Secondary malignancies are new cancers occurring in patients previously treated with radiation or chemotherapy for a primary tumor. Secondary cancers are not related to the primary tumor, and may develop months or years after cancer treatment: they are usually a result of the first cancer therapy. Chemotherapy and radiotherapy may increase the risk of second cancers, such as skin tumors (basal or squamous cell carcinoma) or acute leukemia.
A patient with B-lymphoma and a patient with multiple myeloma, previously treated for breast cancer, are presented.
We report the cases of 2 patients treated with adjuvant therapy for breast cancer who developed secondary bone marrow malignancies 15 years after primary treatment.
By literature review, these 2 cases do not support the relationship between primary tumor treatment and secondary cancer, but strongly suggest the need for histologic samples when bone metastasis occurred after years from diagnosis of breast cancer. In this setting, the oncologist should take into account a secondary bone marrow tumor before starting treatment for breast cancer.
Tumori 2016; 102(Suppl. 2): e29 - e31
Article Type: CASE REPORT
AuthorsDavid Rossi, Donatella Sarti, Lara Malerba, Silvia Tommasoni, Giuseppe Visani, Angelo Martignetti, Giammaria Fiorentini
- • Accepted on 08/02/2016
- • Available online on 14/03/2016
- • Published online on 11/11/2016
This article is available as full text PDF.
Adjuvant therapies for early-stage breast cancer are anthracyclines (epirubicin and doxorubicin), alkylating agents (cyclophosphamide), antimetabolites (methotrexate and 5-FU), and taxanes (docetaxel and paclitaxel) (1). These drugs induce fatigue, dental problems, xerostomia, diabetes, endocrine changes, anemia, decreased muscle mass, depression, weight gain, alopecia, hypothyroidism, incontinence, infertility, lymphedema, neuropathy (tingling or burning feeling in hands/feet), organ damage (heart, lungs, liver, or kidneys), and osteoporosis (2). Chemotherapy and radiotherapy also have long-term effects, and some patients may develop secondary lymphoma as a result of their primary tumor treatments (3). Nevertheless, there are a number of reports describing the relationship between anthracyclines and increased risk of acute myeloid leukemia in women with breast cancer (4, 5). In addition, by a PubMed search, we found few reports concerning patients with multiple myeloma mimicking bone metastases of breast cancer (6, 7) or association of vertebral breast cancer metastasis and multiple myeloma (8).
In this article, we report the cases of 2 women with diagnosis of breast cancer who developed bone marrow malignancies (multiple myeloma and B-lymphoma) after years from adjuvant chemotherapy. Implications for clinical practice are discussed.
The first report concerns a woman of 59 years with ductal infiltrating breast cancer (pT1c N0 M0); estrogen and progesterone receptors and Her2 status were negative and Mib-1 was high. After left quadrantectomy, the patient was treated with CMF for 6 cycles (CTX 600 mg/mq, MTX 40 mg/mq, and 5-FU 600 mg/mq). Three years later, the patient developed a ductal infiltrating breast carcinoma on the right breast (estrogen and progesterone receptors were negative and Her2 was not amplified). After right quadrantectomy, the patient was treated with adjuvant AC for 4 cycles (adriamycin 60 mg/mq, CTX 600 mg/mq) and after 10 years follow-up was stopped.
Fifteen years after AC, the patient reported bone pain and weight loss. Clinical and instrumental monitoring, including bone scan, thorax x-rays, abdominal echography, mammography, and breast echography, were negative for secondary cancer. Due to negative bone scan, a bone marrow biopsy was performed that showed lymphocytes of small to middle size related to B indolent lymphoma (CD20+, Bcl2+, CD5-, CD23-, Cyclin d1-, CD11c, Annexin−, CD10-, Bcl6-). Chemotherapy for lymphoma was started with good disease remission.
