Introduction
Triple-negative breast cancers account for 10-15% of total breast cancers [1]. Cytotoxic drugs linked to monoclonal antibodies by chemical linkers are known as antibody-drug conjugates (ADC). They deliver ultra-toxic payloads selectively to cancer cells. Sacituzumab- Govitecan is an antibody-drug conjugate (ADC) given in triple negative breast cancer patients who have had two or more chemotherapy, at least one of them for secondary breast cancer and the tumour cannot be removed by surgery. It is a combination of two drugs Sacituzumab – a monoclonal antibody and SN-38, a chemotherapy drug.

Sacitizumab acts by blocking a protein called TROP 2 on cancer cells thus reducing its dividing capacity while SN-38 destroys the tumour cells. Trop-2 is a transmembrane Calcium channel transducer that is heavily expressed in breast cancer tissue and in other tumours. The binding of the antibody component of SC to Trop-2 facilitates targeted delivery of the anti-neoplastic agent SN-38 to tumour cells. The expression of Trop 2 is associated with unfavourable prognosis in advanced breast cancer [2].

Although the remarkable efficacy of ADC has been demonstrated, they can cause adverse events in multiple organ systems such as the respiratory, digestive, circulatory, nervous and haematological systems [3]. Among these is pneumonitis which could impact ongoing treatment. Pneumonitis is defined as non-infectious causes of lung inflammation, including interstitial lung disease (ILD).

It is essential to determine the incidence of antibody-drug conjugate associated pneumonitis to prevent drug associated pneumonitis and ensure patient safety considering the seriousness of pneumonitis.

There has been a case report which reported pneumonitis caused by Trastuzumab-Deruxtecan which is an ADC [4]. There have been no case reports on Sacituzumab Govitecan associated pneumonitis.

Discussion
In the phase 3 randomized control trial (ASCENT), [9] SG monotherapy showed improved objective response rate, progression- free survival and overall survival when compared with other single- agent chemotherapies (Eribulin, Vinorelbine, Capecitabine, or Gemcitabine) in patients with metastatic Triple Negative Breast Cancer. SG use was associated with an increased incidence of treatment-related adverse events [3] when compared to single-agent chemotherapy including grade3 or higher neutropenia, diarrhoea and febrile neutropenia. While there is an increased incidence of neutropenia and diarrhoea [5], incidence of pneumonitis is not reported.

Although the detailed mechanism of ADC induced pneumonitis has not been fully elucidated, the theoretical pathogenesis may be related to 1) low expression of ADC target antigen in normal tissues 2) the instability of linker leads to premature release of cytotoxic drugs into blood 3) cytotoxic payloads of ADCs and their drug antibody ratios 4) bystander effect of ADCs 5) drug-drug interactions.

Key risk factors that predict an increased risk of drug-induced ILD [8] include a history of pre-existing lung disease and reduced lung function, poor performance status, smoking, age older than 60 years, Japanese or African Ethnicity, and male sex. From an Oncology point of view, risk factors are multiple chemotherapy regimens, thoracic radiotherapy, the presence of lung cancer, and treatment with a combination of molecularly targeted and cytotoxic agents.

Many patients who develop ILD have no identifiable pre-existing risk factors which increased the importance of vigilance.

ADC induced ILD is a diagnosis of exclusion, and other causesof respiratory failure including cardiogenic pulmonary oedema, pneumonia and diffuse alveolar haemorrhage should be excluded.

All patients receiving SG should be monitored be monitored for signs and symptoms of ILD/Pneumonitis. If a patient develops cough, dyspnoea, fever, and a new or worsening symptom, evaluation of ILD should be started promptly. Radiological imaging should be obtained in all suspected cases, and a pulmonologist consultation should be considered.

For asymptomatic pneumonitis (grade 1), treatment should be interrupted until resolved and corticosteroids can be considered (0.5 mg/kg/day of prednisolone or equivalent). If adverse event is resolved at less than 28 days, the same dose can be maintained, and if resolved in more than 28 days, the dose is to be reduced by one level. However, if a patient develops symptomatic pneumonitis, treatment should be discontinued permanently and corticosteroid treatment should be promptly initiated (1mg/kg/day of prednisolone or equivalent) for at least 14 days followed by a gradual tapering for at least 4 weeks.

Factors that increase the risk of poor outcomes from ADC induced ILD

[8] are acute symptomatic disease with rapid symptom onset, hypoxaemia, need for mechanical ventilation, pre-existing interstitial lung disease, male sex, age over 65 years and diagnosis of small cell lung cancer.

Conclusion
The identification and monitoring of patients at risk of ADC induced ILD are crucial for timely intervention. It is important to identify the patient at risk of ADC induced ILD at an early stage by quantification of risk factors and comorbidities. When they are placed on a closer monitor after grading the risk factors treatment can be started to prevent the progression of ADC inducedILD. Unfortunately, there are no effective strategies for identification and monitoring ADC induced ILD in clinical practice beyond CT imaging and monitoring of oxygen saturation.