Revamped combat - basic questions - do I understand this right?

Putting aside special runes, tactics, planning, etc.

Attack causes a fixed amount of damage.
Damage Pen causes a % amount of damage.
Defense causes a fixed amount that negates Attack
Damage Red causes % amount to negate Damage Pen
Skill enhances abilities.

Do I understand this right?

So is the best defense a combo of both Defense and Damage Pen, or?
So is the best offense a combo of both Attack and Damage Pen, or?

I really have no desire to have to change runes before every fight and was accustomed to following others' "rune guides" - would rather develop guidelines based on basic rune stats.

Any basic "get-by-good-enough" advice appreciated.
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