The guide camera should roughly be pointing at the same patch of sky as your main cam. A few arcmin/arcsec offset does not matter, as long as the mechanical connection between the cams is stiff enough and does not change too much with the moving mount and changing temperature. YMMV.
The guiding keeps the stars on the same position on the guiding cam sensor (average). Small rotations around that set-up can still happen and can become „large“ if your main cam is pointing somewhere else, as we are talking a few micron for a pixel. For large focal lengths and large equipment an off-axis guider can become necessary as the weight and flexure may become so large, that you cannot neglect it anymore and need guide cam and main cam use the same optical train, to correct for deviations caused by these.
I believe they're asking about how the guide camera is oriented in the guide scope and if it matters in general or in relation to the imaging camera.
The guide calibration will determine the camera orientation so it doesn't really matter. Just keep in mind that if you're setting up the equipment each night then you need to redo the calibration.