Breast Cancer and Lymphoma: Key Points to Know

Breast cancer and lymphoma are distinct malignancies, yet research suggests they can sometimes occur together or share underlying biological traits. Understanding their potential connections is important for improving detection and treatment strategies.

While these cancers originate in different tissues—breast tissue for breast cancer and the lymphatic system for lymphoma—overlapping genetic, immunological, and molecular factors may be involved. Exploring these links can provide insight into disease mechanisms and guide more personalized patient care.

Possible Patterns Of Co-Occurrence

Studies indicate that individuals diagnosed with one of these malignancies may have an elevated risk of developing the other. Epidemiological data suggest breast cancer survivors exhibit a higher incidence of lymphoma compared to the general population, and vice versa. A retrospective cohort study published in The Lancet Oncology found that women with a history of breast cancer had a significantly increased likelihood of developing non-Hodgkin lymphoma (NHL) within five years post-diagnosis. Similarly, lymphoma patients, particularly those who underwent radiation therapy, showed a higher-than-expected occurrence of secondary breast cancer.

Cancer treatments themselves may contribute to this pattern. Chemotherapy regimens, particularly those involving alkylating agents such as cyclophosphamide, have been linked to an increased risk of secondary malignancies, including hematologic cancers. Radiation therapy directed at the chest area, commonly used for Hodgkin lymphoma, has been associated with a higher incidence of breast cancer, especially in younger patients treated before age 30. A long-term follow-up study in JAMA Oncology reported that women treated with mantle field radiation for Hodgkin lymphoma had a breast cancer risk nearly 20 times higher than that of the general population, with risk persisting for decades.

Beyond treatment-related factors, shared environmental and lifestyle influences may contribute to the co-occurrence of these cancers. Exposure to carcinogens such as tobacco smoke, industrial chemicals, and endocrine-disrupting compounds has been implicated in both diseases. Chronic inflammation, often driven by obesity or persistent infections, has also been proposed as a contributing factor. A meta-analysis in Cancer Epidemiology, Biomarkers & Prevention found that individuals with elevated body mass index (BMI) had a modestly increased risk of both malignancies, suggesting metabolic and inflammatory pathways may play a role.

Genetic And Molecular Mechanisms

The genetic and molecular landscape of breast cancer and lymphoma reveals overlapping pathways that may contribute to their co-occurrence. Mutations in DNA repair genes, particularly those involved in homologous recombination, have been implicated in both diseases. BRCA1 and BRCA2 mutations, well-known for their role in hereditary breast cancer, have also been linked to hematologic malignancies. A study in Blood found that individuals carrying BRCA1/2 mutations had a higher risk of developing lymphoma, suggesting deficiencies in DNA repair mechanisms may predispose to both solid and hematopoietic cancers. Additionally, TP53 mutations, frequently observed in triple-negative breast cancer, have been linked to aggressive forms of non-Hodgkin lymphoma.

Epigenetic alterations also influence both malignancies by modifying gene expression. Hypermethylation of tumor suppressor genes such as CDKN2A (p16) has been reported in breast cancer and B-cell lymphomas, leading to unchecked cellular proliferation. Histone modifications regulating chromatin accessibility have similarly been implicated, with studies in Nature Genetics identifying aberrant histone methylation patterns in diffuse large B-cell lymphoma (DLBCL) that resemble those in basal-like breast cancer. These findings suggest disruptions in epigenetic regulation may contribute to tumorigenesis in both tissues.

Genomic instability, a hallmark of cancer, is another shared feature. Chromosomal translocations, characteristic of many lymphomas, also appear in certain breast cancer subtypes. MYC rearrangements, commonly associated with Burkitt lymphoma, have been detected in highly proliferative breast tumors. Similarly, HER2 gene amplifications, a defining feature of HER2-positive breast cancer, have been found in some cases of primary mediastinal B-cell lymphoma (PMBCL). Targeted therapies such as trastuzumab, effective in HER2-positive breast cancer, have shown promise in treating lymphomas with similar molecular profiles, supporting the idea that shared genetic drivers may influence treatment response.

Shared Immunological Characteristics

The immune environment plays a complex role in both malignancies. While lymphoma originates from malignant transformations in B or T lymphocytes, breast cancer also interacts with B-cell populations in ways that influence tumor growth. Tumor-infiltrating B cells (TIL-Bs) have been detected in breast tumors, where they can produce cytokines that either enhance or suppress tumor development. A study in Clinical Cancer Research found that in triple-negative breast cancer, B-cell infiltration correlated with improved responses to immunotherapy, a phenomenon also observed in certain B-cell lymphomas.

