Undertreatment of breast cancer in the elderly.

AIMS: The effect of undertreatment with adjuvant hormonal therapy, chemotherapy or radiation was studied in elderly women with breast cancer.
METHODS: A prospectively maintained database was used to identify women undergoing potentially curative surgery between 1997 and 2011. The presentation, pathologic findings, treatment and outcomes of 449 women over 65 were compared to the findings in 1049 younger patients. Moreover, conventionally treated and undertreated elderly patients were identified and their characteristics and outcomes were compared.
RESULTS: Both young and old patients presented most frequently with mammographic findings, but older patients presented more frequently with mammographic masses while younger patients presented more frequently with mammographic calcifications. Cancers of older patients were signicantly more favorable than cancers in younger patients with more infiltrating lobular, fewer ductal carcinoma in situ and more frequently estrogen receptor positive and fewer were poorly differentiated. Elderly patients had less axillary surgery, less adjuvant radiation therapy and more hormonal therapy. Fourty-six percent of the 449 elderly patients were undertreated by conventional criteria. Undertreated patients were more frequently in situ, better differentiated, smaller, and more often estrogen receptor positive. Forty-four percent of the undertreated patients died during follow-up without disease recurrence.
CONCLUSIONS: Despite undertreatment, local and distant disease-free survival was comparable to patients who were not undertreated.

Introduction

The population of elderly individuals in developed countries is increasing. Between 2000 and 2010 the population of women aged 65 and over increased by 11.3% with those 70 and over increasing by 6.4% [1]. According to the Surveillance Epidemiology and End Results (SEERs) database, from 2000 to 2009 the median age for breast cancer diagnoses in the USA was 61 years of age. Approximately 41% were diagnosed above the age of 65, of which 21% were above the age of 75 [2]. As the developed countries population of women over 65 increases, breast cancer in older individuals has and will continue to become more prevalent.

The management of breast cancer in the elderly has been a topic of debate. There is a lack of evidence on the optimal management of this group of patients secondary to low enrollment in randomized clinical trials [3,4]. As a result, treatment decisions have been largely based on studies in younger patients which may not be applicable to elderly patients with breast cancer.

Breast cancers in elderly women compared to younger women are histologically less aggressive and have a good response to hormonal therapy. This favorable biologic profile impacts the decision as to whether an elderly patient should be subjected to adjuvant therapy.

The consequences of these considerations are that elderly patients are often undertreated when compared to younger patients [5-7], but the question that needs to be answered is: are there any clinical implications to the undertreatment of breast cancer in elderly women [6,8,9]?

Diab and colleagues demonstrated that the impact of breast cancer on the expected survival of these elderly patients decreases with age [9] and the risk of dying from comorbid conditions often exceeds the risk of cancer recurrence and breast cancer mortality [10].

Although recommendations based on expert opinion are emerging, there is a paucity of level 1 evidence [11,12].

Determining the optimal treatment for an elderly patient depends largely on clinical judgement, weighing the patients' comorbid conditions with the biology of the tumor [13].

Methods

We reviewed our breast cancer database with the follow-up of patients who have been cared at General and Geriatric Surgery Department of University of Naples "Federico II" from 1997 to 2011. Women 65 years of age and older at the time of diagnosis (449) were identified and compared to women younger than 65 years of age at the time of diagnosis (1049).

Data were collected on age, clinical presentation, mammographic findings, diagnostic method, histopathologic findings, tumor differentiation, tumor size, estrogen receptor status, axillary node status, resection margins, number of pathologically examined nodes, surgical treatment, re-excision, adjuvant hormone treatment, chemotherapy and radiation therapy. Follow-up information was acquired from hospital and office records, patients, and their families. The last date of follow-up and the date of local or distant recurrence were recorded.

The local and distant disease free survival rates were then calculated from the date of definitive surgery. For estimates of local and distant disease recurrence rates, patients in whom a recurrence did not develop were censored at the last follow-up or death, whichever occurred first.

Patients over 65 years of age who were undertreated by conventional criteria were compared to their appropriately treated counterparts. Our criteria for undertreatment included: (1) omission of axillary surgery in patients with invasive cancers; (2) lack of postoperative radiation therapy in patients treated with breast conserving surgery; (3) lack of hormonal treatment in estrogen receptor positive patients with invasive cancers; (4) lack of chemotherapy in node-positive patients; (5) lack of chemotherapy in estrogen receptor negative patients with tumors larger than 2 cm.

