SAN DIEGO—One woman’s curiosity and self-described “aggressive” approach to research have led to some unexpected discoveries about acute leukemias.
Isabel Cunningham, MD, of Columbia University in New York, has found evidence to suggest that treatment resistance in leukemia patients may sometimes result from an interaction between leukemic cells and the breast.
She discovered that leukemic cells in extramedullary niches can adopt a tumor phenotype similar to breast cancer.
And many genes are similarly upregulated in leukemic and epithelial breast tumors.
Her research indicates that a new approach to resistant leukemias that incorporates the principles of solid-tumor treatment—scans to identify any tumors and surgery to remove them—could decrease marrow relapse and death.
Dr Cunningham and her colleagues presented these findings in a poster at the AACR Annual Meeting 2014 (abstract 3996*).
“Chemotherapy resistance is our main problem in treating leukemia,” Dr Cunningham said. “It’s been known for a long time that, occasionally, leukemia forms tumors in an organ, but there’s never been a unified approach to treatment, except for leukemia that occurs in the testis and the meninges.”
Dr Cunningham had encountered many patients with resistant leukemia throughout her career, but her research actually began with a patient she had never met. A case study of a leukemia patient with a breast tumor sparked Dr Cunningham’s interest, and she emailed the study’s author to find out what ultimately became of the patient.
The response she received peaked her curiosity further. So she began seeking more of these cases, contacting authors, and collecting information on this phenomenon.
“I took this on as sort of a hobby,” Dr Cunningham said. “I never had any idea where this was going to lead.”
Eventually, she had amassed information on 235 cases—163 patients with acute myeloid leukemia (AML) and 72 with acute lymphoblastic leukemia (ALL)—who ranged from 1 year to 75 years of age. And an analysis of these cases led to some surprising discoveries.
Dr Cunningham found these leukemic breast tumors can occur before, during, or after marrow leukemia. And, clinically, they resemble breast cancer. Most tumors were palpable, and some were detected only on routine mammograms.
There were single or multiple nodules that may have involved the entire breast. Sixty percent of cases were unilateral on presentation, but, often, the other breast became involved. Seventy percent of cases exhibited axillary lymphadenopathy that was ipsilateral.
Most tumors grew rapidly, to as large as 12 cm. The tumor behavior was similar in AML and ALL. And the tumors had a metastatic pattern similar to lobular breast cancer—spreading to the contralateral breast, the abdomen or pelvis, the meninges, and culminating in death.
However, some patients did survive. Four percent of patients who were treated only with chemotherapy were alive at 4 years. Twenty-five percent of patients had their tumors excised prior to chemotherapy and were alive anywhere from 3 years to more than 26 years after treatment.
Histology and gene expression
To build upon these findings, Dr Cunningham set her sights on patient samples. She was able to obtain paraffin blocks of leukemic breast tumors from 25 patients and perform immunohistochemical staining.
“It became clear that the leukemic tumors—which are marked by leukemic markers and not breast cancer markers—look, histologically, like breast cancer, specifically, lobular breast cancer,” Dr Cunningham said. “An additional pathologic finding was a specific type of desmoplastic fibrosis seen in all 25 contributed biopsies.”
Dr Cunningham also performed gene expression studies on 3 of the tumors (2 ALL and 1 AML), which were collected 8 months to 22 months after diagnosis, while marrows were in remission. The analyses revealed that a number of genes are significantly upregulated in both leukemic breast tumors and breast cancer.
These include genes involved in adhesion and interactions with the extracellular matrix (ADAM8, COMP, and CDH22), genes involved in the ubiquitin-proteasome pathway (UBE2S, USP32, MDM2, and UBE2C), genes encoding for kinases (MAP4K1, PIM1, and NEK2), and genes involved in RAS signaling (RANBP1 and RAB10).
Conclusions and next steps
“It seems that there’s some kind of crosstalk between the organ microenvironment and leukemic cells that make the leukemic cells have the phenotype of breast cancer,” Dr Cunningham said. “And it may well be that relapse sometimes results from the presence of an undiagnosed collection of these cells.”
Therefore, Dr Cunningham suggests performing scans in treatment-resistant leukemia patients. If a patient relapses, and particularly if lactic dehydrogenase levels are increased, a scan might be in order.
“If we can recognize these tumors and cut them out, the patient could be cured, because we’re successful at treating the bone marrow,” Dr Cunningham said. “We’ve had very good bone marrow drugs for 50 years.”
For her part, Dr Cunningham is delving further into this phenomenon. She is now conducting gene expression studies on the rest of the 25 leukemic breast tumor samples and comparing these tumors to breast cancer to identify the most significant dysregulated genes in both entities. The long-term goal is to find a way to predict which patients will develop leukemic breast tumors.
*Information in the abstract differs from that presented at the meeting.