Breast Cancer Receptors
Breast cancers can over-express the estrogen (ER), progesterone (PR) and Her2/neu receptors which can have prognostic impact for the patient as there are therapeutic options for these tumors.
Tumors can be tested for ER/PR or Her2 protein expression via either immunohistochemical (IHC) staining. HER2 gene expression can be detected via fluorescent in situ hybridization studies (FISH).
Testing requires the specimens be properly fixed in formalin. (ER/PR = 6-72 hours whereas HER2 = 6-48 hours fixation time)
Tumors are scored as negative, equivocal or positive based on a variety of different factors
When to perform ER/PR/Her2 studies
Any new diagnosis of ductal carcinoma in situ (DCIS) on a breast biopsy (ER/PR only)
Any new diagnosis of invasive ductal or invasive lobular carcinoma (ER/PR/Her2) on a breast biopsy
When to repeat receptor studies
If the initial testing performed on a breast biopsy resulted in an “equivocal” or “negative” result for HER2 testing, you should repeat the HER2 tests
Ideally, you want to perform Her2 on a resection specimen (lumpectomy/mastectomy) or a portion of tumor that has metastasized (thought to represent the most aggressive part of the tumor). This is because tumors may display heterogeneity in their receptor expression (i.e. some areas of tumor are “bad” and overexpress receptors whilst other areas do not). However, HER2 studies can be performed on a biopsy with a caveat that negative or equivocal results be re-tested on larger resection specimens.
If you believe the specimen was not properly fixed resulting in a "false negative" outcome
Staining with Keratin, Vimentin and CD31. If these are strongly positive, it means the specimen was properly fixed and you can trust the her2 results to be negative.
Any recurrent or metastatic disease
Tumors may change their expression pattern as they recur or metastasize (~8% of ER/PR+ change to negative; 20% of HER2- tumors to HER2+). Thus, you may repeat ER/PR/Her2 studies on any recurrent or metastatic disease. In 20% of cases, HER2 status will be different than the primary site (tumor was initially negative, but has HER2 over-expression on metastatic focus).
Now let's go a little bit deeper into ER/PR and Her2 testing process and interpretation...
ER/PR Receptor Testing
The immunoperoxidase (IHC staining) technique allows determination of the degree of ER positivity within the nuclei of just the neoplastic cells without interference from other cells. ER/PR immunohistochemical stains are nuclear stains. The normal breast is positive for ER expression in ~35% of the cells.
Some breast cancers have increased ER/PR expression. Often multicentric and bilateral in 20-40% of cases. In general, ER/PR positivity = better prognosis because they are better differentiated and more amenable to hormonal manipulation (will go into detail in another post).
About 8% of breast cancers will change their ER expression in metastatic foci (from pos to neg); recommend re-testing of receptors in recurrent or metastatic cancers.
HER2/Neu Testing
Pathologists can test for Her2 overexpression via immunohistochemical staining (IHC detects Her2 protein) or fluorescent in situ hybridization (FISH detects HER2 DNA).
There is a 95% concordance rate between IHC and FISH testing for Her2. 3% of IHC negative cases can be detected by FISH
Ideally, Her2 testing should be performed on resection specimens rather than biopsies due to tumor heterogeneity (could miss “hot spots” of Her2 overexpression in the tumor). See the testing algorithm below.
When to repeat the Her2/neu receptor studies:
If you perform Her2 on a biopsy and it comes back as equivocal IHC (1+ or 2+), REPEAT THE RECEPTORS on the resection specimen!
Tumors can lose or gain Her2 expression after chemo/radiation. You should REPEAT RECEPTOR STUDIES on these specimens.
Her2 stain can also be used to highlight clusters of malignant cells in the epidermis (Paget disease)
Summary
Breast cancers can over-express estrogen (ER), progesterone (PR) or her2/neu receptors. Receptor status can change following chemo/radiation or upon recurrence/metastases. The receptor studies should be repeated in these instances as they can affect treatment options.
ER/PR positive tumors have a better prognosis whereas Her2 amplification/over-expression has a poorer prognosis.
Receptor testing for tumors requires properly fixed tissues (6-48 or 72 hours) and should be performed on all breast cancer cases.
ER/PR receptors are nuclear stains and are detected by IHC staining.
HER2/neu protein can be detected via IHC; HER2 DNA (located on chromosome 17) can be detected via FISH.
HER2 is considered amplified if the ratio of HER2 genes: # of chromosome 17 present is >2.2 or if the number of HER2 gene signals is >6.
HER2 testing is best performed on resection specimens. If a negative or equivocal result occurs on biopsy, the HER2 status should be repeated on the resection specimen due to tumor heterogeneity.