Combined-modality treatment for locally advanced cervical cancer in a woman with Bloom-like syndrome: A case report and review of the literature

We report the case of a 46-year-old woman with Bloom-like syndrome affected with locally advanced cervical cancer. She was treated with induction chemotherapy and radical radiation therapy concurrent with chemotherapy (carboplatin and paclitaxel). She was able to complete treatment, but grade III toxicities were observed. The limited relevant literature is presented. We conclude that the management of patients with DNA repair deficiency is challenging for the team in charge because of the potentially high sensitivity to treatment and the lack of clear recommendations in the literature. The main objective remains to deliver the optimal treatment while reducing toxicities.


Introduction
Bloom syndrome (BS) is a rare autosomal recessive genetic disorder affecting the BLM gene that codes for a DNA helicase, a protein involved in DNA replication and repair. Clinically, patients present with short height, photosensitivity reactions, and an increased risk of carcinomas and hematological malignancies [1]. The profile of cancers seen in patients affected with BS seems to resemble the spectrum of cancers within the general population, but they occur at a much younger age, causing a short life expectancy.
Leukemia and lymphoma are the most commonly diagnosed malignancies [2].
Patients with a DNA repair disorder disease such as Fanconi anemia, ataxia-telangiectasia, xeroderma pigmentosum, and BS may show extreme sensitivity to DNA-damaging treatments such as radiation and chemotherapy, thus leading to severe acute reactions and a higher incidence of second malignancies [3]. However, due to the rarity of BS, the literature is sparse. There are few data concerning cancer treatment in patients with BS and no clear guidelines for their management and treatment adjustment, making it particularly challenging for the physician in charge.
We report the management and the tolerance of breast radiation therapy and pelvic irradiation with concurrent chemotherapy in a young woman with BS treated at our institution for breast cancer in 2015 and who developed cervical cancer in 2020, along with a systematic review of the literature.

Case report
A woman born in 1973 was referred to our institution in 2015 for management of right breast carcinoma. There was no family history of a genetic disorder or personal history of chronic diseases. Her parents were related. She was treated for invasive right breast cancer discovered by self-examination. It was an invasive breast carcinoma of no special type, grade III, poorly differentiated, estrogen receptor positive, progesterone receptor negative, HER2 negative, Ki67 80%, classified T1N0M0. A genetic syndrome was suspected with the particular morphotype phenotype of the patient. She weighed 34 kg with a height of 139 cm, and she had a head circumference of 46 cm and an elongated "bird's head" face (which is common in microcephaly cases). She had "café au lait" spots on her back. There was no facial skin rash or high-pitched voice, and she had been menopaused since the age of 36. No alteration of the BLM gene could be found, nor for the Bloomlike syndrome genes known to date: TOP3A, RMI1, and RMI2. However, the cytogenetic study found a high rate of sister chromatid exchanges (SCE; 21 by metaphase on 21 metaphases of the 25 analyzed metaphases and > 50 in 4), which is associated with the patient's phenotype and leads to a Bloom syndrome diagnosis hypothesis. She underwent right breast-conservating surgery followed