The patients were divided into two groups by age (younger than 65 vs. 65 and over) and compared.

The signicance of differences in discrete variables was evaluated using chi-square test, and the signicance of differences in continuous variables was evaluated using Student's t - test.

Results

The 1498 patients ranged in age from 20 to 92 years and 449 (30%) were of age 65 and above, considered elderly (Table 1).

Table 1

Demographic variables in patients < 65 years and > 65 years.

Demographic variable	< 65 years	> 65 years	p
N	1049	449
Mean age (years)	52	76
Presentation
Palpable mass	314 (31%)	130 (29%)	NS
Mx calcification	304 (29%)	63 (14%)	<0.01
Mx mass	199 (19%)	130 (29%)	<0.01
Mx abnormality	10 (1%)	4 (1%)	NS
Other	222 (20%)	122 (27%)	<0.01
Diagnostic method
Excisional biopsy	241 (23%)	108 (24%)	NS
Fine-needle aspiration	524 (50%)	229 (51%)	NS
Core Needle aspiration	283 (27%)	112 (25%)	NS

The 1049 younger patients ranged in age from 20 to 65, with a median age of 47 and the patients over 65 years ranged in age from 65 to 92 years with a median age of 76.

Most patients presented with a palpable mass (31%). Older patients presented more frequently with mammographic masses while younger patients presented more frequently with mammographic calcifications. Both the elderly and the younger patients were most commonly diagnosed by fine-needle aspiration followed by core needle biopsy and excisional biopsy.

Numerous signicant differences were observed between the elderly and younger patients in terms of their pathology (Table 2).

Table 2

Pathologic findings in patients < 65 years and > 65 years.

Pathologic finding	< 65 years	> 65 years	P value
Histopathology
Infiltrating ductal	739 (70,5%)	323 (72%)	NS
Infiltrating lobular	79 (7,5%)	54 (12%)	<0,01
Ductal Carcinoma In Situ DCIS	231 (22%)	72 (16%)	<0,01
Grading
G1	262 (25%)	112 (25%)	NS
G2	451(43%)	238 (53%)	<0,01
G3	336 (32%)	99 (22%)	<0,01
Tumor size
Median	1.2	1.2	NS
0-2	786 (75%)	327 (73%)	NS
2-5	199 (19%)	103 (23%)	NS
>5	64 (6%)	19 (4%)	NS
Node positive	245/818 (30%)	102/377 (27%)	NS
Involved nodes
Mean	3.9	3.7	NS
0	573 (70%)	275 (73%)	NS
1-3	155 (19%)	64 (17%)	NS
>4	90 (11%)	38 (10%)	NS
Estrogen receptor positive	797 (76%)	386 (86%)	<0,01
Axillary node surgery	793 (97%)	301 (80%)	<0,01
Surgery
Breast Conservation	776 (74%)	125 (28%)	<0,001
Mastectomy	273 (26%)	324 (72%)	<0,001
Neoadjuvant chemotherapy	189 (18%)	13 (3%)	<0,001
Postoperative chemotherapy	367 (35%)	36 (8%)	<0,001
Tamoxifen/Aromatase inhibitor	598/797 (75%)	301/386 (78%)	NS
Radiation therapy after BCS	753/776 (97%)	66/125 (53%)	<0,001

Older patients had signicantly more infiltrating lobular cancers and fewer cases of ductal carcinoma in situ than younger patients and signicantly fewer poorly differentiated cancers. The T stage distribution among the elderly and younger patients was comparable. Estrogen receptor positivity was more frequent among the elderly.

Axillary node sampling, sentinel node excision or axillary dissection was more frequent in younger patients.

Adjuvant therapy with both radiation and chemotherapy was significantly less frequent in the elderly.

97% of the 776 young patients treated with breast conservation received radiation therapy compared to 53% of the 125 elderly patients treated with breast conservation (p < 0.001).

Among patients with invasive cancers, 18% of the young patients received neoadjuvant chemotherapy and 35% adjuvant chemotherapy compared to 3% and 8% of the comparable elderly patients (p < 0.001).

The main form of systemic therapy for the elderly patient was hormonal: either Tamoxifen or Aromatase inhibitor.

Despite these differences, the elderly and younger patients had similar 5-year local and distant recurrence-free survival (Table 3).

