Understanding breast cancer metastasis
Metastasis is a complex process in which malignant
cancer cells from the breast spread into other regions of the body. Once metastasis has occurred, it is much more difficult to effectively treat breast cancer.
If breast cancer has metastasized to other areas of the body, it is termed a ‘Stage IV‘ breast cancer. Sometimes metastasis has occurred at the time the original breast cancer is diagnosed.
However, in other cases, the metastasis of breast cancer is found months or even years after the initial treatment. This would be termed a ‘recurrent’ breast cancer.
How Do Breast Cancer cells spread around the Body?
Breast cancer cells travel through the body like any other cancer cells. Firstly, cancer cells can invade neighbouring healthy tissue. Following this, the cancer cells then invade local lymph nodes or blood vessels.
When breast cancer spreads to the axillary lymph nodes (under the arm) this is still a relatively early stage of metastasis, and potentially curable.
The cancer cells will typically travel through the lymphatic system or blood vessels to other distant parts of the body.
Once the breast cancer travels beyond the lymph nodes to other parts of the body, it is termed a ‘distant’ metastasis, and this is not curable.
However, cancer cells can remain inactive for many years at a distant site, causing no problems or symptoms.
If breast cancer has metastasized beyond the lymph nodes it is termed a systemic disease. This means that the whole body must be treated and not just a particular area. The only way to effectively treat the whole body is usually through chemotherapy and hormonal therapy.
Treatment is aimed at slowing the progression of the disease process and controlling symptoms.
Mechanisms of Breast Cancer Metastasis
No one really knows what factors will make a certain patient more or less susceptible to breast cancer metastasis.
There is growing awareness that part of that susceptibility is due to ‘host factors’. The host factors are the characteristics of the non-malignant cells and the general biological environment surrounding the malignant breast tumor.
Sometimes the host factors are referred to as the pre-metastatic niche and it is thought that bone-marrow-derived progenitor cells may directly influence the dissemination of malignant cells to distant areas.
Non-neoplastic ‘host cells’ within the tumor may also play a key role in the regulation of breast cancer metastasis.
Breast Cancer Metastasis: Secondary Sites
Over the years there have been significant improvements and advancements in the diagnosis and treatment of breast cancer. Indeed, breast cancer is now considered to be a manageable disease.
However, there are still over half a million deaths worldwide from breast cancer and over 90% of these women die of metastasis. Consequently, research into metastasis is of vital importance in overcoming deaths from metastatic breast cancers.
Stage IV or metastatic breast cancer, as mentioned earlier, are cancer cells that have spread from the breast to distant sites around the body. Common secondary sites are:-
- Bone: (Most common secondary site occurring in around 70% of metastatic breast cancer cases).
- Regional lymph nodes
De novo metastatic Breast Cancer and Recurrent Breast Cancer
It is important to understand the two types of Stage IV Breast Cancer and the differences between them:-
- De Novo metastatic breast cancer: This term refers to women who are Stage IV at the initial diagnosis of breast cancer. That is, cancer has already spread to other parts of the body. De novo metastatic breast cancer accounts for only around 6% of cases at diagnosis in the US.
- Recurrent Breast Cancer: More often, breast cancer returns or spreads after the initial diagnosis and treatment of breast cancer. This recurrence can happen months, or even years, after the first presentation and treatment.
Survival Rates for Stage IV Breast Cancer
Stage of breast cancer at diagnosis is one of the most important prognostic factors. Above is a bar chart from the National Cancer Institute (SEER) statistics for 2012. As we can see, the 5-year survival rate for women diagnosed with Stage IV breast cancer was 22%.
Remember, these figures are still quite dated as it takes 5 years to determine survival rates and treatment is improving all the time.
A recent study found that 37% of women survived for three years after a Stage IV breast cancer diagnosis, although some women do survive longer.
However, although the 5-year survival rates are much higher for earlier stages of breast cancer at diagnosis, there is no predicting which cases will progress to metastatic breast cancer in the future.
Recurrent Breast Cancer: Facts and Figures
Breast cancer can return at any point after the initial diagnosis and treatment. This is one of the most anxiety-provoking factors for many women after breast cancer diagnosis and treatment.
