outcome.
●●
Four databases were searched, with inclusion criteria from January 1990 to December 2013 for all relevant articles.
●●
Eleven studies were included for analysis from a total of 130 abstracts.
●●
Five studies reported that the incidence of lobular cancer increases with increasing age.
●●
Four out of 11 studies included survival outcome data for elderly patients with primary breast cancer.
●●
No studies specifically linked histological type to survival outcome.
●●
In conclusion, there is very little data on the influence of histological type on clinical outcome in primary breast cancer in elderly patients.
●●
Further studies may elucidate any potential influence and its relationship with tumor biology.
References
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Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, (1998). CA Cancer J. Clin. 48(1), 6–29 (1998).
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Li CI, Anderson BO, Daling JR, Moe RE. Trends in incidence rates of invasive lobular and ductal breast carcinoma. JAMA 289(11), 1421–1424. (2003).
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Acs G, Lawton TJ, Rebbeck TR, LiVolsi VA, Zhang PJ. Differential expression of E-cadherin in lobular and ductal neoplasms of the breast and its biologic and diagnostic implications. Am. J. Clin. Pathol. 115(1), 85–98. (2001). Wahed A, Connelly J, Reese T. E-cadherin expression in pleomorphic lobular carcinoma: an aid to differentiation from ductal carcinoma. Ann. Diagn. Pathol. 6(6), 349–351. (2002). De Leeuw WJ, Berx G, Vos CB, Peterse JL et al.Simultaneous loss of E-cadherin and catenins in invasive lobular breast cancer and lobular carcinoma in situ. J. Pathol. 183(4), 404–411. (1997).
9
between the two. 16 Durbecq V, Ameye L, Veys I et al. A
significant proportion of elderly patients develop hormone-dependant “luminal-B” tumours associated with aggressive characteristics. Crit. Rev. Oncol. Hematol. 67(1), 80–92 (2008).
Carter D, Orr SL, Merino MJ. Intracystic papillary carcinoma of the breast. After mastectomy, radiotherapy or excisional biopsy alone. Cancer 52(1), 14–19 (1983).
10 Albrektsen G, Heuch I, Thoresen SO.
Histological type and grade of breast cancer tumors by parity, age at birth, and time since birth: a register-based study in Norway. BMC Cancer 10, 226 (2010).
17 Pierga JY, Girre V, Laurence V et al.
Characteristics and outcome of 1755 operable breast cancers in women over 70years of age. Breast 13(5), 369–375 (2004). •
11 Daidone MG, Coradini D, Martelli G,
Veneroni S. Primary breast cancer in elderly women: biological profile and relation with clinical outcome. Crit. Rev. Oncol. Hematol. 45(3), 313–325 (2003). •
Reported on the different histological types and survival, but without direct correlation between the two.
18 Diab SG, Elledge RM, Clark GM. Tumor
characteristics and clinical outcome of elderly women with breast cancer. J. Natl Cancer Inst. 92(7), 550–556 (2000). •
12 Fisher CJ, Egan MK, Smith P, Wicks K,
Millis RR, Fentiman IS. Histopathology of breast cancer in relation to age. Br. J. Cancer 75(4), 593–596. (1997). elderly. The impact of histological features on the prognosis and survival. Eur. J. Cancer 01, 34 (1998). 14 Cheung KL, Wong AW, Parker H et al.
de la RA, Asselain B, Campana F et al. Age as prognostic factor in premenopausal breast carcinoma. Lancet 341(8852), 1039–1043. (1993).
15 Djordjevic N, Karanikolic A, Pesic M. Breast
Rosen PP, Lesser ML, Kinne DW. Breast carcinoma at the extremes of age: a
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Pathological features of primary breast cancer in the elderly based on needle core biopsies – a large series from a single centre. Crit. Rev. Oncol. Hematol. 67(3), 263–267 (2008). cancer in elderly women. Arch. Gerontol. Geriatr. 39(3), 291–299 (2004). Reported on the different histological types and survival, but without direct correlation
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Reported on the different histological types and survival, but without direct correlation between the two.
19 Li CI, Uribe DJ, Daling JR. Clinical
characteristics of different histologic types of breast cancer. Br. J. Cancer 93(9), 1046–1052 (2005).
13 Botos CJ, Minik K. Breast cancer in the
Ellis IO, Galea M, Broughton N, Locker A, Blamey RW, Elston CW. Pathological prognostic factors in breast cancer. II. Histological type. Relationship with survival in a large study with long-term follow-up. Histopathology 20(6), 479–489. (1992).
