What To Look For In Your Pathology Report
When you have a biopsy for a breast tumor, the pathology report tells you a lot more than whether its cancerous or not. It provides crucial information about the makeup of your tumor.
This is important because some types of breast cancer are more aggressive than others, meaning they grow and spread faster. Targeted treatments are available for some types, but not for all.
Each type of breast cancer requires its own approach to treatment. The information in your pathology report will help guide your treatment goals and options.
Two important items on the report will be your HR status and your HER2 status.
Continue reading to learn more about how HR and HER2 status in breast cancer affects your treatment and your outlook.
Will I Need To Do Anything To Prepare For The Test
You won’t need any special preparations if you are getting local anesthesia . If you are getting general anesthesia, you will probably need to fast for several hours before surgery. Your surgeon will give you more specific instructions. Also, if you are getting a sedative or general anesthesia, be sure to arrange for someone to drive you home. You may be groggy and confused after you wake up from the procedure.
Cish And Silver In Situ Hybridization
The CISH approach and SISH method capture the advantages of both IHC and FISH. It detects HER2 gene-copy number by using a single HER2 probe. The CISH was approved by the FDA to evaluate feasibility for anti-HER2 agent. In addition, CISH has the lowest correlation with IHC 2 staining and highest with IHC 0, 1, and 3 results. Previous researches have shown about 9799% of concordance between CISH and FISH. Several clinical trials have defined criteria as 3+ for IHC test or FISH-positive tumors whereas others, like the Finland Herceptin trial, have relied on the CISH results. However, this method needs further investigations in future.
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Immunohistochemistry Criteria: Past Present And Future
The HER2 status assessment was establishment by The American Society of Clinical Oncology and the College of American Pathologists , with the publication of guidelines with recommendations for testing the level of HER2 protein overexpression by IHC and the HER2 gene amplification determined by ISH, both on FFPE breast tumor tissues. The first ASCO/CAP guideline was published in 2007 , and updated in 2013 and 2018 . In the last update, the experts refined some controversial criteria of the older guidelines and tried to systematize the testing algorithm for the unusual categories of HER2 ISH results . The results of these tests are graded semi-quantitatively as either 0 , 1+ , 2+ or 3+ by IHC, and classify as amplification , equivocal or negative by ISH. In all of these guidelines, when the HER2 status is negative by IHC and/or ISH, is not indicated the confirmation by an alternate assay. In contrast, the HER2 equivocal cases, by either HER2 IHC or HER2 ISH assays, must be analyzed with an secondary HER2 testing method, or on different tissue blocks with the same testing approach . The answer about which of the two methods is better for evaluating the HER2 status, continues to be unknown. Also, with the two latest updates, an important problem was added respecting the 2007 ASCO/CAP guidelines: more HER2 equivocal cases are diagnosed which an increase in reflex HER2 testing .
Table 3. 2018 ASCO/CAP summary recommendations .
Her2 And Survival Analyses
Among the 420 women with available HER2 status, a total of 102 women experienced recurrences during follow-up. HER2 positivity in the primary DCIS was not a risk factor for IBE in women undergoing BCS ), . Interestingly, divided by type of IBE, HER2 positivity showed a borderline statistically significant increased risk of in situ IBEs , and no association with risk of invasive IBEs ), . Results from the multivariate analyses did not differ substantially from the univariate analyses .
Fig. 1
Ipsilateral Breast cancer Events according to HER2 status of the primary DCIS. Kaplan-Meier plots showing ipsilateral recurrence-free survival analyses among women with DCIS treated with breast conserving surgery with respect to HER2 status of the primary DCIS regarding all ipsilateral events , ipsilateral in situ events , and ipsilateral invasive events
The risk of IBCRs was statistically significantly lower subsequent to a HER2 positive DCIS compared to a HER2 negative primary DCIS ) . Remarkably, the curves in the Kaplan-Meier plot did not separate until after almost 10 years . In the multivariate analyses, HRs after adjustments were very similar to the crude analyses .
Fig. 2
Invasive recurrence-free-survival according to HER2 status of the primary DCIS. Kaplan-Meier plot showing invasive recurrence-free survival analyses among women with a DCIS with respect to HER2 status of the primary DCIS
Fig. 3
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Trastuzumab With Chemotherapy After Progression
Evidence is emerging that supports continued use of trastuzumab with second- and third-line chemotherapeutic agents after disease progression on trastuzumab . The German Breast Group 26/Breast International Group 03â05 trial randomly assigned 156 patients who had progressed on trastuzumab to capecitabine alone versus capecitabine with trastuzumab. Median TTP and ORR were significantly better in the combination arm compared to capecitabine alone .
