ATYPICAL RESPONDERS LANDSCAPE REVIEW ∙ OCTOBER, 2017 20 that the tumor microenvironment can mediate resistance or sensitivity to therapy, and that this effect on efficacy can be intrinsic or acquired [40]. Co-morbidities Co-morbidities and the drugs that patients take for them may impact atypical responses and survival in cancer patients. Cardiovascular co-morbidities reduce survival time in patients with ovarian cancer [41]. Other studies have shown variable impacts of cardiovascular [42], autoimmune [43], and diabetic [44] co-morbidities on patient outcomes. Certain diseases or conditions may disqualify patients from taking specific cancer-related medications, as exemplified by patients with heart disease who may be precluded from taking anthracycline drugs. Furthermore, development of treatment-related co-morbidities such as cardiovascular problems induced by anthracyclines and Herceptin® (trastuzumab) may preclude patients from taking the very drugs that may be the most effective for treating their disease [45]. A review of more than 2,500 published articles relating co-morbidity and patients with colon cancer, breast cancer, and lung cancer concluded that patients with a co-morbidity had worse survival than those without a co- morbidity. With 5-year mortality hazard ratio is as high as 5.8, some co-morbidities may be associated with rapid cancer progression [46]. These complex situations warrant further studies relative to atypical responses. Lifestyle Factors Lifestyle factors include but are not limited to diet, physical activity, body mass index, smoking, alcohol consumption, and social factors such as depression, anxiety, and support. These attributes may play a role in a patient’s response to therapy, QOL, and overall survival. Unfortunately, investigation of whether lifestyle factors can specifically impact the efficacy of a particular cancer treatment has received little attention [47, 48]. One example is a study indicating that cancer patients who drank one glass of grapefruit juice per day achieved the same benefits from the mTOR inhibitor Rapamune® (sirolimus) at a dose of 25 mg as they would have obtained with a 90-mg dose of the drug [49]. The researchers noted that grapefruit juice can inhibit enzymes in the intestine that break down Rapamune® and several other drugs. The effects were observed within a few hours of grapefruit juice ingestion and gradually subsided over a few days. Physical activity and diet can also considerably enhance survival after a breast cancer diagnosis [50]. A cohort study of self-reported dietary habits in breast cancer survivors suggested that a combination of a healthy diet (five servings per day of fruits and vegetables) and physical activity (equivalent to walking 30 minutes 6 days per week) is associated with a 50% reduction in mortality overa7-yearfollow-upperiod[51]. Exercisefollowingacancerdiagnosisisassociatedwithreductions Investigation of whether lifestyle factors can specifically impact the efficacy of a particular cancer treatment has received little attention.