Reported on the different histological types and survival, but without direct correlation between the two.
•
Correlated the histological types of breast cancer with favorable and unfavorable tumor biological features.
20 Chuan-Dong Maa QZ, Xiu-Qing Nie,
Guang-Yu Li et al. Breast cancer in Chinese elderly women: pathological and clinical characteristics and factors influencing treatment patterns. Crit. Rev. Oncol. Hematol. 71, 258–265. (2009). 21 Rakha EA, El Sayed ME, Powe DG et al.
Invasive lobular carcinoma of the breast: response to hormonal therapy and outcomes. Eur. J. Cancer 44(1), 73–83 (2008).
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Silliman RA, Ngo L, McCarthy EP. Breast cancer among the oldest old: tumor characteristics, treatment choices, and survival. J. Clin. Oncol. 28(12), 2038–2010 (2045).
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23 Syed BM, Green AR, Paish EC et al. Biology
of primary breast cancer in older women treated by surgery: with correlation with long-term clinical outcome and comparison with their younger counterparts. Br. J. Cancer 108(5), 1042–1051 (2013).
•
Systematic Review
Recently demonstrated a distinct biological type of breast cancer in the elderly population.
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Primary breast cancer in the elderly: a systematic literature review on histological type and clinical outcome Samuel O Ogunbiyi1, Sooyoung Lee1, John Mathew1 & Kwok Leung Cheung*,1
ABSTRACT The objective was to determine whether histological types of breast cancer in elderly women influence clinical outcome. Four major databases were searched. All relevant articles, from January 1990 to December 2013, were screened. After applying inclusion and exclusion criteria, 11 studies were included. Invasive ductal carcinoma was the commonest (68.5–87.1%) histological type, followed by lobular carcinoma (6.9–17.7%). Four studies reported on survival. However, none specifically looked at survival according to different histological types. There are very little data on the influence of histological type on clinical outcome in primary breast cancer in elderly patients. Further studies may elucidate any potential influence and its relationship with tumor biology. The incidence of breast cancer increases with age [1] . It is a heterogeneous disease, but can be classified according to histological types. The two most common histological types of invasive breast carcinoma are ductal and lobular cancer, comprising about 75 and 15%, respectively, of newly diagnosed cases [2] . In current clinical practice, less emphasis is placed on histological subtypes, with more attention on the traditional biomarkers (tumor grade, estrogen receptor [ER], progesterone receptor [PR] and HER2), due to the prognostic information they provide. However, the advent of the biomarker E-Cadherin, has enabled better distinction between invasive ductal carcinoma and lobular phenotypes [3,4] , as the majority of invasive lobular carcinomas (classified by traditional histological features) show a complete loss of E-Cadherin expression [3,5–6] . This does somewhat emphasize the importance of the different histological types of breast cancer. Breast cancer in the elderly is thought to have a good prognosis, compared with breast cancer in younger patients [7,8] . However, evidence for this is primarily based upon retrospective comparative studies of histological features in old and young patients [7–9] demonstrating a higher incidence of high grade cancers in younger women [10–12] . These studies do not appear to look specifically at survival outcome in the elderly, according to the histological type. The aim of this study was to evaluate the distribution of the different histological types of breast cancer in elderly patients and to look at their relationship with survival outcomes, by conducting a systematic review of the literature.
