Understanding the Biology and Treatment Options for Breast Cancer

by Anthony M Magliocco MD

Breast cancer is a common disease with up to 1 in 8 women receiving this diagnosis in her lifetime. It is more common in older women but it certainly can strike the young and even can occur in men at about 1/100 the rate seen in women.

We have learned a lot about the biology of breast cancer over the years and the condition is becoming easier to detect at an earlier stage and fortunately more effective therapies are now being developed.

We now know that breast cancer is complex and has multiple molecular and biological subtypes. The main types are called Luminal A, Luminal B, HER2 positive, and Triple Negative.

Luminal Cancers – Endocrine responsive tumors

The Luminal types of breast cancer are defined by expressing estrogen receptor. They tend to have better differentiation and generally a more indolent course. The standard treatment is surgery, potentially radiation, and endocrine treatment (an anti estrogen agent) for 5 to 10 years. If the tumor appears more aggressive- ie involves lymph nodes, or has higher grade, chemotherapy may be added to the treatment in an adjuvant way. One of the problems with luminal type breast cancer is it can recur many years after the original cancer has been treated. Its thought the cancer cells can spread and remain dormant in distant organs or bone for many years with some mysterious events causing them to become reactivated.

 

The HER2 positive breast cancers

A subset of breast cancers, about 15% seem driven by the oncogene ERBB2 (which produces the protein HER2).  For some reason this gene can become “amplified” – ie many copies are made in a single cell leading to vast over production of the HER2 protein. This over production seems to drive the cancer cell to proliferate and metastasize.

Fortunately, therapies have been designed for HER2 cancer, these include Trastuzumab and Pertuzumab – antibodies that react and block the function of the HER2 gene. These treatments appear to be able to halt the grow of the cancer and prevent metastases from occurring.

The Triple Negative Breast Cancers (TNBC)

The third main type of breast cancer are the Triple Negative Cancers or TNBC. This group is actually a mixed group of tumors defined by lack of expression of estrogen receptor or HER2.  They frequently occur in younger women, they may be familial, are over represented in African American women and often progress more quickly. Some of them seem to have a high immune infiltrate, some carry the BRCA gene mutation, and some show strange growth characteristics such as bone formation or “metaplasia”.

 

 

The problem with TNBC is they are a generally a diagnosis by exclusion. However there are certain tests a pathologist can order to help prove that a cancer is TNBC such as Nestin.

Because the TNBC is diagnosed by exclusion there is a significant possibility of error. For example some tumors are heterogenous, and only a small portion might be sampled. If the portion is ER negative or HER2 negative the tumor might be erroneously classified as TNBC.

In other cases, TNBC cancers with very low false expression of HER2 or ER may end up being misclassified as HER2 positive or ER positive which could lead to erroneous use of potentially toxic and ineffective anti -HER2 therapy

Use of Second opinion Expert Review Pathology 

A second opinion pathology review by an expert pathologist can help a patient and her oncology be confident that a tumor is indeed a TNBC. The pathologist may order a repeat immunohistochemical stain on additional case material which frequently changes a diagnosis of TNBC to ER positive or HER2 positive. Occasionally a ER positive or HER2 positive will be reclassified as TNBC also.

TNBC is a unique form of breast cancer with subtypes. further classification of TNBC into tumors with BRCA mutation will help with selection of Parp inhibitor or chemotherapy with carboplatinum.

Further, some TNBC tumors have been shown to be sensitive to immunotherapy.

Some TNBC also seem to express androgen receptor, which could be a therapeutic target.

 

Use of Liquid Biopsy

In some patients a liquid biopsy could also be helpful. If a patient has metastatic disease the cancer cells can be isolated and analyzed from a blood sample.  ER and HER2 status can be measured in these circulating tumor cells. In addition fragments of DNA from disintegrating cancer cells can also be measured and classified providing further evidence as to the amount of cancer and whether the cancer is changing or responding to therapy.

Of interest, it seems that breast cancers may undergo biomarker change as they progress or metastasize. for example an ER positive tumor might change and become ER negative or switch to HER2 overexpression.

Patients should seek second opinion pathology review if they have concern regarding the accuracy of their diagnosis or want to ensure that all treatment opportunities are properly considered.

 

 

As treatment options continue to expand, and testing methods improve, it is important that patients with breast cancer have access to the highest quality pathology services and they should also not hesitate to seek second opinion if there is concern regarding the accuracy of diagnosis.

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