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.

BRCA Mutation Predicts Carboplatinum Response in Women with TNBC

Anthony M Magliocco MD

 

A recent study published in Nature Medicine reports that women with triple negative breast cancer with a BRCA mutation were much more likely to respond to treatment with carboplatin compared to treatment with docetaxel, which is the current treatment recommendation for these patients.

https://www.nature.com/articles/s41591-018-0009-7

Triple negative breast cancer remains a difficult disease to treat as standard anti-estrogen or anti-HER2 treatments are not considered.

In this study there were 376 women with advanced triple-negative breast cancer across the trial, regardless of BRCA gene status, the researchers found the 2 drugs worked similarly well. But among the 43 women in the study who also had BRCA gene mutations those who received carboplatin were twice as likely to respond to therapy as those given docetaxel.

The researchers have reported an observed resesponse of 68% of the patients treated with carboplatin, but only in 33% of the women on docetaxel.

 

 

 

Furthermore Carboplatin also appeared to cause fewer side effects along with prolonged tumor progression for longer in women with BRCA mutations—with a progression free survival of  7 months compared with 4 months for those treated with standard docetaxel.

The researchers believe carboplatin is more effective for this patient group because it works by damaging tumor DNA, and BRCA mutations impair the ability of cancer cells to repair the type of DNA damage created by this kind of platinum drug.

This study further highlights the need for availability of BRCA gene testing in women with breast cancer.

This study further highlights the need for NGS gene testing in women with breast cancer for the purpose of appropriate therapy selection

 

One curious feature of the study was women with BRCA1 gene methylation, low BRCA1 mRNA expression, or Myriad HRD analysis was not clearly associated with benefit of treatment with platinum based agents.

 

A study at the Moffitt Cancer Center recently showed many triple negative breast cancers may actually be misclassified due to errors in primary pathology biomarker analysis.

Second opinion analysis should be considered for women diagnosed with triple negative breast cancer as the original biomarker analysis may frequently be flawed and an actionable target such as estrogen receptor or HER2 is identified on reanalysis

 

TRIPLE NEGATIVE BREAST CANCER IS OVER DIAGNOSED

 

New Mechanism Involving NFkappaB Drives Metastasis in Cancer with Chromosomal Instability

By Anthony M Magliocco MD

An interesting and important new study recently published in Nature gives new insights into possible targetable molecular mechanism linking chromosomal instability observed in some cancers and progession and metastasis.

https://www.nature.com/articles/nature25432

A subset of cancers develop chromosomal instability via disjunction errors during mitosis. This can lead to highly aneuploid and abnormal karyotypes more prevalent in certain cancers than other. For example, ovarian cancer is notorious for developing a  disrupted and unstable karyotype.

Metastatic Cancer

It appears that chromosomal instability in itself does not promote metastasis, however, in an intriguing observation it was noted that tumors with chromosomal instability also developed micronuclei when under mechanical stress.

These micronuclei are more prone to cytoplasmic rupture. Free DNA in the cytoplasm triggers a non-canonical NFkappaB cascade which may lead to mesenchymal transformation and a propensity to metastasis.

Interestingly cancers with high aneuploidy do not generally develop a high mutational burden such as cancers like melanoma. Nor do they tend to have targetable driver mutations.

“Cytosolic DNA from micronuclear rupture appears to trigger non-cannonical NFKappaB signaling which could lead to tumor metastasis”

 

DNA in the cytoplasm triggers NFKappaB as part of a host response to viral infection, but cancer may subvert this mechanism. In addition,  NFkappaB non-cannonical activation by cytosolic DNA from ruptured micronuclei may lead to a variety of effects immune activation which could assist with tumor metastasis.

These new insights into the consequences of chromosomal instability create opportunities for developing new therapeutic strategies for these types of cancer that lack specific driver mutations and significant neoantigen loads

 

TRIPLE NEGATIVE BREAST CANCER IS OVER DIAGNOSED

By Dr. Anthony Magliocco

Getting a second opinion for a cancer diagnosis is highly recommended, but even more so if you face triple negative breast cancer, which can be aggressive and difficult to treat.

A new study led by Moffitt Cancer Center pathologist Dr. Marilin Rosa shows that triple negative breast cancer may be frequently overdiagnosed and reclassified after expert review and biomarker retesting. Moffitt investigators presented the data at the 2018 United States & Canadian Academy of Pathology Annual Meeting in Vancouver.

Researchers reviewed over 560 cases of breast cancer referred to Moffitt and found that 113 were initially classified as triple negative by external evaluation. After biomarker retesting, about 28 percent of the triple negative cases were reclassified as hormone receptor positive.

Moffitt’s study demonstrates the value of biomarker retesting for triple negative breast cancers before selecting an appropriate treatment plan. A second opinion that changes your diagnosis can have a huge impact on survival.

In triple negative breast cancer, the three most common types of receptors known to fuel most breast cancer growth — estrogen, progesterone and the HER-2 gene — are not present. This makes common treatments such as hormone therapy and drugs that target the three missing receptors ineffective.

Up to 20 percent of breast cancer diagnoses are triple negative and are more likely to affect younger patients, blacks, Hispanics and those with a BRCA1 gene mutation. This disease is also more likely to spread and recur.

The takeaway: Having an accurate cancer diagnosis is critical to planning appropriate treatment. If you are diagnosed with triple negative breast cancer, consider getting a second opinion before starting a treatment plan.