The Breast 34 (2017) 53e57

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The Breast
journal homepage: www.elsevier.com/brst

Original article

Follow-up of patients with localized breast cancer and first indicators

of advanced breast cancer recurrence: A retrospective study
lia Meurisse c, Xavier Pivot a, Fre
Julien Viot a, Martin Bachour b, Aure ric Fiteni a, c, *
de
a
University Hospital of Besançon, Department of Medical Oncology, France
b
Bregille Reeducation Center, Besançon, France
c
University Hospital of Besançon, Methodology and Quality of Life in Oncology Unit, France

a r t i c l e i n f o a b s t r a c t

Article history: We conducted a retrospective study to assess the follow-up of patients with localized breast cancer and
Received 20 January 2017 the first indicators of advanced breast cancer recurrence.
Received in revised form All patients with advanced breast cancer recurrence treated between January 2010 and June 2016 in
9 May 2017
our institution were registered. Among these patients, 303 patients initially treated for early breast
Accepted 10 May 2017
cancer with curative intent were identified.
After initial curative treatment, follow-up involved the oncologist, the general practitioner and the
gynecologist in 68.0%, 48.9% and 19.1% of cases, respectively. The median DFI was 4 years for luminal A,
Keywords:
Breast cancer
3.8 years for luminal B, 3.7 years for HER2-positive and 1.5 years for TNBC (p ¼ 0.07). Breast cancer tumor
Diagnosis marker was prescribed for 164 patients (54.1%). No difference in terms of follow-up was observed ac-
Follow-up cording to the molecular subtype. Symptoms were the primary indicator of relapse for 143 patients
Recurrence (47.2%). Breast cancer recurrence was discovered by CA 15.3 elevation in 57 patients (18.8%) and by CAE
elevation in 3 patients (1%). The rate of relapse diagnosed by elevation of CA 15.3 or CAE was not sta-
tistically associated with the molecular subtype (p ¼ 0.65). Luminal A cases showed a significantly higher
rate of bone metastases (p ¼ 0.0003). TNBC cases showed a significantly higher rate of local recurrence
(p ¼ 0.002) and a borderline statistical significant higher rate of lung/pleural metastases (p ¼ 0.07).
Follow-up recommendations could be adapted in clinical practice according to the molecular subtype.
General practitioners should be more involved by the specialists in breast cancer follow-up.
© 2017 Elsevier Ltd. All rights reserved.

1. Introduction in costs has been observed between different regimens, with no

Ten-year survival of breast cancer exceeds 70% in most European
regions, with 89% survival for local and 62% for regional disease [1].
The aims of follow-up are to detect early recurrences and to eval-
uate and treat therapy-related complications. International or na-
tional organizations (American Society of Clinical Oncology (ASCO),
European Society for Medical Oncology (ESMO), Haute Autorite  de
Sante) have published evidence-based clinical practice guidelines
on breast cancer follow-up and management in asymptomatic
patients after primary, curative therapy [2e4]. Nevertheless, vari-
ations in practice exist and have different cost implications. In the
follow-up of patients with localized breast cancer, a large difference
* Corresponding author. University Hospital of Besançon, Department of Medical
Oncology, 3 boulevard Fleming, 25000, Besançon, France.
E-mail address: fredericfiteni@gmail.com (F. Fiteni).
change in health outcomes expected. De Bock et al. conducted a
meta-analysis of 12 studies which assessed the proportion of iso-
lated locoregional recurrences diagnosed during routine visits or
routine tests in asymptomatic patients compared with the pro-
portion of isolated locoregional recurrences in symptomatic pa-
tients. In these 12 studies, 40% of patients had been diagnosed as
having no symptoms and 18% as having symptoms [5]. In a retro-
spective study conducted by Pivot et al. of 1145 patients with
metastatic breast cancer, symptoms were the primary indicator of
relapse in 57.6% of patients [6]. Moreover, the annual hazard of
recurrence peaks in the second year after diagnosis, but remains at
2%e5% in years 5e20 and many studies have demonstrated that the
time and the sites of recurrence depend on the breast cancer mo-
lecular subtype [7e10].
In this retrospective study, we describe the follow-up of patients
with localized breast cancer and the first indicators of advanced
recurrence.

http://dx.doi.org/10.1016/j.breast.2017.05.005
0960-9776/© 2017 Elsevier Ltd. All rights reserved.
54 J. Viot et al. / The Breast 34 (2017) 53e57

