Annals of Oncology 18: 288–292, 2007
Published online 6 November 2006
Breast cancer in Hodgkin’s disease and non-Hodgkin’s
G. Sanna1*, K. Lorizzo1, N. Rotmensz2, V. Bagnardi2,4, S. Cinieri3, M. Colleoni1, F. Nole `1&
1European Institute of Oncology, Medical Oncology;2European Institute of Oncology, Epidemiology and Biostatistics;3European Institute of Oncology, Haematology;
4Department of Statistics, University of Milan-Bicocca, Milan, Italy
Received 20 June 2006; revised 15 September 2006; accepted 18 September 2006
Background: Better therapeutic approaches for patients with Hodgkin’s disease (HD) and non-Hodgkin’s
lymphomas (NHL) resulted in high cure rates, at cost of serious late side effects. Second primary tumours are
a major concern for long-term survivors, and breast cancer (BC) is the most common solid tumour among
women treated for HD.
Materials and methods: Fifty-three women treated for primary BC with previous history of malignant lymphoma
were identified in our institution, 35 with HD (66%), 18 (34%) with NHL. A comparison group was randomly selected
from our database matching for each patient with previous lymphoma, two patients with primary BC (rate 1 : 2) for
age, stage (pathological tumour size [pT] status and nodal status), year of diagnosis, and estrogen and progesterone
status (positive versus negative). The primary end points were disease-free survival (DFS) and overall survival (OS).
Results: The two groups of patients were compared for biological features: histopathological diagnosis, grading,
lymphatic invasion, c-erbB2 overexpression, and Ki-67. Considering these variables, no significant differences were
observed between the two groups with the exception of Ki-67, which was found higher in those with previous HD or
NHL (65% versus 49%, respectively, P = 0.0526, borderline significant). Comparing the two groups for treatment
approach, no differences were found for surgical and medical therapy (endocrine therapy and chemotherapy).
However, regarding patients with node-positive disease (14 versus 35 patients), five patients in the lymphoma group
(36%), compared with 24 (69%) in the matched group received anthracycline-based therapy (P = 0.0345). As
expected, radiotherapy was used very differently in the two groups, with 36% of patients in the study group
undergoing intraoperative radiotherapy with electrons versus 10% in the control group (P = 0.0001). Five-year
DFS was 54.5% for the study cohort compared with 91% for controls (P < 0.0001). Five-year OS percentages
were also statistically different (86.6% and 98.6%, respectively, P = 0.031).
Conclusions: Previous history of malignant lymphoma is a negative prognostic factor for women diagnosed
subsequently with BC. Some undertreatment of women with the latter might be hypothesised as the reason for the
worse outcome. Influence of other variables, like previous exposure to cytotoxics, or some unknown biological
features related to the previous disease and treatment, should still be investigated in the attempt to improve the dire
outcome of these patients.
Key words: breast cancer, Hodgkin’s disease, non-Hodgkin’s lymphoma
Prolonged disease-free survival (DFS) is observed in up to 90%
of patients presenting with early stage Hodgkin’s disease (HD)
, resulting in a large number of long-term survivors, at risk
for serious late effects of therapy. Second cancers are currently
the primary cause of mortality in these patients [2, 3], with
breast cancer (BC) being the most common solid tumour
among women [4, 5]. Current treatment of HD involves
multiagent chemotherapy associated with limited field
radiotherapy for some patients. However, until recently, mantle
radiotherapy was a standard regimen for patients with
supradiaphragmatic HD [6, 7].
It is widely accepted that irradiation is the major risk factor
for second solid tumours, especially in younger patients [8, 9].
BC is the major concern in women treated with mantle
It is also noteworthy that cumulative absolute risk
increased with age, time since HD diagnosis, and radiation
dose . However, significantly reduced risk of breast
tumours has been shown repeatedly in women after HD treated
with chemotherapy which included alkylating agents, the effect
was greater with an increasing number of courses and was
possibly related to cytotoxics-induced ovarian function
*Correspondence to: Dr G. Sanna, Department of Medicine, Unit for Medical Care,
European Institute of Oncology, Via Ripamonti 435, 20121 Milan, Italy.
Tel: +39 02574 89460; Fax: +39 02574 89457; E-mail: firstname.lastname@example.org
ª 2006 European Society for Medical Oncology
by guest on June 1, 2013
The incidence of non-Hodgkin’s lymphoma (NHL) has
increased during the past 40 years in most Western countries
[18, 19]. Life expectancy of patients with NHL has improved,
result of better treatments, thus increasing the risk of second
malignancies in long-term survivors . In this population,
information is scarce on second malignancies in general, and on
BC in particular.
