Do you recommend adjuvant RT to patients with non-ATM genetic mutations (e.g. BRCA, NF) who elect to have lumpectomy and are otherwise PRIME II/CALGB candidates for RT omission (i.e. low risk disease characteristics: strongly ER+, <1cm, grade 1-2, no LVI, widely negative margins, and committed to endocrine therapy)?

Again, as in the previous hypothetical, this patient is otherwise well-qualified and has chosen to forego surgical prophylaxis. Is she eligible for PBI? If not, she should have whole-breast?… And perhaps contralateral “radiation prophylaxis”? 

I don’t believe so. In the studies you referenced, we didn’t have perfect information regarding genetics, Oncotype, or even HER2(!). Certainly, there was a non-zero number of participants who were at higher risk than their basic phenotype suggested. Do we need to insist on genetic testing and Oncotype before considering an otherwise qualified patient for observation?

The patient already knows she is the higher-than-average risk for a metachronous primary. HT is an acceptable and proven method of medical prophylaxis for high-risk/genetic patients. Also, we are going to assume active radiologic surveillance and proper risk management of non-breast malignancies. We are also talking about a patient whose life expectancy is more properly measured in years rather than decades. 

Taken all together, I’d be comfortable offering observation (HT alone), or PBI with HT (see my previous answer), or whole-breast with HT (if you insist!!). I probably would advise against “subbing” XRT for HT as we sometimes do for patients in this category.