There are 3 types of cancer recurrence:-
- Localized: The cancer returns to the original site where it started.
- Regional: The cancer has spread to nearby lymph nodes, tissues or organs
- Distant: The cancer has spread to distant body sites such as the bone, brain, liver or lungs.
It is very difficult to predict how many breast cancers of all stages recur, at local, regional and distant sites.
Indeed, breast cancer incidence and mortality rates are documented over the years. However, data on most cancer registries do not document the incidence of recurrence.
Furthermore, a local or regional recurrence does not have the same prognostic impact as distant metastasis. Even more difficult to handle, is that cancer can recur at any given point in time.
Are there any statistics on Recurrence rates or incidence of Metastasis?
As mentioned, it is very difficult to find statistics on metastatic breast cancer that has recurred after initial diagnosis. However, these cases represent a large proportion of Stage IV breast cancer cases and overall deaths.
Most of the statistical data on Stage IV or metastatic breast cancer is from those women presenting at diagnosis. According to the Metastatic Breast Cancer Network (MBCN) in 2012 new cases of Stage IV breast cancer were between 13,776 to 22,096.
The number of breast cancer recurrences at Stage IV is estimated to be between 20% and 30% of all breast cancer diagnoses.
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A note from Dr Halls regarding the Statistics for Metastatic Recurrence in Breast Cancer
What are the chances of breast cancer recurring?
Despite huge advancements in breast cancer screening, early detection and treatment, a percentage of breast cancers will recur and spread to distant sites.
Although at the moment, it is almost impossible to say which cancers will recur and at what time period from diagnosis, there are a few factors that are known to increase the risk for recurrence.
These risk factors include:-
- (i) Lymph node involvement and number of lymph nodes affected at the time of diagnosis
- (ii) Tumor Size at the time of diagnosis
- (iii) A subtype of Breast Cancer and hormonal receptor Status
- (iv) The time span from the initial diagnosis to recurrence of breast cancer
(i) Lymph Node Involvment
Whether or not cancer has spread to nearby or distant lymph nodes, is part of the staging process for cancer, and also an important prognostic factor for survival.
Furthermore, the number of lymph nodes affected remains a prognostic factor too with the more lymph nodes affected, the poorer the long-term prognosis.
A 2013 medical study from China examined 2,591 patients with breast cancer, all of whom had adjuvant chemotherapy following surgery.
The 5-year overall survival rates were 89.3% and the 5-year disease-free survival rate was 81.6%. Likewise, the 10-year overall survival rate was 78.8% and the 10-year disease-free survival rate was 83.5%.
This medical study found that the use of the lymph node ratio was an independent predictor of survival for Chinese patients with breast cancers. Furthermore, the lymph node ratio is superior to assessment of the number of positive lymph nodes alone in determining disease prognosis.
The Lymph Node Ratio is defined as:-
“…the number of positive lymph nodes over the total number of lymph nodes removed.“
In general, the overall survival of women with breast cancer decreases as the size of the tumor increases.
The study found that tumor size can be a strong predictor of 15-year survival in breast cancer cases with and without lymph node involvement. However, in some cases, the subtype of cancer plays a role too, with some small tumors behaving in a very aggressive way.
However, Narod found that for every 1 cm decline in tumor size the 15-year mortality rate decreased by 10.3% in the node-positive group and by 2.5% in the node-negative group.
A decline of 1.5 cm in tumor size was associated with a 23% reduction in the node-positive group and 10.8% in the node-negative group.
Although this medical study shows the relevance of tumor size and survival rates, interestingly, the impact of tumor size on 15-year survival was greater in women with node-positive tumors.
(iii) Breast Cancer Subtypes, hormonal and HER2 Status
Although the term ‘breast cancer’ is used in general, there are many different sub-types of breast cancers. The sub-types behave in different ways, with some responding better to treatments and some growing and spreading at faster rates.
Obviously, the sub-type of breast cancer affects survival rates.
There are 5 molecular types of breast cancer:-
- Luminal A: This type of breast cancer is hormone receptor positive (ER+ and/or PR+) and HER2 negative. Furthermore, Luminal A cancers tend to be low-grade and slow growing. These tumors respond well to hormone therapy.