2. Methods and proportions for categorical variables. We compared pro-

portions using a chi-squared test, or Fisher's exact test where
2.1. Study population appropriate. A p-value of 0.05 or lower was considered statistically
significant. Disease-free interval (DFI) was defined as the time be-
Patients were identified using a computerized software for tween the primary breast cancer and the local or distant recur-
chemotherapy prescriptions that transfers prescriptions from the rence. An ANOVA regression was performed to analyze the
medical office to the centralized pharmaceutical unit in charge of association between the DFI and the breast cancer subtype. All
antineoplastic drugs preparation BPC (acronym for Bonne Pratique analyses were performed using SAS software, Version 9.3 (SAS
de Chimiothe rapie). Through this database, all patients with Institute).
advanced breast cancer (ABC) (i.e. with any unresectable recur-
rence) treated between January 2010 and June 2016 in the uni-
3. Results
versity hospital of Besançon were registered. Among these patients,
only those who were initially treated for early breast cancer with
3.1. Clinicopathological features
curative intent were identified for follow-up screening. Our study
population was divided into four subtypes: luminal A (estrogen
Among 574 patients with ABC, 303 patients were initially
receptor (ER) þ and/or progesterone receptor (PR) > 20%, human
treated for localized breast cancer with curative intent. Mean age at
epidermal growth factor receptor type 2 (HER2) - and Ki-67 < 10%);
diagnosis of localized breast cancer was 52 (range, 27e87). Among
luminal B (ER þ and/or PR  20%, HER2 - and Ki-67  10%; HER2-
the 303 patients, 95 (31.4%) were luminal A, 32 (9.9%) luminal B, 34
enriched (HER2 þ); and triple-negative breast cancer (TNBC) (ER
(11.2%) were HER2 þ, 35 (11.6%) were TNBC and 107 (35.3%) were
-, PR - and HER2 -) [2].
unknown. The characteristics of patients are presented in Table 1.

2.2. Statistical analysis 3.2. Follow-up

We used the mean and range to analyze continuous variables, After initial curative treatment, follow-up involved the

Table 1
Patients' characteristics.

Characteristics All patients (n ¼ 303) Luminal A (n ¼ 95) Luminal B (n ¼ 32) HER2 þ (n ¼ 34) TNBC (n ¼ 35)

Age at diagnosis, years [mean (range)] 52 (27e87) 52 (27e79) 56 (34e87) 52 (32e87) 51 (31e82)
Type, n (%)
Ductual 199 (65.7) 66 (69.4) 23 (71.9) 30 (88.2) 28 (80)
Lobular 55 (18.2) 23 (24.2) 6 (18.8) 2 (5.9) 3 (8.6)
Unknown 49 (16.2) 6 (6.3) 3 (9.4) 2 (5.9) 4 (11.4)
Tumor size, n (%)
T1 85 (28.1) 31 (32.6) 10 (31.3) 15 (44.1) 8 (22.9)
T2 105 (34.7) 43 (45.3) 15 (46.9) 11 (32.4) 16 (45.7)
T3-T4 26 (8.6) 12 (12.6) 4 (12.5) 1 (2.9) 3 (8.6)
Unknown 87 (28.7) 9 (9.5) 3 (9.4) 7 (20.6) 8 (22.9)
N stage, n (%)
N0 57 (18.8) 13 (13.7) 9 (28.1) 4 (11.8) 10 (28.6)
N1 77 (25.4) 22 (23.2) 6 (18.8) 14 (41.2) 10 (28.6)
N2 46 (15.2) 22 (23.2) 5 (15.6) 6 (17.7) 4 (11.4)
N3 27 (8.9) 11 (11.6) 4 (12.5) 8 (8.8) 5 (14.3)
Unknown 96 (31.7) 27 (28.4) 8 (25) 7 (20.6) 6 (17.1)
Histologic grade, n (%)
I 27 (8.9) 9 (9.5) 1 (3.1) 0 (0) 1 (2.9)
II 124 (40.9) 53 (55.8) 15 (4.7) 13 (38.2) 6 (17.2)
III 67 (22.1) 21 (22.1) 12 (37.5) 16 (47.1) 22 (62.9)
Unknown 85 (28) 12 (12.6) 4 (12.5) 5 (14.7) 6 (17.2)
Local treatment, n (%)
breast conservation 131 (43.2) 29 (30.5) 14 (43.8) 16 (47.1) 24 (68.6)
Mastectomy 153 (50.5) 60 (63.2) 18 (56.3) 13 (38.2) 10 (28.6)
Unknown 19 (6.3) 6 (6.3) 0 5 (14.7) 1 (2.9)
Neoadjuvant chemotherapy, n (%)
Done 65 (21.5) 28 (29.5) 11 (3.6) 9 (26.5) 16 (45.7)
Not done 238 (78.6) 67 (70.5) 21 (65.6) 25 (73.5) 21 (54.3)
Adjuvant chemotherapy, n (%)
Done 168 (55.4) 53 (55.8) 17 (53.1) 23 (67.6) 17 (48.6)
Not done 125 (41.3) 39 (12.9) 14 (43.8) 10 (29.4) 18 (51.4)
Unknown 10 (33) 3 (3.2) 1 (3.1) 1 (2.9) 0
Endocrine therapy, n (%)
Done 209 (69.0) 87 (91.6) 25 (78.1) 17 (50) 0
Not done 83 (27.4) 6 (6.3) 6 (18.8) 16 (47.0) 35 (100)
Radiotherapy, n (%) 11 (3.6) 2 (2.1) 1 (3.1) 1 (2.9) 0
Done 266 (87.8) 85 (89.5) 27 (28.4) 32 (94.1) 33 (94.3)
Not done 25 (8.3) 7 (7.4) 3 (3.2) 1 (2.9) 1 (2.9)
Unknown 12 (4.0) 3 (3.2) 2 (2.1) 1 (2.9) 1 (2.9)
Anti-HER2 therapy, n (%)
Done 0 0 0 26 (76.5) 0
Not done 0 0 0 8 (23.5) 0
 J. Viot et al. / The Breast 34 (2017) 53e57 55

