ESR1 and obesity due to melanocortin 4 receptor deficiency: The age at first birth for US women has increased from 1970 to 2017 across all races and ethnicities.28 Older age at first birth has been associated with increased risk of ER+/PR+ tumors and reduced risk of ER−/PR− tumors.29,30 Decreased parity number is another reproductive factor associated with increased risks of ER+ tumor among young women29,31 and the number of live births has decreased in the US from 1966 to 2015.31 Obesity may also be one of the possible reasons for the decrease in ER− tumor among young US women.