- Luminal B: These tumors are ER+ and can be HER+ or HER-. Luminal B cancers tend to grow faster, be of a higher grade and larger tumor size.
- Triple negative/basal-like. As the name suggests these tumors are ER- PR- and HER-. Triple-negative breast cancers have a poorer prognosis and do not respond as well to treatment.
- HER2-enriched: ER- PR- and HER2 positive. These tumors used to have a poor prognosis but since targeted therapy survival rates have improved.
- Normal-like: These cancers are hormone receptor positive and HER2 negative. Normal-like breast cancers have a good prognosis.
What does it mean?
Breast Cancer Subtypes, hormonal and HER2 Status and Survival Rates
Many research studies over the years have shown that Estrogen-positive (ER+) breast cancers have better survival rates (when adjusted for all factors) than all of the Estrogen-negative (ER-) subtypes.
Progesterone-positive (PR+) breast cancer also appears to have improved survival rates in comparison to progesterone-negative (PR-) cases.
For ER+ sub-types (ER+ PR+ HER2-) survival rates were significantly better than all other subtypes. For example, at stage 1b,
ER+ PR+ HER2- 5-year survival rates were 98.6%
ER+ PR- HER2+ 5-year survival rates were 97.3%
The subtype triple negative (ER- PR- HER2-) breast cancer had the worst survival rates over all three stages. At stage I the 5-year survival rate was 92.9% and at stage III 48.9%.
(iv) Disease Free Intervals and Prognosis in Metastasis
The time that passes between the primary diagnosis and treatment of breast cancer and a diagnosis of metastasis is also of prognostic significance.
A 2015 medical study from the Netherlands looked at 815 patients with metastatic breast cancer between 2007 and 2009 in eight hospitals.
Of these 815 patients, 154 had metastatic spread (Stage IV) at diagnosis. 176 patients had a metastatic free interval of less than 2 years and 485 patients had been metastasis-free for longer than 2 years.
The ladies presenting with metastatic breast cancer at diagnosis had a longer survival rate than those who experienced a recurrence at distant sites in under 2 years from the initial diagnosis of breast cancer.
However, there were no differences in survival rates between those diagnosed at Stage IV and those women who had metastatic spread over 2 years after an original breast cancer diagnosis and treatment.
Furthermore, some medical studies show that survival rates vary for different types and subtypes of breast tumors according to the time intervals of recurrence. So, for example, breast cancer survival rates comparing two cancers may be better at a 5-year interval for some cancers but even out over 15 years.
Questions and Answers
Can any type of cancer form a metastatic tumor?
Virtually all cancers, including the cancers of the blood and the lymphatic system, can form metastatic tumors. Although rare, the metastasis of blood and lymphatic system cancers to the lung, heart, central nervous system, and other tissues have been reported.
What are the symptoms of metastatic cancer?
Can someone have a metastatic tumor without having primary cancer?
No. A metastatic tumor is always caused by cancer cells from another part of the body.
If a person who was previously treated for cancer gets diagnosed with cancer a second time, is the new cancer a new primary cancer or metastatic cancer?
The cancer may be a new primary cancer, but in most cases it is metastatic cancer.
What treatments are used for metastatic cancer?
Metastatic cancer may be treated with chemotherapy, biological therapy, targeted therapy, hormonal therapy, radiation therapy, surgery, or a combination of these treatments.
The choice of treatment generally depends on the type of primary cancer; the size, location, and the number of metastatic tumors. Also, the patient’s age and general health and the types of treatment the patient has had in the past.
Are new treatments for metastatic cancer being developed?
- Xin Jin, Ping Mu3 (2015) Targeting Breast Cancer Metastasis Breast Cancer (Auckl). 2015; 9(Suppl 1): 23–34. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559199/
- Toriola AT, Colditz GA. (2013) Trends in breast cancer incidence and mortality in the United States: implications for prevention. Breast Cancer Res Treat. 2013 Apr;138(3):665-73. https://www.ncbi.nlm.nih.gov/pubmed/23546552
More references for this section are on this page
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