KEYWORDS
• elderly woman • histological type • outcome • primary breast
cancer
Methods ●●Search strategy
Medline, PubMed, EMBASE and Science Direct databases (from January 1990 to December 2013), were searched for titles in English, by combining the equation ([breast cancer or breast carcinoma] and [histological type]) and [breast cancer] and [elderly or older woman]). In some cases (Science Direct), equivalent free text search terms, such as ‘breast cancer histological types School of Medicine, University of Nottingham, Nottingham, UK *Author for correspondence: Tel.: +44 1332 724881; Fax: +44 1332 724880; [email protected] 1
10.2217/FON.14.210 © 2015 Future Medicine Ltd
Future Oncol. (2015) 11(2), 259–265
part of
ISSN 1479-6694
259
Systematic Review Ogunbiyi, Lee, Mathew & Cheung in elderly women’ were put into the all fields tab, and the search narrowed by limiting it with the topics ‘breast cancer’ and ‘elderly patient’. The titles were then screened for the presence of the key terms mentioned above, and relevant titles selected. All the abstracts for papers with relevant titles were retrieved. ●●Study selection
All abstracts deemed relevant were examined. The inclusion criteria for studies were that they included 500 or more patients with primary breast cancer and had a minimum of 20% of their patients over the age of 65 years. There is no agreed definition by age for elderly patients though the cut offs of 65 years, 70 years and 75 years have been used in various studies. For the purpose of the search, the lowest cut-off was used to attempt to capture studies which were most representative of this population. All abstracts that fulfilled these criteria had their full articles retrieved and reviewed. Multiple publications that involved the same series of patients (or same patient population) were identified; only the most recent or parent study was included for the purpose of this review. ●●Data extraction
The following data were extracted from the full articles selected: year of publication, number of patients with primary breast cancer in the study, number and percentage of patients over the age of 65 years, distribution of histological types in the cohort of elderly patients, details of any data on survival outcome. Results ●●Data retrieval from literature search
The literature search strategy and abstract selection are detailed in Figure 1. A total of 11 studies were available for full analysis of results. ●●Study characteristics
Basic characteristics such as sample size and percentage of elderly patients are summarized in Table 1. All were retrospective studies, eight of which were from single centers. Eight studies were from Europe [10–17] , two from North America [18–20] and one from Asia [20] . Most studies carried out their pathology reporting on surgical specimens [10–13,15–20] , with only one study using needle core biopsies from breast tumor tissue [14] . Three studies [10,18–19] retrieved pathology data from a pathology registry
260
Future Oncol. (2015) 11(2)
database, while in seven studies [11–12,14–17,20] the pathology reporting was done by a team of pathologists in the respective institutions. One study did not specify who did the pathology reporting [13] . ●●Histological types of breast cancer by age
All studies reported invasive ductal carcinoma as the commonest histological type of invasive breast carcinoma in elderly patients (range: 68.5–87.1%). The incidence of lobular carcinoma was reported as 6.9–17.7%. Five studies [10–12,16,18] reported a gradual increase in the incidence of lobular cancers with increasing age. Six studies reported on the incidence of mucinous carcinomas in the elderly [10,12,14,18–20] . Two studies [18,20] reported a higher incidence of mucinous breast cancers in elderly patients, compared with patients below the age of 65 years with primary breast cancer. ●●Survival outcome
Four out of 11 studies (Table 2) reported on survival outcome for elderly patients with primary breast cancer [11,15,17–18] that had surgery for loco-regional disease. Daidone et al. [11] reported a 6-year diseasefree survival of 84, 75 and 70% for tumors 2 cm in diameter, respectively, in elderly patients with primary breast cancer that underwent surgery. Diab et al. [18] reported on the 8-year survival for patients over the age of 65 years, that had surgery with or without adjuvant therapy for breast cancer, from the Surveillance, Epidemiology and End Results (SEER) registry database (Table 2) . Diab et al. also showed that the subgroup of older patients with lymph node negative breast cancer, had survival rates that were similar to that of age-matched controls in the general population. Similar comparisons on lymph node negative patients were not made in the other studies that reported on survival. Djordjevic et al. [15] reported a disease-free survival of 85% after a mean follow up period of 39.3 months [15] , for patients over 65 years, that had surgery, with or without adjuvant therapy for primary breast cancer. This survival outcome was similar to the outcome they reported (90%) for the cohort of patients less than 65 years in that study. Pierga et al. [17] reported a 10-year diseasefree survival rate of 64% in elderly patients (>70 years) that had curative surgery for breast
future science group
Primary breast cancer in the elderly
Systematic Review
Potentially relevant titles from searching multiple databases n = 1388 Irrelevant titles n = 1258 Selected titles based on key terms within title n = 130 Failed to fulfil inclusion criteria n = 111 Selected studies based on inclusion criteria n = 19 Duplicate studies, n = 7 Study done on previous set of patients, n = 1 Total number of studies for analysis n = 11
Figure 1. Flow chart showing selection of articles for review.
cancer. The overall cancer related death rate was 49% and the local relapse rate was 14% [17] . ●●Relationship between survival outcome &
histological types
As mentioned above, four studies reported on both the survival outcome and the different histological types [11,15,17–18] . However, no correlation was made between the two parameters. Daidone et al. [11] , in addition to survival outcome and histological types, also looked at the expression of pathobiological variables-like tumor size, estrogen receptor (ER) status and proliferative rate. They reported a correlation between survival with ER status and tumor size. They demonstrated that for patients with tumors that were lymph node negative, those that were ER positive and less than 2 cm in diameter, had a better survival outcome than patients with a tumor diameter more than 2 cm or tumors that were ER negative. In summary, there were no studies identified which looked at correlation between histological types and survival outcome. On the other hand, survival outcome data were reported in a number of studies in association with major prognostic factors such as grade and stage.