Table 3

Local and distant disease-free survival.

	N	Recurrence	Cumulative 5-year recurrence-free survival (%)	RR (95% CI)	P value
Local recurrence
< 65 years	1049	58	94
>= 65 years	449	27	94	1.09 (0.68-1.73)	NS
Distant recurrence
< 65 years	1049	84	92
>= 65 years	449	28	94	0.78 (0.50-1.20)	NS

Undertreated elderly patients were identified as described above.

Undertreatment consisted of omission of radiation therapy in 59 of the 125 patients treated with breast conservation, omission of axillary node surgery in 301 of the 377 elderly patients with invasive cancers, omission of chemotherapy in 66 of 102 elderly patients with involved nodes, and omission of hormonal therapy in 85 of 386 elderly patients with estrogen receptor positive cancers.

By these criteria many patients were undertreated with more than one modality. As a consequence, 206 (46%) of the elderly patients were undertreated with at least one modality.

The cancers of the undertreated elderly were more frequently in situ, better differentiated and more often estrogen receptor positive (Table 4).

Table 4

Pathologic findings in undertreated and properly treated aged > 65 years.

Pathologic finding	Full treatment	Undertreated	P value
Histopathology
Infiltrating ductal	199 (82%)	138 (67%)	<0,01
Infiltrating lobular	19 (8%)	27 (13%)	NS
DCIS	25 (10%)	41 (20%)	<0,01
Grading
G1	34 (14%)	37 (18%)	NS
G2	134 (55%)	140 (68%)	<0,01
G3	75 (31%)	29 (14%)	<0,01
Tumor size
Median	1.4	1.0
0-2	168 (69%)	159 (77%)	NS
2-5	63 (26%)	39 (19%)	NS
>5	12 (5%)	8 (4%)	NS
Involved nodes
Mean	1.1	0.5
0	182 (75%)	167 (81%)	NS
1-3	29 (12%)	29 (14%)	NS
>4	31 (13%)	12 (6%)	<0,05
Estrogen receptor positive	194 (80%)	185 (90%)	<0,01
Surgery
Breast conservation	59 (24%)	66 (32%)	NS
Mastectomy	184 (76%)	140 (68%)	NS
Postoperative chemotherapy	66 (27%)	8 (4%)	<0,01
Tamoxifen/Aromatase inhibitor	197 (81%)	107 (52%)	<0,01
Radiation therapy	204 (84%)	62 (30%)	<0,01

Reflecting the criteria used to identify undertreated patients, two-thirds did not receive radiation, almost half did not receive hormonal therapy and a few received chemotherapy.

Despite these differences in treatment, elderly undertreated patients generally fared as well as the appropriately treated elderly (Table 5). Equal numbers of patients in both groups developed local recurrences resulting in five-year cumulative local disease-free rates of 94% for the appropriately treated and 93% for the undertreated.

Table 5

Local and distant disease-free survival in undertreated and properly treated patients aged > 65 years.

	N	Recurrence	Cumulative 5-year recurrence-free survival (%)	RR (95% CI)	P value
Local recurrence
Undertreated	206	12	93
Properly treated	243	14	94	1.01 (0.45-2.27)	NS
Distant recurrence*
Undetreated	165	7	93
Properly treated	218	20	89	0.46(0.18-1.12)	NS

*Invasive cancers

9% of the 218 appropriately treated elderly patients with invasive cancers developed distant disease compared to 4% of undertreated patients causing the cumulative five-year distant disease free rate to be 89% in appropriately treated patients compared to 93% in the undertreated one.

Undertreatment was not significantly related to local or distant recurrence (RR 1.01 [C.I. 0.45-2.27] and 0.46 [C.I. 0.18-1.12] respectively).

Discussion

This study found that elderly patients with breast cancer present with palpable masses and mammographic findings similar to younger patients, although mammographic masses were more frequent in the elderly and mammographic calcifications were more frequent among the young patients.

Cancers of the elderly tended to be less often in situ than in younger patients but invasive cancers were generally better differentiated, more frequently estrogen receptor positive, and with less nodal involvement.

Older patients were treated less aggressively than younger patients. They received less radiation after breast conservation and very seldom they received chemotherapy even for node-positive cases. Elderly patients received hormonal therapy as frequently as younger patients. Despite often being undertreated, elderly patients experienced outcomes comparable to younger patients presumably because their cancers were better differentiated and with fewer involved nodes.