Table 2
Follow-up.

Follow-up All patients (n ¼ 303) Luminal A (n ¼ 95) Luminal B (n ¼ 32) HER2 þ (n ¼ 34) TNBC (n ¼ 35) p-value

Oncologist, n (%) 206 (68.0) 75 (78.9) 23 (71.9) 26 (76.5) 28 (80.0) 0.98

Gynecologist, n (%) 58 (19.1) 22 (23.1) 4 (12.5) 7 (20.6) 7 (20.0) 0.86
General practitioner, n (%) 148 (48.9) 46 (48.4) 16 (50.0) 13 (28.2) 14 (40.0) 0.75
Visits schedule, n (%)
2 times/year 118 (38.9) 52 (54.7) 15 (46.9) 18 (52.9) 17 (48.6)
2 times/year 73 (24.1) 17 (17.9) 6 (18.8) 5 (14.7) 7 (20.0)
<2 times/year 19 (6.3) 3 (3.2) 2 (6.3) 0 1 (2.9) 0.79
Mammography/breast ultrasound, n (%) 200 (66) 73 (76.8) 21 (65.6) 17 (50.0) 22 (62.9) 0.62
Mammography schedule, n (%)
>1 time/year 11 (3.6) 3 (3.2) 2 (6.3) 1 (2.9) 1 (2.9)
1 time/year 165 (54.5) 64 (67.4) 18 (56.3) 15 (44.1) 18 (51.4)
<1 time/year 2 (0.7) 1 (1.1) 0 0 1 (2.9) 0.77
Routine blood tests, n (%) 81 (26.7) 32 (33.7) 9 (28.1) 12 (35.3) 10 (28.6) 0.58
CA 15.3, n (%) 164 (54.1) 64 (67.4) 19 (59.4) 17 (50.0) 17 (48.6) 0.14
CAE, n (%) 27 (8.9) 8 (8.4) 2 (6.3) 3 (34.3) 5 (14.3) 0.68

oncologist, the general practitioner and the gynecologist in 68.0%, Table 4

48.9% and 19.1% of cases, respectively. During the first 5 years, Methods of first recurrence detection in asymptomatic patients.