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Discussion ●●Study characteristics
The ratio of elderly patients in the 11 included studies varied considerably. This may be related to the different selection criteria for the study population in the respective studies (cohort studies focusing on the elderly population or registry-based studies), and the timing of the various studies. Because the incidence of breast cancer increases with age [1] , changing demographics of the western population over the last few decades may also account for the different proportions of elderly patients in the different studies. The demographics of all but one of the studies [20] are representative of a western population (Europe and USA). ●●Histological types of breast cancer by age
We have demonstrated a similar pattern of distribution of the different histological types of breast cancer in the elderly to that in younger patients. Of note though, all but one of the studies [14] , carried out histology on tissue from surgical specimens. However, we know that some patients, due to comorbidity or preference, undergo nonoperative management, notably
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Systematic Review Ogunbiyi, Lee, Mathew & Cheung Table 1. Patient characteristics and different histological types of breast cancer in 11 selected studies for systematic review. Study (year) Number of patients
Percentage of patients >65 years of age (n)
Distribution of histological Results types in elderly subgroup (%)
Fisher et al. (1997)
n = 1869 single center
20.4% (382)
Botos et al. (1998) Diab et al. (2000)
n = 560 single 38.6% (216) center n = 50,828†, n 45.4%† (23,053†) = 256,287‡
Daidone et al. (2002)
n = 14,007 single center
26% (3653)
Djordjevic et al. (2004)
n = 2196 single center
39.3% (862)
Ductal: 73 Lobular: 17 Mucinous: 3 Medullary: 0.8 Ductal: 75.3 Lobular: not stated Ductal: 81 Lobular: 9 Mucinous: 4 Tubular: 1 Medullary: 1 Ductal: 68.5 Lobular: 17.7 Mixed (ductal and lobular): 6.6 Ductal: 70.3 Lobular: not stated
Pierga et al. (2004) Li et al. (2005)
n = 1755 single center n = 135,157 (SEER database)
>70 years 100%
Not stated
> 70 years 30.0% (37,787)
Cheung et al. n = 1996 (2008) single center
>70 years 100% (1996)
Durbecq et al. (2008)
>61 years 37% (988)
Ductal: 73.5 Lobular: 10.7 Mucinous: 4 Medullary: 0.5 Ductal: 87.1 Lobular: 6.9 Mucinous: 3.1 Ductal: 69.3 Lobular: 14.9 Mixed: 10.6 Mucinous: 0.6 Ductal: 82.7 Lobular: 3.1 Mucinous: 3 Medullary: 0.6 Ductal: 74.2 Lobular: 9.5 Mucinous: 3.4 Tubular 1.9
n = 2723 single center
Chuan-Dong n = 866 (>60) et al. (2009) single center
>70 years 37.3% (323)
Albrektsen et al. (2010)
20.5% (60–74 years) 2.5% (70–74 years)
† ‡
n = 22,867 multiple centers
Ref.
Infiltrating lobular carcinomas showed a gradual increase in incidence with increasing age
[12]
Infiltrating ductal carcinoma most common in both age groups but better prognosis in elderly Advancing age is associated with more favorable tumor biology, older patients had more lobular and mucinous carcinomas
[13]
Advancing age is associated with favorable tumor biological features. Increasing incidence of lobular carcinomas in elderly patients Ductal carcinoma was the most frequently observed histological type. There is no significant difference in disease-specific survival by age Breast cancer in the elderly is more hormone dependent with a lower proliferation index Ductal carcinoma is the most common type. Elderly women more likely to be diagnosed with stage III or IV disease.
[11]
Greater preponderance of estrogen receptor positive cancers compared with cohort of younger patients Infiltrating ductal carcinoma was commonest type at any age. The incidence of lobular carcinomas increased with age
[18]
[15]
[17] [19]
[14]
[16]
Elderly women had larger tumors at diagnosis with more mucinous carcinomas
[20]
Ductal carcinoma was the most common type. The proportion of lobular tumors increased with age
[10]
San Antonio database. Surveillance, Epidemiology, and End results database.
primary endocrine therapy leading to a potential selection bias toward more patients with ERpositive disease in this case. As not all elderly patients have their primary breast cancer treated by surgery, pathological features obtained from needle core biopsies may provide a more accurate depiction of the distribution of the different histological types in this group of patients. On the other hand, whether we can reliably establish the histological type of an invasive carcinoma from the core biopsy sample remains debatable.