More than one-half of our elderly patients were undertreated according to current breast cancer treatment guidelines: omission of axillary surgery in patients with invasive cancers, omission of radiation in patients treated with breast conservation, omission of chemotherapy in patients with involved nodes or omission of hormonal therapy in patients with estrogen receptor positive cancers. Despite the large number of undertreated patients, there were no signicant differences in local or distant disease free survival among undertreated and appropriately treated patients.

Previous studies of elderly patients with breast cancer have not universally observed that cancers in the elderly are biologically more favorable and less advanced than those seen in younger patients. This is in part due to differences in the populations studied. Generally when one compares the cancers of patients over 65 to patients between 50 and 65, differences are not striking [14,15]. However, if one includes all patients younger than 65, the more favorable biology becomes more apparent [16]. In addition, many studies included elderly patients who were not treated with surgery for a variety of reasons including comorbidity, advanced disease, and patient refusal [17-20]. All of the patients in the current study were potentially curable at presentation, all had surgery and no stage IV patients are included. A universal finding in all the studies is the increasing frequency of estrogen receptor positivity with increasing age. This usually results in the increased use of hormonal therapies in the elderly.

Undertreatment of the elderly is also a universal finding. In fact several authors have found that undertreatment, that is lack of adherence to guidelines, is frequent at all ages [14]. The controversy that exists is whether undertreatment of patients, particularly the elderly, results in adverse outcomes. There is no question that radiation therapy reduces local recurrence rates after breast conservation for invasive and in situ disease regardless of the patient's age. However, a reduction of 3% in local recurrence does not signicantly benefit an 80-year-old woman with a life expectancy of ten years who has only a 50% chance of experiencing the benefit of radiation therapy [21].

Previous studies reported that elderly patients with invasive cancers experience higher mortality when axillary dissection is omitted [22]. Among these studies, a few measured breast cancer specific survival. It is likely that patients not undergoing axillary dissection have higher comorbidities causing the higher mortality, not that the omission of axillary surgery caused the higher mortality. The recently completed trial randomizing patients with involved sentinel nodes to completion axillary dissection versus no additional surgery showed no benefit for completion axillary dissection [23].

Finally, with respect to chemotherapy, a few elderly patients are willing to participate in randomized trials with chemotherapy arms and a few are willing to accept chemotherapy even with relatively advanced disease [3,4,24-26].

Only 63 of our elderly patients were estrogen receptor negative and 16 of these had nodal involvement. All received chemotherapy and an additional 11 patients with node negative and estrogen receptor negative larger cancers received chemotherapy. Because of the small numbers of patients and the association of chemotherapy with advanced estrogen receptor negative disease, patients receiving chemotherapy fared worse than patients not receiving chemotherapy.

Potential limitations of this study derive from the study design:. it is a retrospective database review (observational study).

This includes a potential physician bias and bias as a result of confounding by indication. It must be mentioned, however, that in today's world of cancer treatment, care is individualized and the patient ultimately determines what treatment she is to receive.

Breast cancer in elderly patients has a favorable biological profile and therefore treatment does not need to fall under the confines of traditional guidelines. Moreover, coupled with comorbid conditions that are frequently encountered as people age, optimal treatment should be determined largely by clinical judgement on a case by case basis. It is known that elderly patients are undertreated but this study did not find that the omission of conventional surgery or adjuvant therapies adversely affected outcome among patients over 65 years of age.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

N.R, C.R: conception and design, interpretration of data, given final approval of the version to be published.

G.P, S.A, R.C, M.D: acquisition of data, drafting the manuscript, given final approval of the version to be published

A.A, B.A: critical revision, interpretation of data, given final approval of the version to be published

Authors' information

NR: Specialist in General Surgery, University of Milan.

CR: Specialist in General Surgery, Cardinale Ascalesi Hospital of Naples.

GP: Resident in Geriatrics at University Federico II of Naples.

SA: Specialist in Plastic Surgery, Second University of Naples.

RC: doctoral fellow in surgery at University Federico II in Naples.

MD: Aggregate Professor of Surgery at University "Federico II" of Naples.

AA: Specialist in General Surgery, University Federico II of Naples.

BA: Associate Professor of Surgery at University "Federico II" of Naples.