The second report concerns a woman of 51 years with lobular infiltrating breast cancer (pT1cN0M0, G2, positive estrogen and progesterone receptors, negative Her2 status). After right quadrantectomy and lymphadenectomy, the patient was treated with adjuvant CMF for 6 cycles followed by radiotherapy; adjuvant endocrine therapy with tamoxifen was started for 5 years. After 15 years, the patient reported increasing bone pain and a 99TC scan showed lesions in sternum, collarbones, and spine (a vertebroplasty was performed). The histologic specimen of vertebroplasty biopsy did not show neoplastic proliferation of breast cancer but bone scan images induced the oncologist to start a first endocrine line therapy with letrozole and zoledronic acid. The next year, the patient again reported bone pain, with evidence on 99TC scan of disease progression, and a second-line therapy with fulvestrant was started (zoledronic acid was stopped after 4 months for creatinine increase). Due to unclear worsening of renal function, a new disease staging was performed with total body computed tomography scan, magnetic resonance imaging, and positron emission tomography scan, which showed a number of lesions suspected for multiple myeloma in spine, sternum, sacral wings, and femurs. Histologic specimen of bone marrow biopsy on sternum confirmed multiple myeloma, with presence of 70% monotypic k plasma cells and grade 1 fibrosis. The patient was admitted to the hematology department for treatment.
Breast cancer survival has significantly improved in recent years with new chemotherapy treatments (especially in patients with HER2 amplified). However, chemotherapy agents are related to a higher risk of bone marrow tumors that may appear decades after primary treatment (4). The earliest report of the association between hematologic malignancies and solid tumors appeared in the late 1950s (9). However, the link between chemotherapy and predisposition to secondary cancer was not made until 2 decades later, after a follow-up study (10) of over 400 cases of Hodgkin lymphoma, in which ~3% of patients developed secondary cancer. This study raised the problem about the role of chemoradiotherapy in the induction of these tumors. The availability of data on follow-up of almost 3 decades has shown that secondary cancers may develop in a number of patients.
Although therapy-related acute myeloid leukemia is the most commonly occurring hematologic malignancy, review of these data identified a consistent excess of B-lymphoma in the first 10 years of follow-up and an increasing incidence after that. In the study of Krishnan and Morgan (3), data of 207,834 patients were included; about 6,915 secondary cancers were recorded. Of these, non-Hodgkin lymphoma was diagnosed in 425 patients with a weighted average of 5% (range 0.88%-16.8%). This is in agreement with most reports, where the incidence rates varied from 0% to 5.9% (11). The majority of primary tumors in these patients was Hodgkin lymphoma; typically, non-Hodgkin lymphoma develops after the first 5 years of initial therapy for primary cancer, and up to 10-17 years after. These tumors often have an extranodal presentation mainly involving the gastrointestinal tract and central nervous system (most are B-lymphoma but T-lymphoma has also been reported). In the same article, data documented that non-Hodgkin lymphoma occurred in 12 out of 493 patients with secondary cancer when the primary tumor was breast carcinoma. However, the percentage of 0.16% and a relative risk of 1.19 (0.61-2.08) does not seem to demonstrate a clear relationship between primary cancer and non-Hodgkin lymphoma (no information about chemotherapy treatment is available).
Unlike lymphoma, the correlation between secondary acute leukemia and active treatments for primary solid tumors is well-known. Adjuvant chemotherapy, particularly alkylating agents and anthracyclines (cyclophosphamide, doxorubicin, and epirubicin), are associated with acute myeloid leukemia (AML), especially for patients treated with full-dose epirubicin (100 mg/m²) (5). In the prospective analysis of the phase III Belgian trial, which compared 3 different schedules in early breast cancer (epirubicin and cyclophosphamide full-dose, epirubicin/cyclophosphamide standard dose, and classical CMF), 3 cases of AML were recorded in the arm with full-dose EC and no case in standard dose EC and CMF. The relationship between anthracyclines dose and induction of acute leukemia was confirmed in another trial by Praga et al (4): patients with standard cumulative dose of adjuvant epirubicin (≤720 mg/m²) and cyclophosphamide (≤6,300 mg/m²) had a lower probability of secondary leukemia than patients treated with higher cumulative dose.
The relationship between CMF regimens and secondary malignancies has been studied by a Milan group (12), which reported data on 2,465 patients treated from 1973 to 1990. Compared to the general female population, the relative risk following CMF-based adjuvant chemotherapy was 1.29; however, 3 patients developed acute nonlymphocytic leukemia (cumulative risk 0.23% ± 0.15%; relative risk 2.3). The aforementioned trials demonstrate that acute leukemia, due to cancer treatment, is still a concern for breast cancer survivors, while scarce data are available for lymphoma.
