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Brown, who made three RBS 6 Nations substitute appearances earlier this year, impressed in his first international start for four years despite England’s 22-17 first-test defeat to the Springboks in Durban on Saturday.
However, the 26-year-old injured his thumb when trying to prevent South African captain Jean de Villiers from scoring his side’s second try, while centre Brad Barritt will also miss Saturday’s second Test in Johannesburg because of an operation to repair a lacerated eyeball.
Lancaster said: “Mike has pulled a ligament in his thumb. We're still waiting for specialist opinion as to whether he needs surgery but the reality is that he's out for six to eight weeks.
“He'll return home later in the week. It's very disappointing for him. He's worked hard for his opportunity and to get his place in the starting XV.
“I've told him to remember the quality of the season he's had and to keep in mind that he's got a lot to be proud of this season.
"Brad has got a laceration on his eyeball so he had a minor operation to stitch that. That means he can't fly so he'll be staying in Durban and join us for light training at the end of the week and be ready for full training at start of the following week.”
Lancaster has called up up South African-born Nick Abendanon, who made his debut in South Africa five years ago, as England look to restore parity on Saturday.
Meanwhile, Ireland centre Keith Earls was also ruled out of their second Test against New Zealand after sustaining a pectoral muscle injury late-on in the 42-10 series opener defeat against the All Blacks.
Connacht's Gavin Duffy was called up but Earls will remain with the Irish squad and will be monitored ahead of the Third test a week on Saturday, while front row pair Cian Healy – rated 50/50 – and Declan Fitzpatrick will be assessed prior to Saturday’s clash following more injuries.
Wales are also counting the cost of their defeat to Australia with No.8 Toby Faletau definitely out of their remaining two Tests with Scarlets duo George North and Liam Williams also doubtful after picking up knocks.
Elsewhere, Scotland’s Tim Visser and Max Evans are set to join the Scotland side for Saturday's clash against Fiji after Sean Lamont and Joe Ansbro were sidelined.
Lamont sustained a rib injury and Ansbro suffered a badly cut eye during their shock 9-6 victory over Australia last week in which Evans was unavailable due to his club commitments in France and free-scoring Visser was still serving residency qualification period.