Discussion

This patient developed sarcoma within a previously irradiated field. The latent period was 7·5 years. Because >5% of the prescribed dose had been delivered to the axillary area and there was no evidence of tumour on a previous PET scan, this case also fulfilled the revised criteria for radiation-induced malignancies suggested by Murray et al.^{Reference Murray, Werner, Greeff and Taylor2} She underwent radical excision of the breast in the form of MRM. Although the survival rates after breast cancer treatment are typically high, the risk of secondary malignancies, particularly sarcomas, increases. Therapeutic radiation for a childhood malignancy has been associated with malignant thyroid neoplasms.^{Reference Acharya9} But a population-based retrospective cohort study regarding the risk of thyroid carcinoma after RT for breast cancer showed no significant increase in the risk of thyroid carcinoma in either the RT cohort or the non-RT cohort compared with the general population.^{Reference Huang, Walker, Groome, Shelley and Mackillop10} According to a large retrospective study of 16,705 patients previously treated for breast cancer, adjuvant RT significantly increased the rate of sarcomas and lung cancers compared with a non-RT group (p = 0·020 and 0·022, respectively).^{Reference Kirova, Gambotti, De Rycke, Vilcoq, Asselain and Fourquet11} Compared with the general population, the standardised incidence ratio is 10·2% and 1·3% for patients with breast cancer who did or did not receive RT, respectively. Another study using surveillance, epidemiology and end-result data reported a cumulative incidence of sarcoma at 15 years of 0·32% for cases receiving RT, which is more frequent than cases not receiving RT (0·23%, p = 0·001).^{Reference Seinen5} The mean latency periods of the above two studies were 8·7 and 7·5 years, respectively, which is similar to our case. Angiosarcoma is the most prevalent histology among radiation-induced sarcomas.^{Reference Seinen5,Reference Kirova, Vilcoq, Asselain, Sastre-Garau and Fourquet6} Higher radiation doses would increase the risk of soft tissue and bone sarcomas after breast cancer.^{Reference Rubino12} Compared with patients who received <14 Gy, the odds ratios were 1·6 and 30·6 for patients who received 14–44 and >44 Gy, respectively, at the site of the sarcoma. Intensity-modulated RT has been found to improve target coverage and reduce normal tissue complication for breast cancer.^{Reference Krueger, Fraass, McShan, Marsh and Pierce13} According to this finding, our patient who received 50 Gy at the site of sarcoma was at a high risk of developing post-radiation sarcoma. There were no distinguishable imaging features of post-radiation sarcomas.^{Reference Sheppard and Libshitz3} However, the presence of bony destruction with a soft tissue mass, tumour matrix mineralisation at a previously irradiated area and an appropriate latency period could be important clues for a diagnosis of post-radiation sarcoma. In addition to imaging features, a low incidence after a long latency period makes it difficult to diagnose the disease accurately. Thus, a high index of clinical suspicion is warranted. The prognosis of post-radiation sarcomas is generally poor, with 5-year survival rates of 27–36%.^{Reference Seinen5-Reference Erel, Vlachou, Athanasiadou, Hassan, Chandrasekar and Peart7} The standard treatment is surgical resection, but this is often made challenging by tumour location.^{Reference Kirova, Vilcoq, Asselain, Sastre-Garau and Fourquet6,Reference Erel, Vlachou, Athanasiadou, Hassan, Chandrasekar and Peart7,Reference Tabone14} Only a complete surgical resection can guarantee long-term survival.^{Reference Tabone14} Chemotherapy or RT has limited roles in treatment; therefore, early detection is important to enable curative resection. In the present case, the patient was unwilling for surgery or chemotherapy since she was pregnant. She received chemotherapy only after delivering the child. The knowledge regarding post-radiation sarcomas is limited to a few case reports. Despite well-organised nationwide breast cancer databases from Korea,^{Reference Jung15} no large-scale study has been conducted regarding post-radiation sarcomas. The younger age at diagnosis, increased use of RT as a primary treatment for breast cancer^{Reference Veronesi4,Reference Jung15} and longer survival after treatment could lead to more cases of post-radiation sarcoma. In total, 1,831 cases of radiation-induced sarcomas of the breast have been published in the English literature.^{Reference Sheth, Cranmer, Smith, Grasso-LeBeau and Lang16}

Another key factor is the high possibility of familial/hereditary cancer inheritance syndrome like Li-Fraumeni in our patient. Though she was never tested for p53 mutations, her young age at first diagnosis (26 years), extremely strong positive family history and spectra of cancers affecting her first-degree blood relatives (brain tumours, leukaemia) strongly hint at the possibility of such a cancer syndrome. Though the guidelines for cancer treatment in Li-Fraumeni or other hereditary syndromes are not different from non-syndromic patients, preclinical data has suggested the possibility of increased radiosensitivity in patients with such congenital disorders. Similarly, clinical studies have suggested that Li-Fraumeni families might be at a higher risk of secondary radio-induced malignancies. According to a French study, if a germline mutation is detected, then it should be taken into account for decision-making concerning local treatment: (1) Adjuvant RT for localised breast cancer should be extensively discussed and prohibited whenever the risk–benefit ratio is doubtful. (2) Both mastectomy of the cancer-bearing breast and contralateral prophylactic mastectomy (with immediate reconstruction, as frequently as possible) should be advised and discussed with the patient, as is the case for BRCA1/2 mutation carriers, with the additional advantage of potentially avoiding RT if conservative treatment could be avoided.^{Reference Heymann17} Also, there is a role of tumour suppressor protein P53 in the complex response to RT by modulating the radiosensitivity in tissues as well as sensitising cells to chemotherapy. Hence, the P53 pathway remains an attractive target for exploitation in the war on cancer.^{Reference Fei and El-Deiry18} Retrospectively, the question certainly arises, given her young age and family history, whether this patient was a right candidate for RT even once as compared to the fact that she received radiation twice.

Future studies should investigate the incidence or distribution of sarcomas after RT for breast cancer based on the analyses of a large database.