In several NHL cohorts, a reduction in BC risk was observed.
This was described as statistically significant only in a few
studies [21–26]. As previously reported, drugs commonly used
also in NHL can lead to ovarian suppression, with an endocrine
effect in the development of breast tumours .
Most of the studies conducted among long-term survivors
after HD and NHL described the relative risk of developing
second cancers after multimodal treatments. The estimated
actuarial incidence of any second neoplasm 15 years after the
diagnosis of HD was 7.0% (95% CI, 5.2 to 8.8% .
In our study, we identified patients who were referred to our
institution for treatment of breast with the history of treated and
cured malignant lymphoma.
With the aim to better understand the features of BC in HD
and NHL survivors, choice of procedures of care and related
prognosis, we evaluated features of BC in HD and NHL
survivors in comparison with BC in a matched control group of
patients selected among women referred to the same institute.
materials and methods
From February 1997 to September 2005, 53 patients with a history of
lymphoma werereferred to our institute for primary BC. Thirty-five patients
had had a previous diagnosis of HD (66%) and 18 (34%) of NHL were
treated to complete remission of the disease.
All records were reviewed retrospectively.
The patients in the control group were selected from all BC women
undergone surgery during the same period in the same institution. For
each case, we selected two matched patients who did not have a previous
The variables used to make the randomly assigned matches were as
• Age (within 5 years)
• Year of diagnosis (within 2 years)
• Tumours size
• Nodal status 0, 1–3, >3 involved nodes
• Steroid hormone receptors [estrogen receptor (ER) and progesterone
receptor (PgR)] (positive versus negative). An immunohistochemical
staining in at least 10% of tumour cells was considered positive.
If an exact match was not possible on all the five variables, we relaxed the
criteria to only four, attempting to select a comparison patient with a less
favourable prognosis (more positive nodes, bigger tumour size, negative
receptors, and younger age at diagnosis). For two patients, we were able to
match only one woman, leading to a comparison group of 103 patients.
Events were retrospectively identified from routine follow-up data. In
case of unavailability of a clinical examination during the time frame of the
study conduct, the patient was contacted by telephone. If death occurred,
the date was ascertained by the registry office.
The chi-square test was used to assess differences between the study group
and the comparison group in the distribution of prognostic variables and
The primary end points were DFS and overall survival (OS).
DFSwas calculated from the date of surgeryto any relapse, theappearance
of a second primary cancer, or death, whichever occurred first.
OS was defined as the time interval from the date of surgery to death from
Survival curves for study and comparison groups were estimated using
the Kaplan–Meier method . The log-rank test was used to assess the
survival difference between the two groups. A multivariate Cox proportional
hazards model  was fitted to assess the independent prognostic
significance of a previous lymphoma on DFS, controlling for matching
variables and prognostic factors differently distributed between the
All analyses were carried out with the SAS software (SAS Institute, Cary,
NC). All tests were two sided.
patient characteristics (study group)
Median age at diagnosis of HD was 22 years (range 13–49) and
the mean interval to BC diagnosis was 19 years (range 5–46).
For women with previous NHL, median age at diagnosis of
lymphoma was 46 years (18–73) and the median time to BC
occurrence was of 8.5 years (range 0–23).
Treatment of lymphomas consisted of radiotherapy alone,
chemotherapy alone, or combined chemoradiotherapy.
Among patients with previous HD, 11 patients received
only radiotherapy (31%), two patients chemotherapy (6%),
and 22 patients (63%) a multimodality approach.
In the group of NHL, two women (12%) underwent
radiotherapy, six (38%), chemotherapy, and the majority (eight
patients, 50%) a combined treatment. After lymphoma
diagnosis, 21 patients (40%) had one or more pregnancies,
revealing that at least in these women ovarian function was
maintained despite treatments.
Surgery was predominantly conservative, with 18 (47%)
patients undergoing quadrantectomy (QUAD) plus
intraoperative radiotherapy with electrons (ELIOT), 15 patients
lumpectomy plus complementary external beam irradiation,
and five patients QUAD without complementary radiotherapy.
Mastectomy was carried out in 14 patients, with one case of
nipple-sparing mastectomy and ELIOT.