Chronic inflammation further connects these malignancies. Persistent immune activation is a well-established driver of lymphomagenesis, particularly in cases linked to viral infections such as Epstein-Barr virus (EBV) or chronic antigenic stimulation from autoimmune diseases. Breast cancer has similarly been associated with chronic inflammatory states, with elevated levels of pro-inflammatory cytokines such as IL-6 and TNF-α contributing to tumor progression. A report in Nature Immunology highlighted that systemic inflammation not only fosters an environment conducive to cancer cell survival but may also impair immune surveillance, increasing susceptibility to secondary malignancies.

Another immunological link involves immune checkpoint regulation. The PD-1/PD-L1 axis, a critical pathway in immune evasion, is targeted by therapeutic antibodies in both malignancies. In triple-negative breast cancer, PD-L1 expression has been linked to aggressive behavior and poor prognosis. Similarly, in lymphomas such as Hodgkin lymphoma and primary mediastinal B-cell lymphoma, PD-L1 amplification allows malignant cells to escape immune destruction. The success of checkpoint inhibitors like pembrolizumab and nivolumab in treating both cancers underscores their shared reliance on immune escape mechanisms.

Types Of Lymphoma Noted In Breast Cancer Patients

Certain types of lymphoma occur more frequently in individuals with a history of breast cancer, either as a secondary malignancy or as a concurrent diagnosis. Prior treatments, genetic predispositions, or shared molecular pathways may influence these cases.

Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma (NHL) encompasses a diverse group of lymphoid malignancies, with diffuse large B-cell lymphoma (DLBCL) being the most frequently reported subtype in breast cancer patients. DLBCL can arise as a secondary cancer following chemotherapy or radiation therapy, particularly in individuals treated with alkylating agents or anthracyclines. Primary breast lymphoma (PBL), a rare form of NHL that originates in the breast tissue, is most commonly of the DLBCL subtype and presents as a rapidly growing, painless breast mass. Diagnosis requires histopathological examination and immunophenotyping to differentiate it from metastatic breast cancer. Treatment strategies for NHL in breast cancer patients depend on the specific subtype but often involve chemotherapy, targeted agents such as rituximab, and, in some cases, localized radiation therapy.

Hodgkin Lymphoma

Hodgkin lymphoma (HL) is less commonly associated with breast cancer than NHL but has been documented, particularly in patients who have undergone prior radiation therapy. Women treated with mantle field radiation for HL at a young age have an increased risk of developing breast cancer later in life. Conversely, breast cancer survivors who develop HL may face unique treatment challenges due to prior exposure to cytotoxic therapies. HL typically presents with painless lymphadenopathy, often in the cervical or mediastinal regions, and may be accompanied by systemic symptoms such as fever, night sweats, and weight loss. Standard treatment includes ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine) or, in advanced cases, escalated BEACOPP.

MALT Lymphoma

Mucosa-associated lymphoid tissue (MALT) lymphoma is a rare, indolent form of extranodal marginal zone lymphoma reported in breast cancer patients, particularly those with chronic inflammatory conditions. Primary breast MALT lymphoma typically presents as a slow-growing, localized mass. Diagnosis relies on histological and molecular analysis, including detection of the t(11;18) translocation in some cases. Treatment approaches vary based on disease extent, with localized cases often managed through surgical excision or radiation therapy, while disseminated disease may require systemic therapies such as rituximab or low-dose chemotherapy.

Diagnostic Considerations

Accurately diagnosing breast cancer and lymphoma in individuals who present with symptoms of both malignancies requires imaging, histopathology, and molecular testing. Mammography and ultrasound are typically the first-line imaging modalities, but MRI can offer additional insight, particularly when lymphoma presents as a diffuse or multifocal breast mass. For suspected lymphomas, PET-CT is often employed to assess systemic involvement.

Histopathological examination remains the gold standard, requiring biopsies for tissue analysis. Immunohistochemistry (IHC) plays a crucial role in distinguishing between these malignancies. Flow cytometry, fluorescence in situ hybridization (FISH), and polymerase chain reaction (PCR) can further differentiate lymphoid malignancies by identifying unique genetic alterations.

Biological Markers For Detection

Serum biomarkers such as CEA and CA 15-3 are commonly elevated in breast cancer, while LDH and beta-2 microglobulin are frequently elevated in aggressive lymphomas. Circulating tumor DNA (ctDNA) and microRNA (miRNA) profiling have emerged as promising tools for detecting and monitoring both malignancies, enabling early detection of minimal residual disease or relapse.