Therapy-related myeloid neoplasms in epithelial ovarian cancer patients carrying BRCA1 mutation: Report of two cases

To the Editor

Major progress has been achieved during the past few decades in the therapy of epithelial ovarian carcinoma (EOC). Although the disease in most patients with advanced disease is still incurable, the survival has been substantially prolonged. Currently, the standard first line regimen in advanced EOC is the combination of paclitaxel and platinum (cisplatin or carboplatin), with the response rate to this combination being about 60–70% [1]. Recurrent EOC responds to repeat administration of paclitaxel/platinum combination [2]. Marked prolongation of survival resulting from the multimodality treatment is changing the natural course of the disease, with more patients living long enough to develop hitherto unusual late sequels, including metastases in unusual sites (e.g. brain), or second primary tumors. We present here two cases of BRCA1 mutation carriers with repeat responsiveness of recurrent EOC to paclitaxel/platinum that finally succumbed to therapy-related myeloid neoplams.

Case 1 was a woman with history of hysterectomy for leiomyomas who presented in February 2002, at the age of 49 years, with pleural effusion in the right hemithorax. Cytological examination of the effusion revealed malignant cells suggestive of adenocarcinoma. A mass in the right breast was found on subsequent examination. Triple negative breast carcinoma was diagnosed in an excisional biopsy. Systemic chemotherapy with the combination of doxorubicin (50 mg/m²) and paclitaxel (175 mg/m²) administered every three weeks was initiated. After six cycles, a complete response of the pleural effusion was evident and, because of the presence of distant metastases at diagnosis, irradiation of the right breast was performed as the definitive local therapy.

An ovarian mass was detected on control abdominal ultrasound in June 2003. The patient was referred for surgery that included bilateral adnexotomy, omentectomy and lymphadenectomy. Histological examination of the surgical specimen revealed stage IIIC serous cystadenocarcinoma. The patient was subsequently treated with 17 cycles of the combination of paclitaxel (175 mg/m²) and carboplatin (area under the curve 6). The therapy was well tolerated and the patient was without the evidence of disease until May 2005. Prolonged course of chemotherapy was administered because the results of the clinical trials at that time indicated benefit of maintenance chemotherapy [3]. In May 2005 recurrent pelvic mass was diagnosed. Therapy with the combination of paclitaxel (175 mg/m²) and carboplatin (area under the curve 6) was reintroduced. The treatment that continued until February 2006 resulted in complete response. However, serum CA125 concentrations began soon rising, and recurrence was detected by computer tomography (CT)-scan in May 2006. Because of short platinum-free interval tamoxifen 20 mg/day started. The treatment for progressive disease with the combination of gemcitabine (1 g/m²) and cisplatin (40 mg/m²) administered every two weeks was initiated in November 2006. The therapy was well tolerated, but in March 2007, the chemotherapy could not be administered because of prolonged thrombocytopenia and symptomatic anemia. Thrombocytopenia (50 3 10⁹/l), anemia (hemoglobin 50 g/l) and leukopenia (1 3 10⁹/l) gradually worsened with time despite interruption of chemotherapy. The patient was referred for bone marrow biopsy that revealed therapy-related myelodysplastic syndrome (refractory anemia with excess blasts 1). Because of poor general condition of the patient, only symptomatic treatment could be administered. The patient died on 6 June 2007.

On autopsy, necrotizing colitis and pneumonia were considered the principal cause of death. The autopsy also revealed the presence of peritoneal and pleural involvement by metastatic EOC. The cumulative dose of platinum administered during the whole therapy expressed in cisplatin equivalents was 3798 mg. The mother of the patient died of ovarian cancer at the age of 51 years. Genetic analysis revealed BRCA1 mutation in exon 20 (c.5385dupC).

Case 2 was a woman with history of bilateral breast carcinoma treated with lumpectomy, adjuvant chemotherapy, that included anthracyclines and alkylating agents, and adjuvant external beam radiation at the age of 44 years and 54 years who presented in July 2004, at the age of 62 years, with ascites and pleural effusion. Cytological examination of the ascitic fluid revealed the presence of tumor cells with immunocytochemical profile suggesting ovarian primary. The patient was treated with eight cycles of paclitaxel (175 mg/m²) and carboplatin (area under the curve 6) administered every three weeks. The therapy resulted in complete response, and hysterectomy with bilateral adnexotomy and omentectomy was performed in January 2005. In September 2005 ascites recurred, but again a complete response was obtained in March 2006 after the administration of nine cycles of the combination of paclitaxel and carboplatin described above. The second recurrence in September 2006 was also controlled by seven cycles of the same combination chemotherapy, resulting in complete response in February 2007. The patient presented with the third recurrence in June 2007. Seven cycles of the same combination of paclitaxel and carboplatin were administered until October 2007, and a complete response was obtained.

