Purpose Of This Review
The purpose of this review is to critically evaluate the results of trials of neoadjuvant chemotherapy and neoadjuvant endocrine therapy for different breast cancer subtypes, discuss how neoadjuvant responses can inform adjuvant therapy, and highlight the importance of pathological complete response as a surrogate marker of distant disease-free survival , distant recurrence free survival , and event free survival which is interchangeable with disease-free survival , in the age of adaptive trial design. Notably, in contrast to overall survival , precise definitions of DFS and similar, related endpoints vary somewhat from trial to trial. pCR is generally a composite endpoint of primary tumor and lymph nodes. While pCR correlates with lower risk of recurrence, risk of recurrence still occurs and reduction of this risk remains an important goal. We also highlight functional and genomic predictive biomarkers in NET and their prediction of recurrence free survival , essentially equivalent to EFS.
Addition Of Cyclin Dependent Kinase Inhibitors To Adjuvant Endocrine Therapy
Recently, the phase 3 Palbociclib Collaborative Adjuvant Study and monarchE adjuvant trials testing different CDKis in endocrine receptorpositive/HER2-negative breast cancer have reported results. The PALLAS trial investigated a primary endpoint of invasive DFS for patients who received standard endocrine therapy alone or in combination with the CDK4/6 inhibitor palbociclib for 2 years. PALLAS was a multicenter open-label randomized trial that studied patients with stage II or III breast cancer. A preplanned analysis was performed, and the PALLAS trial was stopped because of futility . The monarchE trial also measured a primary endpoint of IDFS for patients who received standard endocrine therapy alone or in combination with the CDK4/6 inhibitor abemaciclib for 2 years. monarchE is a multicenter open-label randomized trial that studies a population of patients at high risk for recurrence with four or more pathologically positive lymph nodes or one to three lymph nodes and high-risk features such as primary tumor of at least 5 cm, grade 3 tumor, or Ki67 of at least 20%. monarchE showed a significant improvement in IDFS with abemaciclib and endocrine therapy versus endocrine therapy alone with respective IDFS rates of 92.2% versus 88.7% at 2 years. The monarchE paper and the PALLAS trial press release indicate a difference between CDKi types in the adjuvant setting. Whether there are differences between CDKis in the neoadjuvant setting remains to be seen.
When Cancer Recurs After 5 Years
When cancer recurs at a distant site it is no longer early-stage breast cancer. The characteristics of cancer may change as well. Tumors that are initially estrogen receptor-positive may now be negative and vice versa . HER2 status can also change.
For this reason, and because there are now a number of alterations that can be targeted , it’s important for people to have a biopsy and genetic testing of their tumor .
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Outcomes According To Hr Status
When HR was positive, the HER2 group and HER2+ + T group had significantly lower LRR , DM and higher DFS at 5 years than that in the HER2+ T group. There were no significant differences in LRR , DM or DFS at 5 years between the HER2 group and HER2+ + T group.
Figure 3 KaplanMeier plots of locoregional recurrence , distant metastasis , disease-free survival , and overall survival of HR-positive patients and HR-negative patients grouped according to HER2 status and trastuzumab treatment. HR, hormonal receptor-negative HR+, hormonal receptor-positive HER2, HER2-negative HER2+ + T, HER2-positive with trastuzumab HER2+ T, HER2-positive without trastuzumab.
When HR was negative, there were no significant differences in LRR, DM, DFS or OS among HER, HER2+ + T, or HER2+ T groups .
What Is A Hormone Receptor
In breast cancer, hormone receptors are the proteins located in and around breast cells. These receptors signal cells both healthy and cancerous to grow. In the case of breast cancer, the hormone receptors tell the cancer cells to grow uncontrollably, and a tumor results.
Hormone receptors can interact with estrogen or progesterone. Estrogen receptors are the most common. This is why ER-positive is the most common form of breast cancer.
Some people are diagnosed with progesterone receptor-positive breast cancer. The key difference is whether cancerous cells are getting growth signals from estrogen or progesterone.
Testing for hormone receptors is important in treating breast cancer. In some cases, there are no hormone receptors present, so hormone therapy isnt a good treatment option. This is called hormone receptor-negative breast cancer.
According to BreastCancer.org, about 2 out of 3 people with breast cancer have some form of hormone receptors present. This makes them candidates for hormone therapy.
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Vaccine Derived From Her2 Protein May Help Prevent Breast Cancer Recurrence
A new breast cancer vaccine that is derived from the HER2 protein may help prevent recurrence in patients with HER2-positive disease and appears safe. Phase II study results of the vaccine were released at the 2014 Breast Cancer Symposium, September 46, in San Francisco.
The HER2 protein, also known as human epidermal growth factor receptor 2, is found on the surface of certain cancer cells, including breast cancer. In normal cells HER2 helps control cell growth. Cancer cells, however, can make too much of the protein, which can cause cells to grow more quickly and be more likely to spread to other parts of the body.
The HER2-derived vaccine, known as GP2, is designed to provoke the bodys immune system to fight cancer by recognizing tumor cells that express HER2. It is administered in addition to standard breast cancer treatment, such as Hercpetin® , with the goal of preventing recurrence.