follow-up visits were performed greater than 2 times per year in
38.9% of cases, 2 times per year in 24.1% of cases and less than 2
times per year in 6.3% of cases (Table 2). Breast examination and
node examination were performed in 72% of cases. Six patients (2%)
were counseled to perform breast self-examination.
Two hundred patients (66%) had mammography and breast
ultrasound during the follow-up and for 165 patients (54.5%) these
imaging studies were performed yearly. Breast magnetic resonance
imaging (MRI) was performed in 8 cases (2.6%). Routine blood tests
were performed in 81 cases (26.7%). Breast cancer tumor marker
was prescribed for 164 patients (54.1%). Among these 164 patients,
CA 15.3 was measured in 164 cases (100%) and CAE in 27 cases
(16.5%) (Table 2).
No difference in terms of follow-up was observed according to
the molecular subtype (Table 2).
3.3. Breast cancer recurrence
The median DFI was 4 years (range: 1.1e15.8) for luminal A, 3.8
years (range: 0.3e32.9) for luminal B, 3.7 years for HER2-positive
(range: 0.1e15.0) and 1.5 years (range: 0.7e12.7) for TNBC
(p ¼ 0.07).
Symptoms were the primary indicator of relapse for 143 pa-
tients (47.2%). Among these patients, bone symptoms, lung symp-
toms, asthenia, abdominal and neurological symptoms were the
first symptoms in 83 (25%), 23 (7.6%), 14 (4.6%), 11 (3.6%) and 9 (3%)
patients, respectively (Table 3).
There were 134 asymptomatic patients (43.6%). Node, chest wall
and breast cancer recurrences were discovered by self or physician
examination in 24 (7.9%), 24 (7.9%), 12 (4.0%), respectively. Breast
cancer recurrence was discovered by CA 15.3 elevation in 57 pa-
tients (18.8%) and by CAE elevation in 3 patients (1%) (Table 4). The
rate of relapse diagnosed by elevation of CA 15.3 or CAE was not
statistically associated with the molecular subtype (p ¼ 0.65).
Table 3
First symptoms of recurrence.
Recurrence detection Symptomatic patients (n ¼ 143)
Bone symptoms 83
Lung symptoms 23
Abdominal 14
Asthenia 11
Neurological Symptoms 9 for women with breast cancer in remission in hospital versus in
Other 3
Recurrence detection Asymptomatic patients (n ¼ 134)
Self or physician examination
Node 24
Chest wall/skin 24
Breast 12
Mammography/breast ultrasound 14
Biological markers elevation
CA 15.3 57
CAE 3
Bone, lung/pleural, liver, chest wall/skin, nodes, breast, central
nervous system metastases were detected in 154 (50.8%), 82
(27.1%), 47 (15.5%), 42 (13.9%), 30 (9.9%), 12 (4.0), 9 (3%) patients,
respectively. Luminal A cases showed a significantly higher rate of
bone metastases (p ¼ 0.003). TNBC cases showed a significantly
higher rate of local recurrence (p ¼ 0.002) and a borderline sta-
tistical significant higher rate of lung/pleural metastases (p ¼ 0.07)
(Table 5).
4. Discussion
Many studies have demonstrated that there is no benefit in
terms of survival, quality of life or cost benefit of an intensive
follow-up with CA 15.3 detection [11e13].
The present study indicates that most patients were seen more
than 2 times per year during the first five years with yearly
mammography regardless of the molecular subtype. These results
are in accordance with the recommendations provided by the Eu-
ropean Society for Medical Oncology (ESMO) and the American
Society of Clinical oncology (ASCO). ESMO recommends regular
visits every 3e4 months in the first 2 years, every 6 months from
years 3e5 and annually thereafter [2]. ASCO recommends physical
examination every 3e6 months for the first 3 years after primary
therapy; every 6e12 months for years 4 and 5; and then annually
[3]. We also demonstrated that CA 15-3 is frequently used for the
early diagnosis of recurrence during the follow-up of patients,
although the guidelines do not recommend it [2,3]. Moreover, in
our study, the general practitioner was involved in the follow-up
for only 48.9% of patients while the Haute Autorite  de Sante  in
France underlines the key role of the general practitioner in breast
cancer follow-up [4]. Furthermore, Grunfeld et al. compared the
time to diagnosis of recurrence and the quality of life of follow up
general practice. General practice follow up is not associated with
56 J. Viot et al. / The Breast 34 (2017) 53e57

Table 5
Sites of relapse.