In this article, we reported one case of B-lymphoma and a case of multiple myeloma developing after 15 years from adjuvant chemotherapy with CMF/AC and CMF, respectively. In case 1, the patient reported bone pain; due to negative bone scan, the oncologist decided to perform a biopsy, which revealed B-lymphoma; in case 2, the bone scan was positive, but worsening renal function indicated the need for bone marrow biopsy on sternum, with the finding of multiple myeloma.
By PubMed search, we found a few cases of multiple myeloma masquerading as metastatic breast cancer (6, 7), but no data are available about relationship between myeloma and treatment for primary breast cancer. The cases described by Savage and Garrett (6) concern 2 patients in whom, on the basis of prior therapy for breast cancer 11 and 8 years before and the presence of painful, lytic bone lesions, an initial diagnosis of metastatic breast cancer was made. As a result, one received radiotherapy and in both cases there was a delay in beginning chemotherapy for multiple myeloma.
In another case report published by Tomono et al (7), a patient with a history of early breast cancer with a fracture of the 8 thoracic vertebra, resulting in paraplegia, was treated with radiotherapy; a following bone marrow aspiration and biopsy revealed plasma cell proliferation rather than adenocarcinoma.
In our case report, patient 2 was treated with 2 endocrine lines before worsening of renal function induced the oncologist to perform a bone marrow biopsy: in this patient, bone involvement on 99TC scan seemed to be clear for metastasis of breast cancer. Unlike patient 2, patient 1 reported increasing bone pain without evidence of disease progression on bone scan. On the basis of available data, we cannot conclude that chemotherapy for breast cancer induced secondary hematologic malignancies in these 2 patients but we can underline the need for histologic findings when bone metastasis occurs years after a diagnosis of primary tumor.
When disease progression is limited to bone and without a histologic sample, the risk in treating a patient for breast cancer is losing time for treating potentially curable malignancies. Therefore, we may conclude that 1) in patients with diagnosis of breast cancer and bone scan positive for metastasis, the risk of secondary malignancies, especially of multiple myeloma, should be taken into account even many years after adjuvant treatment when disease progression is limited to bone; 2) other findings (such as worsening renal function) should induce the oncologist to perform bone marrow aspiration or biopsy before starting chemotherapy and/or endocrine therapy in these patients.
The authors thank the patients for their participation.
Martín M Lluch A Seguí MA et al. Toxicity and health-related quality of life in breast cancer patients receiving adjuvant docetaxel, doxorubicin, cyclophosphamide (TAC) or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC): impact of adding primary prophylactic granulocyte-colony stimulating factor to the TAC regimen. 2006 17 8 1205 1212
Bernard-Marty C Mano M Paesmans M et al. Second malignancies following adjuvant chemotherapy: 6-year results from a Belgian randomized study comparing cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with an anthracycline-based regimen in adjuvant treatment of node-positive breast cancer patients. 2003 14 5 693 698
- Rossi, David [PubMed] [Google Scholar] 1, * Corresponding Author (firstname.lastname@example.org)
- Sarti, Donatella [PubMed] [Google Scholar] 1
- Malerba, Lara [PubMed] [Google Scholar] 2
- Tommasoni, Silvia [PubMed] [Google Scholar] 3
- Visani, Giuseppe [PubMed] [Google Scholar] 2
- Martignetti, Angelo [PubMed] [Google Scholar] 4
- Fiorentini, Giammaria [PubMed] [Google Scholar] 1
Oncology Unit, Azienda Ospedaliera “Ospedali Riuniti Marche Nord,” Pesaro - Italy
Hematology Unit, Azienda Ospedaliera “Ospedali Riuniti Marche Nord,” Pesaro - Italy
Pathology Department, Azienda Ospedaliera “Ospedali Riuniti Marche Nord,” Pesaro - Italy
Oncology Department, USL7 Siena, Alta val d’Elsa Hospital, Poggibonsi (Siena) - Italy