by adjuvant chemotherapy, without dose reduction. She had two cycles of anthracycline-based chemotherapy (5 fluorouracil 500 mg/m 2 [5FU], epirubicin 100 mg/m 2 , and cyclophosphamide 500 mg/m 2 ) complicated by grade II mucositis leading to the discontinuation of 5FU for the last cycle. She did not receive taxane-based chemotherapy because of a break of more than 6 months for digestive investigation. The patient had whole right breast adjuvant conformational 3D radiation therapy at 50 Gy (2 Gy/fraction) with a tumor bed boost of 16 Gy (2 Gy/fraction) with no dose reduction. Radiation therapy was well tolerated, and the patient showed no significant radiation sensitivity except a grade I radio-epithelitis. Long-term follow-up did not show substantial late toxicities except a stage I breast fibrosis 4 years after radiation therapy. The patient was followed by annual breast MRI, mammography, and breast ultrasound. During the breast cancer follow-up, a sigmoid adenocarcinoma was diagnosed in 2016 and treated exclusively with surgery. In January 2020, the patient complained of pelvic heaviness associated with metrorrhagia. The radiological assessment showed a locally advanced cervical tumor, and the diagnosis was confirmed with a cervical biopsy revealing an invasive poorly differentiated squamous cell carcinoma, HPV negative, stage IIIC2 FIGO. Fluorodeoxyglucose(FDG)-positron emission tomography (PET) scan found no distant metastasis.
After a multidisciplinary tumor board discussion, we planned neoadjuvant chemotherapy, then concurrent radiation therapy and brachytherapy, whereas no dose reduction was planned. The patient received induction chemotherapy with three cycles of paclitaxel 175 mg/m 2 and carboplatin AUC 4. After C1, the paclitaxel dose was reduced to 135 mg/m 2 because of anorexia with 10% weight loss in 3 weeks, grade I asthenia, and persistent nausea. There was good tolerance of the two other cycles. Then concomitant radiochemotherapy was planned: pelvic irradiation including the para-aortic region at 45 Gy in 25 fractions and a simultaneous integrated boost of 55 Gy in 25 fractions to involved nodes with a volumetric modulated arc therapy technique (VMAT) using high-energy photons (6 MV), guided by imaging and associated with weekly cisplatin 40 mg/m 2 . After the second cycle of cisplatin-based chemotherapy with the concurrent pelvic radiation therapy (dose: 10 Gy), the patient presented a grade III hematological toxicity: thrombocytopenia (47,000/mm 3 ) and anemia (7.6g/dl) with grade II diarrhea, which required a short break from radiation therapy and hospitalization and had a favorable evolution under symptomatic treatment. We decided to stop concurrent chemotherapy due to the toxicity.
At the end of external radiation therapy, the physical examination revealed a partial response with around 80% persistent tumoral residue.
The patient received uterovaginal high-dose-rate brachytherapy with 7 Gy per fraction for 4 fractions, with no significant acute toxicity (grade I digestive and urinary toxicities). A radiologic and metabolic evaluation with pelvic MRI and 18 FDG-PET scan, respectively, were performed 8 weeks after the brachytherapy to assess treatment response. This revealed a pelvic nodal progression and a complete cervical response. The patient received six cycles of checkpoint immune inhibitor NIVOLUMAB but presented a retroperitoneal lymph node progression and a rapid deterioration in her general state, leading to a multidisciplinary decision to halt the specific treatment. The patient passed away 5 months later in a support oncology care unit.