Sites of recurrence All patients (n ¼ 303) Luminal A (n ¼ 95) Luminal B (n ¼ 32) HER 2 (n ¼ 34) TNBC (n ¼ 35) P value

n (%) n (%) n (%) n (%) n (%)

Bone 154 (50.8) 61 (64.2) 15 (46.9) 14 (41.2) 8 (22.9) 0.003

Lung/pleural 82 (27.1) 19 (20) 9 (28.1) 11 (32.4) 12 (34.3) 0.07
Liver 47 (15.5) 15 (15.8) 6 (18.8) 12 (35.3) 6 (17.1) 0.1
Chest wall/skin 37 (13.9) 10 (10.5) 4 (12.5) 4 (11.8) 13 (37.2) 0.002
Node 30 (9.9) 5 (5.3) 3 (9.4) 2 (5.9) 9 (25.8) 0.2
Breast 12 (4.0) 4 (4.2) 1 (3.1) 2 (5.9) 1 (2.9) 0.3
Central nervous system 9 (3.0) 2 (2.1) 0 2 (5.9) 2 (5.7) 0.5

an increase in time to diagnosis, increase in anxiety, or deteriora-
tion in health related quality of life. They reported that most gen-
eral practitioners wish to follow their patients with breast cancer if
they can work in collaboration with specialty centers [14]. The
National Institute for Health and Clinical Excellence has published a
guideline for general practitioners designed to achieve earlier
detection of cancer in people in the UK by using a symptom-based
approach [15].
Regarding the diagnosis of relapse, the majority of recurrences
detected were symptomatic (bone and lung symptoms being the
two most frequent) which is in concordance with the results from
Pivot et al. [6]. Increased CA 15.3 led to the diagnosis of 18.8% of
recurrences that is concordant with Chourin et al. results (18%) [16].
Nevertheless, in Pivot et al. study, biochemical tests and radiolog-
ical imaging detected only 10% of all relapses [6].
Moreover, different patterns of recurrence were observed across
breast cancer subtypes. A higher incidence of bone metastasis was
observed for patients with luminal A subtype (64.2%). TBNC
showed the highest rate of chest wall/skin and lung/pleural re-
currences, and the lowest rate of bone metastases. In Metzger-Filho
et al. study, luminal B subtypes had higher rates of bone as first
recurrence site than other subtypes (P ¼ 0.005). Visceral recurrence
as the first site was lower for the luminal A subgroup, with similar
incidence among the other subgroups when treated with chemo-
therapy (P ¼ 0.003) [9]. Park et al. showed that luminal A cases
showed the lowest incidence of locoregional (2.4%) and systemic
relapse (10.3%), it frequently recurred in the bones and rarely
metastasized to visceral organs [8]. TNBC frequently presented
with visceral or lung metastases and rarely metastasized to bones
while the HER2 þ subtype frequently metastasized to the central
nervous system.
In terms of timing of recurrence, our analysis shows that re-
currences of TNBC occur earlier than other molecular subtypes and
recurrences for luminal A occur later, which is consistent with the
results of previous studies. Saphner et al. first demonstrated in a
retrospective study in which breast cancer was classified as ER-
positive or ER-negative that the ER-negative recurrences occur
more frequently in early follow-up while the ER-positive re-
currences occur in late follow-up [10]. Park et al. showed a peak of
recurrence for luminal A at 36 months postoperatively, while TNBC
peaked at 12 months [8]. In a retrospective study of 1601 women
with breast cancer, Dent et al. found that for patients with TNBC,
the risk of any recurrence rose sharply, peaked at 1e3 years, and
then dropped quickly thereafter whereas for patients with other
breast cancers, there seemed to be a steady risk of recurrence [17].
Nevertheless, no guideline has been published to adapt the
schedule of follow-up according to the molecular subtype.
In conclusion, the follow-up guidelines are globally adhered to
by physicians, except for the prescription of CA 15.3 measurement.
A prospective study which would compare the standard follow-up
with or without CA 15.3 in terms of disease-free survival or overall
survival could help to address this issue. Moreover, molecular
subtypes influence the patterns of recurrence in terms of localiza-
tion and DFI. A prospective study which would compare adaptive
follow-up according to the subtypes could also be useful. The cost/
efficiency balance should be taken into account in these trials.
Finally, the general practitioners took part in the follow-up for only
half of the patients which seems insufficient. They should be more
involved by the specialists.
Conflict of interest statement
All authors declare no conflict of interest.
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