Previous radiotherapy field influenced the subsequent local
treatment of BC; patients who did not receive radiotherapy for
lymphomas underwent more frequently conventional
radiotherapy for BC (62%), compared with women who did
carry out previous radiotherapy (24%). In the latter subgroup,
the majority of patients received ELIOT.
comparison with the matched group
The matched groups of patients were compared for different
features: familiarity, medical treatment, surgical treatment,
histopathological diagnosis, grading, lymphatic invasion,
c-erbB2 overexpression, and Ki-67 (Table 1).
Most of the tumours were ER/PgR positive (72% in the study
versus 77% in the control group), pT1 tumours at diagnosis
(70% versus 74%), and nodal negative (55% versus 55%).
Considering biological variables, no significant differences
were found between the two groups with the exception of
Annals of Oncology
Volume 18 | No. 2 | February 2007 doi:10.1093/annonc/mdl399 | 289
by guest on June 1, 2013
proliferation index (Ki-67) which was found higher in the study
group (P = 0.0526).
Regarding BC treatment, we stratified patients for age (£40
years and >40 years) and no differences were observed in the
surgical and medical approaches (chemotherapy and hormonal
In the subgroup of patients with node-positive disease (14
versus 35 patients), five women out of 14 in the study group
(36%), compared with 24 out of 35 (69%) in the matched
one, however, received anthracycline-based therapy
(P = 0.0345).
Radiotherapy was used very differently, with 36% of patients
in the study group receiving ELIOT versus 10% in the control
group (P = 0.0001).
Follow-up data are available for 52 patients in the lymphoma
group and for 103 patients in the control group.
The median follow-up from initial BC diagnosis was 41
months (range 1–101).
We observed 15 events in the lymphoma cohort (29%),
compared with seven in the matched one (7%) with a 5-year
DFS of 54.5% and 91%, respectively (P < 0.0001, Figure 1). In
the study group, three patients experienced locoregional events
(second BC or local relapse), six cases (50%) distant metastasis,
and three cases second primary carcinomas other than breast
carcinoma. In the control group, three locoregional relapse
(controlateral or ipsilateral breast tumour), one case of distant
metastases (20%), and one case of second primary carcinoma
The Cox proportional hazards regression model, controlling
for matching variables and proliferation index, yielded a hazard
ratio of 9.4 (95% CI 3.0–29.1) for the study group compared to
the matched group.
Six patients died in the lymphoma cohort, four due to BC
and two from unknown causes. In the matched group, one
patient died for disease progression and one for other causes.
Five-year OS was also significantly different (86.6% versus
98.6%, respectively, P = 0.031, Figure 2).
Better therapeutic approach in the treatment of patients with
HD and NHL have led to high cure rate, with serious late effects
of therapy, in particular second primary tumours, being a major
concern in long-term survivors.
Several studies have reported an increased risk of
development of BC in women with previous diagnosis of HD.
For an HD survivor who was treated at an age of 25 years with
a chest irradiation dose of at least 40 Gy without alkylating
agents, estimated cumulative risk of BC by age 35, 45, and 55
years were 1.4%, 11.1%, and 29%, respectively . Assessment
of late effects in a cohort of female HD patients treated with
mantle radiotherapy identified from a database concerning BC
abnormalities in tissues within radiotherapy field .
Multiagent chemotherapy with alkylating drugs in HD and
NHL apparently protects from BC, possibly related to
Table 1. Characteristics of patients with previous diagnosis of lymphoma
(study group) and their comparison group (no matching variables)
(n = 53)
(n = 103)
12 243648 6072 8496
No. at risk
Disease Free Survival
Figure 1. Disease-free survival of patients from time of breast cancer
Annals of Oncology
290 | Sanna et al.Volume 18|No. 2|February 2007
by guest on June 1, 2013
cytotoxics-induced ovarian function suppression in young
Up to date, the majority of retrospective studies conducted
among long-term survivors after HD and NHL were designed to
results may be useful in defining specific guidelines of follow-up,
leading eventually to secondary prevention (early diagnosis). A
recent work concerning BC screening in women surviving HD
indicates that providing risk information may encourage cancer
survivors to take health preventive actions . In patients
treated for HD, breast cancer was the most common solid
with an estimated actuarial incidence in women that
approached 35% (95% CI, 17.4 to 52.6%) by 40 years of age .
We conducted a retrospective study with the aim of defining
clinical history, pathological features, and prognosis of BC
arising in patients with previous lymphoma.
The primary end points were DFS and OS.
Evaluating the biological characteristics of the tumour, only
the proliferation index was found to be higher in the study
group compared with the control group (Ki-67 ‡20% was 65%
versus 49%, with chi-square P value of 0.0526, borderline
significant). We do not know how this observation should be
interpreted, and may be simply related to constitutive
aggressiveness of BC developing in lymphoma patients.