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Future Oncol. (2015) 11(2)
The results also suggest that the incidence of lobular carcinomas [11–12,16,18] and mucinous carcinomas [18,20] increases with age. Though high heterogeneity exists among different types of breast cancer, the fact that these studies were based both in single centers and large registries would imply that this finding is less likely to be due to heterogeneous methodology. Studies by others [21] have shown that patients with invasive lobular cancers tend to be older, and have low-grade tumors that are estrogen receptor
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Primary breast cancer in the elderly
Systematic Review
Table 2. Survival outcome data from the four studies that reported on survival. Study (year)
Elderly patients in study (n)
Mean follow-up (months)
Relative survival (All patients)
Disease-free survival (%) Ref.
Daidone et al. (2003)
3653
72
–
39.3
–
84 (tumors ≤1 cm)† 75 (tumors 1–2 cm)† 70 (tumors ≥2 cm)† 85‡
[15]
96 (median)
–
64§
[17]
96
0.80 (65–69 years) 0.81 (70–74 years) 0.82 (75–79 years) 0.82 (80–84 years) 0.78 (≥85 years)
–
[18]
Djordjevic et al. 2196 (2004) Pierga et al. 1755 (2004) Diab et al. 23,053 (2000)
[11]
All patients were elderly patients with primary breast cancer that had surgery (with or without adjuvant treatment). † 6 years; ‡3.3 years; §10 years.
positive compared with patients with invasive ductal carcinoma. This may contribute to the ‘favorable tumor biology’ that is reported in studies on breast cancer in the elderly [11,14,17–18] . Li et al. correlated the histological types of breast cancer directly with favorable and unfavorable biological features. They demonstrated that lobular, ductal, mucinous, tubular and papillary carcinomas were less likely to be steroid receptor negative and high grade, than medullary and inflammatory cancers [19] . A study based on the SEER database demonstrated similar findings, notably grade and steroid receptor status in the very elderly (over 80 years), compared with their younger counterparts (65–79 years) [22] . ●●Clinical outcome & correlation to histology
All the four studies with data on outcome, reported a good survival outcome for elderly patients that had surgery for primary breast cancer. Survival outcome was either similar to age-matched controls in the general population [18] or similar to survival in cohorts of younger patients treated for breast cancer [15] . This systematic review did not find any data linking the different histological types of breast cancer to survival outcome. The lack of evidence on this topic is suggested by the small number of articles written on both histological types of breast cancer and survival outcome. Furthermore, the correlation between outcome and biology of breast cancer in older women is important as there is emerging data showing differing biology due to age. Our group has recently demonstrated a distinct biological type (low ER luminal type) in the elderly population
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using partitional clustering of tissue microarrays from surgical specimen [23] . It is therefore paramount to tease out detailed biological information from the tumor in order to personalize treatment. Otherwise patients might be at risk of being ‘over’ or ‘under’ treated. Future work could include an integral approach taking into account both molecular and histological subtypes in characterizing the biology of breast cancer. Conclusion & future perspective There is very little data on the influence of histological type on clinical outcome in primary breast cancer in elderly patients. In the current era of molecular medicine, the traditional biomarkers (ER, PR and HER2) drive patient care, and there is evidence linking these biomarkers (ER, PR and HER2) to clinical outcome. Future research would be aimed at identifying biomarkers specifically linked to histological subtypes of breast cancer. This has the potential to complement the current use of histological subtype and traditional biomarkers (ER, PR and HER2) in clinical practice, and move us a step closer to personalizing patient treatment for breast cancer Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
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Systematic Review Ogunbiyi, Lee, Mathew & Cheung EXECUTIVE SUMMARY ●●
Ductal and lobular breast cancer comprise 75 and 15%, respectively, of newly diagnosed cases of invasive breast cancer.
●●
The aim of the study was to see whether the different histological types of breast cancer in elderly women influences clinical outcome.
●●
Four databases were searched, with inclusion criteria from January 1990 to December 2013 for all relevant articles.
●●
Eleven studies were included for analysis from a total of 130 abstracts.
●●
Five studies reported that the incidence of lobular cancer increases with increasing age.
●●
Four out of 11 studies included survival outcome data for elderly patients with primary breast cancer.
●●
No studies specifically linked histological type to survival outcome.
●●
In conclusion, there is very little data on the influence of histological type on clinical outcome in primary breast cancer in elderly patients.
●●
Further studies may elucidate any potential influence and its relationship with tumor biology.
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