Iii Predictors Of Anti
Recent meta-analyses of published data have suggested that anthracycline-containing regimens are more beneficial than nonanthracycline-containing regimens in patients with HER-2 over expression . This is partly because HER-2 is located in the same amplicon of chromosome 17 as the topoisomerase IIa gene , which is a target gene of anthracyclines . As compared to the amplification of the HER2 gene, amplification or deletion of the TOP2A gene in breast cancers is postulated to be more closely associated with responsiveness to anthracycline-containing chemotherapy . However, it remains unclear that HER-2 and/or TOP2A amplification/alteration are ready for routine clinical use in selecting anthracycline-containing chemotherapy. Accurate and reproducible measurement remain crucial .
From one target gene to multiple target genes
HER-2 amplicon has been reported to have other relevant genes co-amplified at human chromosome locus 17q12q21. These genes could have significant impact on the biological phenotype of the tumor when amplified together with HER-2 including topoisomerase II. Data reproduced from Jarvinen TA, Liu ET. Breast Cancer Res Treat. 2003.
Pathologic complete response rates and disease-free survival
BCIRG 006 Trial Design
Study Design of HER2-based Neoadjuvant Chemotherapy
Thus, along with ER, the determination of HER-2 status independently has become an important factor in treating breast cancer patients.
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What Is Her2 Breast Cancer Testing
HER2 stands for human epidermal growth factor receptor 2. It is a gene that makes a protein found on the surface of all breast cells. It is involved in normal cell growth.
Genes are the basic units of heredity, passed down from your mother and father. In certain cancers, especially breast cancer, the HER2 gene mutates and makes extra copies of the gene. When this happens, the HER2 gene makes too much HER2 protein, causing cells to divide and grow too fast.
Cancers with high levels of the HER2 protein are known as HER2-positive. Cancers with low levels of the protein are known as HER2-negative. About 20 percent of breast cancers are HER2-positive. HER2 positive cancers tend to grow and spread faster than other types of breast cancer. But treatments that specifically target HER2-positive breast cancer can be very effective.
HER2 testing looks at a sample of tumor tissue to find out whether you have HER2-positive breast cancer.
Other names: human epidermal growth factor receptor 2, ERBB2 amplification, HER2 overexpression, HER2/neu tests
Locally Advanced Breast Cancer: Neoadjuvant Therapy
In locally advanced breast cancer, neoadjuvant chemotherapy has increased rates of breast conserving surgery . Furthermore, neoadjuvant therapy provides an in vivo assessment of response to therapy based on pathologic response. For these reasons, neoadjuvant therapy is the standard of care in locally advanced and inflammatory breast cancer, and may be considered in patients with early breast cancer.
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Understanding Your Her2 Status
HER2-negative and HER2-positive breast cancers have the same symptoms. Your doctor canât tell which type you have by examining you. Instead, theyâll run a test on a small piece of your tumor. Theyâll get the sample for testing either during a biopsy or in surgery.
Your HER2 status is one of many things that affect how fast your breast cancer will grow. There are other hormone receptors that respond to hormones in your blood as well. Doctors also sometimes refer to receptors separately as estrogen receptors and progesterone receptors .
But doctors often talk about all the different receptors together. So your HER2-negative cancer will be either HR-positive/HER2-negative or HR-negative/HER2-negative. If your cancer is negative for HER2 and both types of hormone receptors, itâs called triple negative.
Knowing your breast cancerâs HER2 status — together with its hormone receptor status — tells you and your doctors about the biology of the cancer. It helps doctors decide which treatment is best to try first and what options you have if you need to try something else later.
Some breast cancer treatments work by targeting HER2. If your cancer is HER2-negative, your doctor wonât use those therapies. Theyâll suggest other options based on how advanced your cancer is and whether itâs positive for hormone receptors. They might also look at other factors, including genetic or other changes in your cancer that could affect how fast itâs likely to grow or spread.
How Her2 Status Affects Treatment
For more than 30 years, researchers have been studying HER2-positive breast cancer and ways to treat it.
Targeted therapies have now changed the outlook of stage 1, 2, and 3 breast cancers from poor to good.
