Hormonotherapy in Precancerous Lesions.    

 shani breuer, MD, MHA

Sharett - Institute of Oncology Hadassah Hebrew University Medical Centers  

 

Precancerous  Lesions  

•  Ductal  carcinoma  in  situ  (DCIS) •  Lobular  carcinoma  in  situ  (LCIS)  •  atypical  lobular  hyperplasia  (ALH)  •  atypical  lobular  hyperplasia  (ALH)  

DCIS  -­‐  Ductal  carcinoma  in  situ    

•  ductal  carcinoma  in  situ  (DCIS)  has  become  one  of  the  most  commonly  diagnosed  breast  condi;ons.    

•  lack  of  understanding  of  its  natural  history  and  the  inability  to  determine  which  DCIS  will  progress  to  invasive  carcinoma.  

•  Cancer-­‐specific  survival  for  the  woman  diagnosed  with  DCIS  exceeds  95%,  regardless  of  the  type  of  local  therapy  employed.  

•  Mastectomy  /  excision  alone  and  excision  plus  RT  is  curaAve  in  approximately  98%  of  pa;ents  regardless  of  age,  DCIS  presenta;on,  size,  or  grade.  

 

Endocrine  Therapy  -­‐  DCIS  

•  ER  is  present  in  about  80%  of  DCIS  lesions.  •  two  poten<al  benefits  :      -­‐  Reduc;on  in  local  recurrence  aNer  BCT.    -­‐  preven;on  of  the  development  of  new  primary  breast  cancers  in  the  contralateral  breast.    

•  Two  trials:  NSABP  B-­‐24  trial  &  UK/ANZ  trial.  

LCIS  -­‐  Lubolar  carcinoma  in  situ  

•  1941  –  first  described.  •  In  the  past,  LCIS  was  most  frequently  diagnosed  in  women  aged  40  to  50,  a  decade  earlier  than  DCIS,  but  recent  literature  indicates  that  the  incidence  in  postmenopausal  women  is  increasing.  

•  typically  not  associated  with  microcalcifica;ons  on  mammography.  

•  LCIS  is  both  mulAfocal  and  bilateral  in  a  large  percentage  of  cases.  

•  Typically  posiAve  for  ER  and  PR,  lacks  expression  of  E-­‐cadherin.  

LCIS  -­‐  Lubolar  carcinoma  in  situ  •  women  with  LCIS  have  anywhere  from  a  3.0-­‐  to  8.0-­‐fold  

higher  risk  of  breast  cancer  •  10  years  folow  up:                                                        15%  had  ipsilateral  invasive  ca                                                        9.3%  had  contralateral  invasive  ca.  •  1%  to  2%  per  year  Increased  rate  of  development  of  

invasive  ca  (with  a  life;me  risk  of  30%  to  40%  ),  and    5.7%  of  the  pa;ents  developed  metasta;c  breast  cancer.  

•  Management  (When  LCIS  is  seen  on  an  excised  ;ssue,  it  is  not  necessary  to  

obtain  nega;ve  -­‐margins  of  resec;on,  and  there  is  no  established  role  for  radia;on  therapy  in  pa;ents  with  LN).  

•  1992  NSABP  started,  examined  the  ability  of  tamoxifen  to  prevent  breast  cancer  in  women  at  increased  risk.    

•  From  13,388  women  randomized  for  this  trail  826  had  LCIS:  risk  reduc;on  was  56  %  .  

•  The  benefits  of  tamoxifen  were  most  prominent  in  par;cipants  with  a  history  of  lobular  carcinoma  in  situ  and  atypical  hyperplasia.  

•  The  major  toxicity  was  an  increase  in  the  rate  of  endometrial  cancer  (risk  ra;o  2.53,  95%  CI:  1.35±4.97),  as  previously  demonstrated  in  treatment  trials  with  tamoxifen.  

•  The  rates  of  stroke,  pulmonary  embolism  and  deep  vein  thrombosis  were  elevated  in  the  tamoxifen  group.  Toxici;es  were  most  evident  in  women  over  50  years  of  age  

•  prospective, double-blind, randomized clinical trial conducted beginning July 1, 1999, in nearly 200 clinical centers throughout North America. •  19, 747 postmenopausal women of mean age 58.5 years with increased 5-year breast cancer risk. •  Intervention Oral tamoxifen (20 mg/d) or raloxifene (60 mg/d) over 5 years.

•  The  trial  established  that  in  post-­‐menopausal  women,  5  years  of  raloxifene  was  almost  as  efficacious  as  tamoxifen,  decreasing  invasive  and  non-­‐invasive  breast  cancer  risk  by  about  38  %  

•  893  par<cipants  gave  a  history  of  LCIS,  and  their  rates  of  subsequent  breast  cancer  were  similar  with  tamoxifen  and  raloxifene  

ADH  -­‐  atypical  hyperplasia  

•  While  some  studies  have  shown  no  difference  in  breast  cancer  risk  between  ADH  and  ALH,  most  suggest  that  the  risk  is  greater  with  ALH  

•  The  odds  raAo  (OR)  for  developing  breast  cancer  in  women  with  ADH  compared  with  women  without  ranges  from  1.47  to  4.88,  whereas  the  OR  with  ALH  ranges  from  4.21  to  5.71  

ADH  -­‐  atypical  hyperplasia  

NSABP  P1  trial:      • 49%  risk  reduc;on  was  seen  with  tamoxifen.  • The  benefits  of  tamoxifen  were  observed  for  both  invasive  and  noninvasive  carcinoma  and  were  seen  in  women  of  all  ages.    • A  par;cular  benefit  was  seen  in  those  at  risk  because  of  atypical  hyperplasia,  with  an  84%  reducAon  in  cancer  incidence  in  this  group.    

Management  of  the  High-­‐Risk  PaAent  

no  formal  defini;on  of  what  cons;tutes  high  risk.  •  BRCA.  •  These  include  premenopausal  women,  younger  postmenopausal  women  without  a  uterus,  and  those  at  risk  on  the  basis  of  atypical  hyperplasia  or  LCIS.  

•  exemestane  in  invasive  and  pre-­‐invasive  breast  cancer  in  postmenopausal  women.  

•  4560  women  with  at  least  one  of  the  following:  Age  >  60  years;  Gail  score  >  1.66;  a  prior  diagnosis  of  atypical  ductal  hyperplasia  (ADH),  lobular  hyperplasia  (ALH),  lobular  carcinoma  in-­‐situ  or  ductal  carcinoma  in-­‐situ  (DCIS)  treated  with  mastectomy.  

•  At  a  median  follow-­‐up  of  3  years:    Risk  reducAon  of  65%  (P  =  0.002).  

MAP.3  Trial