Discussion and review
Bloom syndrome is a rare genetic disorder with only a few hundred cases reported in the literature [4]. Patients with BS usually present with growth deficiency affecting both length and weight and associated with severe microcephaly causing facial dysmorphia (long and narrow face, underdeveloped malar area, retrognathia or micrognathia, head circumference below the third percentile). Most patients develop dermatologic manifestations, with a rash initially on the face exacerbated by sun exposure [5]. They also have endocrine abnormalities (insulin resistance, susceptibility to type 2 diabetes, dyslipidemia hypogonadism) and a deficiency in immune functions [5], but cancer remains the most severe and frequent medical complication seen in patients with BS. Leukemia and lymphoma are the most frequent malignant diseases reported [6]. Among solid tumors, the most common are digestive cancer followed by squamous cell carcinoma of the head and neck and a high incidence of rare cancers like Wilms tumor [6]. All the solid tumors have an early age of onset compared with the same tumor in the general population. Acute leukemia and lymphomas predominate in the first two decades of life, and carcinomas are more common after the second decade [5]. The high incidence of cancers in BS is due to biallelic protein-inactivating variants in the BLM gene [7]. The protein product of BLM is essential for maintaining the stability of the DNA during the replication process. It is involved in the detection, transmission, and resolution of damaged DNA. The absence of BLM activity leads to genomic instability and a high gene mutation rate [7]. There are no established cancer screening protocols for patients with BS [8]. Walsh M et al. suggest raising awareness of patients and their families towards the signs and symptoms of leukemia and lymphoma, the most commonly encountered malignancies in Bloom syndrome. They suggest as a screening program: annual coloscopy with fecal immunochemical testing every 6 months beginning at age 15, and yearly breast MRI scans starting at the age of 18 [9].
Patients with BS present with enhanced sensitivity to DNA-damaging agents like chemotherapy and ionizing radiation, which exposes them to a higher incidence of severe acute toxicities and makes the oncological management of these patients incredibly delicate [3]. Case reports of patients with BS receiving chemotherapy or radiation therapy are scarce. The first case suggesting a high radiosensitivity was published by Kataoka et al. [10]. The case consisted of a 38-year-old patient with BS treated exclusively by radiation therapy for lung cancer and who, 8 weeks after the completion of radiation therapy, developed a severe esophageal stricture requiring tube and intravenous feeding after a total mediastinal dose of 30.6 Gy (1.8 Gy/fraction). The patient died 18 months after treatment despite complete resolution of the tumor. A second case reported the treatment of a 33-year-old woman with BS affected with a squamous cell carcinoma of the oropharynx [3]. The initial course of radiotherapy was well tolerated with only the excepted acute radiation side effects. Once concurrent chemotherapy with 5-fluorouracil and cisplatin was added, the patient developed severe bone marrow suppression, severe oropharyngeal mucositis, and severe diarrhea, leading to early cessation of radiation therapy at a total dose of 60 Gy and stopping of chemotherapy after only one cycle. The recovery from these reactions was slow. For instance, the radiation dermatitis took 3 months to heal, and mucositis more than 4 months to resolve. The patient died 4 months after treatment of her disease. The authors concluded that the addition of radiosensitizing chemotherapeutic agents such as cisplatin and 5-FU was probably responsible for the exacerbation of radiation reactions. They proposed avoiding chemotherapy and preferring radiation alone as a treatment strategy for locally advanced oropha-ryngeal cancer in patients with this disorder [3]. More recently, a case concerning a 33-year-old woman with BS was reported. The patient was diagnosed with oropharyngeal cancer, staged T2N2bM0 and considered unresectable [11]. The physician team anticipated a potentially high radiosensitivity and opted for exclusive irradiation of the tumor with proton beam therapy without prophylactic lymph nodes irradiation to ensure a dose reduction in normal tissues. They avoided concurrent chemotherapy; despite this, the patient developed grade II mucositis soon after proton beam therapy started, which became severe at a dose of 36 Gy in 20 fractions requiring a 2-week treatment break. After a total dose of 59.4 Gy in 33 fractions over 77 days, the patient had a complete clinical tumor response and stopped proton beam therapy. The patient presented 6 months later after a metastatic pulmonary relapse and died 9 months after treating her disease. The author concluded that modern radiation therapy techniques could reduce the dose to normal tissues and are particularly useful in DNA damage repair diseases associated with a higher radiation sensitivity to avoid severe acute toxicities with reasonable tumor control. They also suggest that tumor cells in patients with BS might have, like normal cells, higher radiosensitivity [11].
Patients with BS also have higher chemosensitivity, as described in a few case reports: Candido et al. reported the case of a 21-year-old patient with BS treated for gastric adenocarcinoma. She was operated on immediately, but peritoneal carcinosis was discovered intraoperatively. Adjuvant chemotherapy with capecitabine and oxaliplatin without dose reduction was then proposed. After the first injection of oxaliplatin (130 mg/m 2 ), the patient developed febrile pancytopenia grade III, associated with nausea, vomiting, and diarrhea, requiring hospitalization for 3 weeks. The team in charge decided not to administer capecitabine. Her condition did not allow the treatment to be resumed, and she died 2 months after their discontinuation [12]. Some authors recommend a 50% reduction in doses systematically, regardless of chemotherapy type, in case of genetic disorders including BS [1].
In our case, the BLM gene's alteration, which defines Bloom syndrome, was not identified. Her parents being related, a homozygotic pathogenic variant was expected. The lack of variant detection could be due to technical defect or to a variant located in a non-coding region of the gene. However, based on the clinical phenotype and the presence of SCE, we retained the diagnosis of Bloom-like syndrome. Therefore, we recommend more vigilance when BS is suspected, even if a BLM gene alteration is not found, towards potentially higher treatment toxicity.

Conclusion
Because of the rarity of BS disease, there is no prospective trial in patients developing cancer and no evidence base upon which to design treatment programs. In the absence of consensus regarding the appropriate screening protocol or treatments, patient management is challenging for physicians. This is why multidisciplinary care is highly recommended, with a precise assessment and discussion of the indication and an adequate dose of DNA-damaging agents like chemotherapies and ionizing radiation therapy. Close monitoring for acute and late toxicities within the context of the increased risk of high sensitivity to chemotherapy and radiation therapy is necessary.