While targeted therapies are part of the standard treatment for HER2-positive breast cancer, theyre only used occasionally in HER2-negative breast cancer.
Another difference between HER2-positive treatments and HER2-negative treatments is that HER2-negative treatments are often oral medications. HER2-positive treatments are usually administered intravenously or by injection.
For HER2-positive or HER2-negative breast cancers that are estrogen-positive or progesterone-positive, treatment with hormonal therapy may also be recommended.
Medications that may be used to treat HER2-negative breast cancers that are hormone-negative include:
- sacituzumab govitecan , an IV treatment
Medications that may be used to treat HER2-negative breast cancers that are hormone-positive include:
Some of these medications are taken on their own, while others must be administered with other medications. Factors that affect your treatment regimen include whether:
- youve gone through menopause
- youve already received hormone therapy or chemotherapy
- you have certain gene mutations
Trastuzumab , when used in tandem with chemotherapy, has improved the outlook of those with HER2-positive breast cancer. This targeted drug is often the primary treatment for the condition.
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Combination Her2 Directed Therapy
The combination of lapatinib and trastuzumab has demonstrated synergy in preclinical models and has recently been shown to improve PFS in patients with MBC that had progressed on trastuzumab . In a phase III trial, 296 HER2-positive patients whose disease had progressed on trastuzumab-containing regimens were randomized to receive lapatinib alone or lapatinib with trastuzumab. The median PFS was 12.0 weeks in the lapatinib plus trastuzumab arm and 8.1 weeks in the lapatinib arm . The combination of trastuzumab and lapatinib was well tolerated, with fewer serious adverse events than would be expected with a chemotherapy containing regimen . In an updated analysis, the median OS was 14 months for the lapatinib plus trastuzumab arm, compared with 9.5 months for the lapatinib arm .
Biology Of Her2+ Breast Cancer
The ErbB family of receptor tyrosine kinases is comprised of four cell-surface receptors, HER1 , HER2, HER3, and HER4. Upon receptor dimerization an intracellular signaling cascade is activated, resulting in cell proliferation, survival, invasion, and angiogenesis . In contrast to the other ErbB family members, no ligand has been identified for HER2 . However, HER2 is the preferred dimerization partner within the ErbB family, a feature which contributes to its importance .
The HER2 Signaling Pathway
Ligand binding induces dimerization, leading to activation of the intracellular tyrosine kinase. On auto- and cross-phosporylation of the receptor complex, key downstream effectors are recruited. This figure illustrates a HER2-HER3 heterodimer, but HER2 can also form homodimers or heterodimerize with other members of the HER2 family. FKHR, forkhead in rhabdomyosarcoma Grb2, growth factor receptor-bound protein 2 GSK-3, glycogen kinase synthase-3 MAPK, mitogen-activated protein kinase mTOR, molecular target of rapamycin PI3K, phospatidyl-inositol 3-kinase PTEN, phosphatase and tensin homologue deleted on chromosome 10 SOS, son-of-sevenless guanine nucleotide exchange factor.
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How Is Breast Cancer Categorized
- The tumors grade
- If its positive for estrogen and progesterone hormone receptors or HER2
- If the cancer cells have spread to neighboring tissue and lymph nodes
- If the cancer cells have metastasized
Breast cancer also falls within four HR/HER2 subtypes:
- HR+/HER2+ means the tumor tested positive for estrogen and progesterone receptors and HER2.
- HR-/HER2- means the tumor tested negative for estrogen and progesterone receptors and HER2. Triple-negative tumors tend to grow quickly and are often found later than other forms of breast cancer.
- HR+/HER2- means the tumor tested positive for estrogen and progesterone receptors and negative for HER2. This subtype accounts for most cases of breast cancer.
- HR-/HER2+ means the tumor tested negative for estrogen and progesterone receptors and positive for HER2.
According to rates from the National Cancer Institute, of 100,000 new breast cancer cases among women between 2015 and 2019:
- 12.9 were HR+/HER2+ with a five-year relative survival rate of 90.7 percent
- 13.2 were HR-/HER2- with a five-year relative survival rate of 77.1 percent
- 87.4 were HR+/HER2- with a five-year relative survival rate of 94.4 percent
- 5.2 were HR-/HER2+ with a five-year relative survival rate of 84.8 percent
- 9.2 were of unknown status with a five-year relative survival rate of 75.5 percent
The cancers stage and subtype will guide treatment. For example, treatment for triple-positive breast cancer includes HER2-targeting drugs and hormone-blocking medicines.