As expected, radiotherapy was used very differently in the two
groups, related to previous field irradiation. The incidence of
local relapse is under 5% in the lymphoma cohort indicating
that conservative surgery plus ELIOT radiotherapy may be
a valid alternative to radical mastectomy. Recently, ELIOT has
been described as a new option for early BC patients previously
treated for HD .
On the other side, no significant differences were found in
systemic therapies (rate of patients receiving neo-adjuvant and
adjuvant chemotherapy, endocrine therapy, and
immunotherapy) and surgical treatments.
However, despite anthracycline-based therapy being the
standard adjuvant option for patients with nodal involvement
[32, 33], only five patients out of 14 in the study group (36%),
compared with 24 out of 35 (69%) in the comparison, one
received anthracycline-containing regimens (P = 0.0345).
Considering the DFS, we found a high statistical significant
difference between the two cohorts (5-year DFS 54.5% and
91%, respectively, with a log-rank P < 0.0001), with a particular
higher incidence of distant metastases in the lymphoma group
(six events versus one). Despite different initial therapies for
HD and NHL, the DFS was similar in these two groups (5-year
DFS: 50.2% versus 63.5%, respectively, P = 0.9016).
Five-year OS percentage was also significantly different
(86.6% versus 98.6%, respectively, P = 0.0031).
These results indicate that previous history of malignant
lymphoma is a negative prognostic factor for women diagnosed
subsequently with BC. The reduced use of anthracylines in the
adjuvant setting might be hypothesised as the reason for the
worse outcome. In addition, even the presence of higher grades
(though not significant) might account for the poorer prognosis
of the lymphoma cohort. The vast majority of women have
already undergone multiagent systemic chemotherapy and/or
chest radiotherapy, eventually leading to accumulation of
genetic damage that may determine resistance to further
treatments. In these patients, genetic factors and eventually
differences in the immunitary status might also be considered.
Influence of other variables, or some unknown biological
features related to the previous disease and treatment, should
still be investigated in an attempt to improve the dire outcome
of these patients.
1. Henry-Amar M, Joly F. Late complications after Hodgkin’s disease. Ann Oncol
1996; 7 (Suppl 4): 115–126.
2. Hoppe RT. Hodgkin disease: complications of therapy and excess mortality.
Ann Oncol 1997; 8 (Suppl 1): 115–118.
3. Aleman BMP, van de Belt-Dusebout AW, Klokman WJ et al. Long-term cause-
specific mortality of patients treated for Hodgkin’s disease. J Clin Oncol 2003;
4. Dores GM, Metayer C, Curtis RE et al. Second malignant neoplasms among long-
term survivors of Hodgkin’s disease: a population-based evaluation over 25
years. J Clin Oncol 2002; 20: 3484–3494.
5. Henry-Amar M. Second cancer after the treatment of Hodgkin’s disease: a
report from the International Database on Hodgkin’s disease. Ann Oncol 1992;
6. Deniz K, O’ Mahony S, Ross G et al. Breast cancer in women after treatment for
Hodgkin’s disease. Lancet Oncol 2003; 4: 207–214.
7. Horwich A, Swerdlow AJ. Second primary breast cancer after Hodgkin’s disease.
Br J Cancer 2004; 90: 294–298.
8. Bathia S, Robison LL, Oberlin O et al. Breast cancer and other second neoplasms
after childhood Hodgkin’s disease. N Engl J Med 1996; 334: 745–751.
9. Hancock SL, Hoppe RT. Breast cancer after treatment for Hodgkin’s disease.
J Natl Cancer Inst 1993; 85: 25–31.
10. Swerdlow AJ, Barber JA, Hudson GV et al. Risk of second malignancies after
Hodgkin’s disease in a collaborative British cohort: the relation to age at
treatment. J Clin Oncol 2000; 18: 498–509.
11. Kenney LB, Yasui Y, Inskip PD et al. Breast cancer after childhood cancer: a report
from the Childhood Cancer Survivor Study. Ann Intern Med 2004; 141: 590–597.
12. Travis LB, Hill DA, Dores GM et al. Breast cancer following radiotherapy and
chemotherapy among women with Hodgkin’s disease. JAMA 2003; 290:
13. Janjan NA, Wilson JF, Gillin N et al. Mammary carcinoma developing after
radiotherapy and chemotherapy for Hodgkin’s disease. Cancer 1988; 61:
24 364860 7284 96
No. at risk
Figure 2. Overall survival of patients from time of breast cancer diagnosis.