Based on these findings, the GP2 vaccine appears promising in addition to standard therapy in women with HER2-positive breast cancer, as it might have the potential to safely and effectively prevent recurrences. The researchers also speculate that GP2 works with Herceptin in a specific way to stimulate immune response and that further research into this interaction is warranted.
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Her2 In Breast Cancer
HER2 is overexpressed in 1530% of invasive breast cancers, which has both prognostic and predictive implications . Breast cancers can have up to 2550 copies of the HER2 gene, and up to 40100-fold increase in HER2 protein resulting in 2 million receptors expressed at the tumor cell surface . Even estrogen, working via the nongenomic activity of estrogen receptor outside the nucleus, has been shown to activate HER2 signaling . An aberrant form of HER2 , lacking the extracellular domain, is found in some breast cancers. p95 is constitutively active and causes resistance to trastuzumab which requires the extracellular domain of HER2 for binding. For the same reason, p95 is not detected by antibodies that target the extracellular domain .
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What Does Testing Involve
If a doctor confirms an unusual growth, they will take a biopsy. To collect a sample, they may perform one of the following procedures:
- Use a fine needle to remove a sample of breast cells or a liquid in fine-needle aspiration.
- Use a larger needle in a core needle biopsy.
- Carry out minor surgery as an outpatient procedure.
According to the American Cancer Society, a core needle biopsy is often the preferred option.
The doctor will send the tissue samples to a laboratory to test whether or not breast cancer is present. If it is, the pathologist will test to see if the cancer is HER2-positive.
The two main tests for determining whether or not HER2-positive cancer is present are the fluorescent in situ hybridization test and the immunohistochemistry test.
The FISH test looks for additional copies of the HER2 gene in breast cancer cells. It uses special labels that attach to the HER2 proteins that glow in the dark.
The IHC test uses a chemical dye to stain HER2 proteins and can determine how much HER2 protein is present in breast cancer cells.
Often, the pathologist will carry out the IHC test and then the FISH test. IHC testing is faster and less costly than FISH testing. However, if the results of the IHC test are unclear, a person will need a FISH test to determine whether or not a tumor is HER2-positive.
Blocking Her2 Slows Or Stops Some Types Of Breast Cancer
NCI-funded researcher Dennis Slamon, M.D., was among the many scientists searching for genes that can lead to cancer. In 1987, he and his colleagues discovered that the growth factor receptor gene HER2, which produces HER2 proteins, might be a good candidate.
At the same time, a team of NCI researchers led by Stuart Aaronson, M.D., were among the first to show that the HER2 protein could cause normal cells to grow uncontrollably like aggressive cancer cells.
Dr. Slamons team found that the HER2 protein is present at high levels in about 30 percent of breast cancers. They also discovered that high levels of HER2 are linked to a greater likelihood of metastasis and relapse and an overall decrease in patient survival. The group concluded that HER2 might play a role in the development and growth of breast cancer.
NCI-funded researcher Dennis J. Slamon, M.D., discovered the genetic link between HER2 and breast cancer.
This led researchers to a groundbreaking hypothesis: If HER2 could be blocked, the growth of HER2-positive breast cancer might be slowed.
One way to block the action of a protein is to use laboratory-made monoclonal antibodies that attach to a specific protein and disrupt its function. With NCI support, Dr. Slamon and colleagues from the University of Texas Health Sciences Center had a breakthrough. They showed that an antibody specific to HER2 could slow the growth of metastatic breast cancer cells and other types of cancer in a laboratory dish.
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The Following Statistics Are A Little Old Now They Are Much Better
There are of course many factors that contribute to the survival of breast cancer. However, some older studies show that only about 60%of patients with HER-2 positive status invasive breast cancer are disease free after 10 years.
In addition, about 65% survive overall .
And, a greater number of HER-2 positive patients succumb to the illness during the first five years than those who are negative for HER-2 overexpression.
At the same time, all other factors assumed to be equal, patients with negative HER-2 status tumors tend to be disease free at a rate of 75% over 10 years and have a slightly higher overall survival rate.
From this, we can informally estimate that women with breast cancer which overexpresses HER-2 are about 10% more likely to have significant difficulties and ultimately succumb to the disease within the first five years, than those who do not.
Because some of the Incidence and Prognosis rates are a little old now check out our brand new Index of Posts on Survival Rates.
Her2 In Gastric Cancer
HER2 overexpression in patients with gastric cancer has been reported from 10 to 30% and correlates with poor outcome and a more aggressive disease. Overexpression of HER2 protein in gastric cancer, using immunohistochemistry , was first described in 1986 . In a study by Yano et al. , HER2 overexpression by IHC was found in 23% and gene amplification by FISH in 27% of 200 resected tumors. Gravalos and Jimeno in their study of 166 gastric cancer patients observed that HER2 overexpression was most commonly found in gastroesophageal junction tumors and tumors having intestinal type histology. Other studies also confirmed a higher rate of HER2 positivity in GEJ tumors and intestinal subtype . HER2 overexpression is directly correlated with poorer outcome in gastric cancer. In a study of 260 gastric cancers, HER2 overexpression was an independent negative prognostic factor and HER2 staining intensity was correlated with tumor size, serosal invasion, and lymph node metastases . Other studies also confirmed the negative impact of HER2 overexpression in gastric cancer .
