Schematic illustration of evolutionary trajectories of BRCA-associated cancers.

<p>The hypothesis on the evolutionary trajectories of BRCA-associated cancers is illustrated. Treatment outcomes are determined by the following four conditions: (i) the frequency of BRCA inactivation, (ii) growth advantage of type-2 and -3 cells, (iii) the detection size, and (iv) drug effects on resistant cells. (A) Drug resistance by secondary mutations emerges after long-term treatment in the case of (i) as high, (ii) as large, (iii) as large, and (iv) as large. (B) Drug-sensitive and -resistant cells coexist at relapse and retreatment with the same drugs is conceivable in the case of (i) as high, (ii) as large, (iii) as not large, and (iv) as small. (C and D) Drug resistance due to pre-existing resistant cells emerges in the case of (i) as high, (ii) as small, (iii) as large and (iv) as any, or in the case of (i) as small. The reference numbers indicate clinical observations, each of which corresponds to each outcome in the evolutionary trajectories.