Annals of Oncology
Volume 18 | No. 2 | February 2007 doi:10.1093/annonc/mdl399 | 291
by guest on June 1, 2013
14. Van Leeuwen FE, Chorus AMJ, van den Belt-Dusebout EHM et al. Leukaemia
risk following disease: relation to cumulative dose of alkylating agents, treatment
with teniposide combination, number of episode of chemotherapy and bone
marrow damage. J Clin Oncol 1994; 12 (5): 1063–1073.
15. Aisenber AC, Finkestein DM, Doppke KP et al. High risk of breast cancer after
irradiation of young women with Hodgkin’s disease. Cancer 1997; 79 (6):
16. Travis LB, Hill DA, Dores GM et al. Cumulative absolute breast cancer risk for
young women treated for Hodgkin’s lymphoma. J Natl Cancer Inst 2005; 97 (19):
17. Van Leeuwen FE, Travis LB. Second cancers. In DeVita VT, Hellman S, Rosenberg
SA (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA:
Lippincott Williams & Wilkins 2005; 2575–2602.
18. Swerdlow AJ, dos Santos SI, Doll R. Cancer Incidence and Mortality in England
and Wales: Trends and Risk factors. Oxford, UK: Oxford University Press 2001.
19. Swerdlow AJ. Epidemiology of Hodgkin’s disease and non-Hodgkin’s lymphoma.
Eur J Nucl Med Mol Imaging 2003; 30 (Suppl 1): S3–S12.
20. Leung W, Sandlund JT, Hudson MM et al. Second malignancy after treatment of
childhood non-Hodgkin lymphoma. Cancer 2001; 92: 1959–1966.
21. Greenfield DM, Wright J, Hancock BW et al. High incidence of late effects found
in Hodgkin’s lymphoma survivors following recall for breast cancer screening. Br
J Cancer 2006; 94: 469–472.
22. Travis LB, Curtis RE, Boice JD Jr et al. Second cancers following non-Hodgkin’s
lymphoma. Cancer 1991; 67: 2002–2009.
23. Travis LB, Curtis RE, Glimelius B et al. Second cancers among long-term
survivors of non-Hodgkin’s lymphoma. J Natl Cancer Inst 1993; 85:
24. Brennan P, Coates M, Amstrong B et al. Second primary neoplasms following
non-Hodgkin’s lymphoma in New South Wales, Australia. Br J Cancer 2000; 82:
25. Dong C, Hemminki K. Second primary neoplasms among 53 159
haematolymphoproliferative malignancy patients in Sweden, 1958–1996:
a search for common mechanisms. Br J Cancer 2001; 85: 997–1005.
26. Andre ´ M, Mounier N, Leleu X et al. Second cancers and late toxicities after
treatment of aggressive non-Hodgkin lymphoma with the ACVBP regimen:
a GELA cohort study on 2837 patients. Blood 2004; 103: 1222–1228.
27. Mudie NY, Swerdlow AJ, Higgins CD et al. Risk of second malignancy after
non-Hodgkin’s lymphoma: a British cohort study. JCO 2006; 24: 1568–1574.
28. Kaplan EL, Meier P. Nonparametric estimation from incomplete observation.
J Am Stat Assoc 1958; 53: 457–481.
29. Cox DR. Regression models and life tables (with distribution). J R Stat Soc B
1972; 34: 187–220.
30. Bool JR, Stewart SL, Hancock SL. Breast cancer screening in women surviving
Hodgkin disease. Am J Clin Oncol 2006; 29 (3): 258–266.
31. Intra M, Gentilini O, Veronesi P et al. A new option for early breast cancer
patients previously irradiated for Hodgkin’s disease: intraoperative radiotherapy
with electrons (ELIOT). Breast Cancer Res 2005; 7 (5): R828–R832.
32. Levine MN, Pritchard KI, Bramwell VHC et al. A randomized trial comparing CEF
to CMF in premenopausal women with node positive breast cancer: update of
NCIC CTG MA.5. Breast Cancer Res Treat 2002; 76 (Suppl 1): 335.
33. French Adjuvant Study Group. Benefit of a high-dose epirubicin regimen in
adjuvant chemotherapy for node-positive beast cancer patients with poor
prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05
randomized trial. J Clin Oncol 2001; 19: 602–611.
Annals of Oncology
292 | Sanna et al.Volume 18|No. 2|February 2007
by guest on June 1, 2013