Her2 Status And Patient And Tumor Characteristics
Of all 458 women, 420 could be HER2 classified using available SISH or IHC data 132 were classified as HER2 positive and 288 as HER2 negative. Of 344 cases with available SISH data, 118 were HER2 positive and of 408 cases with IHC data 103 were classified as HER2 positive . In comparison, SISH and IHC data showed concordance in 296 of 332 cases with available data for both SISH and IHC. Twenty-nine of those 332 cases were classified as HER2 2+ by IHC, 21 of those 29 were SISH positive and eight were SISH negative. In 38 cases, data on HER2 status was missing all together. HER2 status was significantly related to tumor size, nuclear grade and hormone receptor status, and the HER2 positive tumours tended to be detected by screening more often than HER2 negative tumors. HER2 status was not associated with age at diagnosis, type of surgery or RT . In analyses assessing risk of recurrences according to established patient-and tumor characteristics, clinically detected DCIS were more prone to recur locally , larger DCIS lesions were correlated to a borderline significant increased risk of in situ IBEs but not invasive IBEs and 0.64 ), respectively. Other assessed factors were not associated with recurrences .
Table 2 Patient- and tumor characteristics of the primary DCIS in relation to risk of a breast cancer event. Risk of an ipsilateral breast cancer event including risk of in situ IBEs and invasive ipsilateral recurrence, respectively, and any invasive recurrence
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How Will Her2 Status Affect Treatments
Standard treatment for most breast cancer starts with surgically removing the tumor, followed by radiation therapy, chemotherapy or a combination of both. Doctors may try other drugs and approaches, such as immunotherapy, depending on the patients general health and the cancers characteristics.
For HER2-positive breast cancer, treatment may also include three kinds of targeted therapy:
- Monoclonal antibodies are manmade antibodies that stick to HER2 receptors to slow tumor growth.
- Antibody-drug conjugates, which are monoclonal antibodies combined with a chemotherapy drug. They deliver chemotherapy directly to cancer cells using antibodies that stick to the HER2 proteins.
- Kinase protein inhibitors block signals from the protein. HER2 is a kinase protein.
Side effects of these treatments vary. While most are mild, there may be some serious side effects:
Targeted Therapeutic Strategies For Neoadjuvant Treatment
Trastuzumab in neoadjuvant therapy
HER2-positive breast cancers may have potential chemosensitivity in combination with trastuzumab, in the neoadjuvant treatment. The trastuzumab treatment in neoadjuvant therapy provides significant clinical benefits and reduces the rate of distant metastasis. The HER2 gene amplification is shown to be related to the growth and survival of breast cancer stem cells, to some extent.,
As seen in both, completed and ongoing clinical studies, the trastuzumab-based neoadjuvant therapy has a higher pathologic complete response in the treatment of HER2-positive breast cancer. Such phenomena results from removing or downregulating HER2-mediated growth signals to inhibit stem cell proliferation and invasion. There is need to explore about HER2-targeted therapy that can convert a HER2-positive into a HER2-negative subtype. As per the previous reports, to achieve pCR in neoadjuvant setting of trastuzumab plus chemotherapy, nearly 33% of patients with HER2 overexpression were converted to HER2-negative subtype in the treatment failure group.
There are still some limitations in this assumption, and it requires further discussion and additional prospective studies to validate.,
Other target therapy in neoadjuvant setting
In order to achieve higher efficacy of anti-HER2 therapies, several randomized phase III studies have explored the hypothesis of lapatinib monotherapy or its addition to trastuzumab regimen.
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Patient And Tumour Characteristics
Baseline characteristics by HER2 status are presented in Table . The mean age at diagnosis was 58.6 years, ranging from 30 to 90 years of age. A total of 202 women were diagnosed in Västerås, whereas the remaining 256 patients were diagnosed in Uppsala. In most cases, the DCIS was detected by mammographic screening . All patients except one underwent surgery with the majority of patients operated with breast conserving surgery . Surgery was followed by postoperative radiotherapy in 35.2 % of all cases, although primarily for patients operated with BCS of whom 44.0 % received RT . None of the patients received hormonal therapy or chemotherapy according to Swedish clinical guidelines.
Table 1 Baseline characteristics by HER2 status in 458 women with a primary DCIS