In February 2008, the patient reported fatigue, weakness, dizziness and dyspnea. Subsequently, epistaxis manifested. Pancytopenia was evident in the peripheral blood. Based on the presence of 24% of blasts in the peripheral blood that were positive for CD34, CD117, CD33, CD7 and terminal deoxynucleotidyl transferase, diagnosis of therapy-related acute myeloid leukemia was made. Because of general condition, after consultation with hematologic oncologist, the patient was treated only symptomatically with red blood cell and platelet transfusions. The patient died one month later. An autopsy was not performed.

The cumulative dose of platinum administered during the whole therapy expressed in cisplatin equivalents was 4050 mg. The mother, daughter and sister of the patient had breast cancer. Subsequent mutation analysis revealed that the patient, her daughter and sister of the patient are carriers of BRCA1 mutation in exon 13 (c.4237G > T/p.Glu1413X).

Present experience indicates that therapy-related myeloid neoplasms may occur in BRCA1 carriers as a complication of recurrent EOC controlled by repeat administration of platinum-based chemotherapy. Both patients described here have been treated with anthracyclines as part of the treatment of breast cancer. Importantly, multiple lines of paclitaxel/ carboplatin were administered resulting in high cumulative platinum dose that was in both cases about a four-fold of the cisplatin equivalent of 1000 mg that was established as a threshold for higher risk of secondary acute myeloid leukemia in an earlier study [4]. In the two cases presented here, therapy-related myeloid neoplasms may be related both to earlier treatment with anthracyclines or radiotherapy for breast cancer and repeat administration of paclitaxel/carboplatin for EOC. Cases of therapy-related myeloid neoplasms, including both therapy-related myelodysplastic syndrome and therapy-related acute leukemia, have been described in a number of patients with EOC [4]. However, to the best of our knowledge, only two more cases of EOC patients carrying BRCA1 mutation have been described in the literature [5]. In a recently published series, BRCA1/BRCA2 mutations were present in three of six patients with therapy-related myeloid neoplasms and primary breast cancer. Two of these three patients also had a history of EOC and paclitaxel/carboplatin chemotherapy [5]. It is interesting to note that all four patients with BRCA mutation, EOC and therapy-related myeloid neoplasms reported so far (two patients reported by Cole et al. [5] and two cases described here) also had history of breast cancer.

Experimental data demonstrate increased chemosensitivity of BRCA1 mutant cells [6]. Retrospective analyses also indicate that EOC patients carrying BRCA1 mutation have significantly better prognosis [7]. This may be explained by increased chemosensitivity of these tumors that could be linked to the biological role of BRCA1. The cells lacking BRCA1 protein are highly sensitive to alkylating agents, platinum derivatives and anthracyclines. The cases presented here illustrate repeat sensitivity of recurrent EOC in BRCA1 mutation carriers to platinum chemotherapy, with the tumor retaining the sensitivity even after several recurrences. The course of recurrent EOC in BRCA1 mutation carriers may thus resemble more a chronic disease rather than a rapidly fatal malignant disorder. The late toxicity may represent a serious limitation of repeat administration of chemotherapy, and the present two cases indicate that therapy-related myeloid neoplasm may be one such complication. Both patients in the present report also had breast carcinoma as the first primary, and breast carcinoma was treated with systemic chemotherapy resulting in tumor control in both cases.

In addition to EOC and breast carcinoma, the carrier status of BRCA1 mutation is associated with increased susceptibility to a number of malignant tumors, and cases of leukemia have also been documented in BRCA1 mutation carriers [8]. Therapy-related acute myeloid leukemia represents a rare late complication of chemotherapy in EOC patients treated with platinum-based chemotherapy [4], with the risk being substantially increased in patients treated with higher cumulative doses of platinum. Therapy-related acute myeloid leukemia or myelodysplastic syndrome may be distinguished based on the blast counts, but these two conditions are thought to represent a single disorder [9]. Because therapy-related myeloid neoplasms represent a late complication of chemotherapy, and both improvement in survival of patients with advanced EOC and discovery of BRCA1 mutations are relatively recent developments, it may currently be difficult to estimate the incidence of therapy-related acute myeloid leukemia in BRCA1 carriers with recurrent EOC. In addition, many patients with EOC and BRCA1 mutation also have breast cancer that is treated mostly with anthracyclines and radiation. Thus, it remains to be determined whether there is increased risk of therapy-related myeloid neoplasms in EOC patients carrying BRCA1 mutation treated with platinum-based chemotherapy and, if this is the case, whether increased risk is due to the presence of the mutation or associated with higher cumulative platinum doses caused by repeat responsiveness. The data available so far indicate that family history of breast or ovarian cancer is associated with increased risk of leukemia in breast cancer patients and that BRCA1 mutations are involved in leukemogenesis [10].

In conclusion, therapy-related myeloid neoplasms may represent a fatal late complication of recurrent EOC responding repeatedly to platinum chemotherapy in patients carrying BRCA1 mutation.

Acknowledgements

Supported by Research Projects MZO 00179906, MSM 6198959216 and MZO MOU 2005.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.