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Where Do These Numbers Come From
The American Cancer Society relies on information from the SEER* database, maintained by the National Cancer Institute , to provide survival statistics for different types of cancer.
The SEER database tracks 5-year relative survival rates for breast cancer in the United States, based on how far the cancer has spread. The SEER database, however, does not group cancers by AJCC TNM stages . Instead, it groups cancers into localized, regional, and distant stages:
- Localized: There is no sign that the cancer has spread outside of the breast.
- Regional: The cancer has spread outside the breast to nearby structures or lymph nodes.
- Distant: The cancer has spread to distant parts of the body such as the lungs, liver or bones.
Four Steps To Avoid A Recurrence
Theres nothing you can do to guarantee that your cancer wont come back, but you can make some changes to help you feel your best after cancer treatment and keep your body stay strong.
Eat a balanced diet. Reach for a colorful mix of fruits and vegetables, good sources of fiber like beans and peas, and whole grains like whole wheat bread and brown rice every day. Avoid or limit drinks that are high in sugar and red or processed meat like beef, pork, hot dogs and sausages. You probably dont need to take vitamin or mineral supplements, unless your care team suggests them. In fact, taking more of certain vitamins or minerals than you need can have a negative effect on your cancer recovery, so be sure to discuss any supplements youre considering with your care team before taking them.
Exercise on most days of the week. Being active can improve your mood, boost self-esteem and reduce fatigue. Its even been shown to lower anxiety and depression and relieve nausea, pain and diarrhea.
Lean on a strong support system. Cancer might be all about the cellular changes in your body, but you know it certainly doesnt stop there. Taking care of your emotional health, whether it be cultivating a strong circle of friends and family as support or getting mental health services, can help you manage the stressors that cancer treatment and recovery can bring.
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Exploring Why Some Cancers Grow And Spread And Others Dont
For years, doctors and researchers have noted that not all cancers are alike. Some patients tumors grow quite slowly and never spread beyond the site where they first formed. But for other patients, their tumors grow rapidly and spread like wildfire.
In the early 1980s, after the discovery that a mutated gene called HER2 could stimulate excessive cell growth and division, many scientists wondered if certain genes might make cancers grow and spread rapidly. Researchers around the world began searching for genes that spur cancer growth.
Breast Cancer : Much Progress But Work Remains
Mention that statistic, and many women in the U.S. immediately know it refers to their lifetime risk of getting breast cancer.
Although the statistic may stir up anxiety, those diagnosed with breast cancer today have a more positive prognosis than ever, experts say. That’s due to better understanding of the disease, wider choices of treatments, and more individualized treatment designed to reduce the risk of recurrence and lessen side effects.
While breast cancer incidence has risen by 0.5% per year in recent years, and it remains the second leading cause of cancer death in women, outpaced only by lung cancer, there are now more than 3.8 million breast cancer survivors in the U.S.
If the disease is caught early, women with breast cancer have a survival rate of an astounding 99%, though that may dip to 28% if the cancer has spread.
But despite the progress, much work remains. Read on to see how far weve come in the fight against breast cancer — and what experts say needs to happen next.
Breast Cancer: Not a Single Disease
“Breast cancer is increasingly viewed as multiple different diseases,” says Harold J. Burstein, MD, a breast oncologist at the Dana-Farber Cancer Institute in Boston.
That discovery, in turn, has helped to individualize treatment and predict exactly how much treatment is needed for a specific patient, he and other experts say.
Molecular Diagnostics and ER-Positive Cancers
New Hope for HER2-Positive Cancers
Expanded Genetic Testing
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Relative Survival Rates For Breast Cancer
The National Cancer Institute gives 5-year relative survival rates for breast cancer based on how far the disease had spread before a doctor found it.
- Localized : 99%
- Regional : 86%
- Distant : 28%
- Unknown stage: 55%
- All stages: 90%
While these numbers can give you a general idea, they are an average for women with any type of breast cancer. They arent specific to the HER2+ type. They also come from data that researchers collected from 2010 to 2016, so they dont reflect more recent treatment advances.
Risk Factors For Overall Recurrence
There are several risk factors that raise the risk of recurrence overall . These include:
- Tumor size: Larger tumors are more likely to recur than smaller ones both early and late.
- Positive lymph nodes: Tumors that have spread to lymph nodes are more likely to recur at any time than those that have not.
- Age at diagnosis: Breast cancer recurrence is more common in younger people.
- Treatments received and response to treatments: Both chemotherapy and hormonal therapy reduce the risk of recurrence in the first five years.
- Tumor grade: More aggressive tumors are more likely to recur than less aggressive tumors , especially in the first five years
There are also factors that do not appear to affect the risk of recurrence. Recurrence rates are the same for women who have a mastectomy or lumpectomy with radiation and are also the same for women who have a single vs. double mastectomy.
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