Welcome to First Incision, the podcast about preparing for the General Surgery Fellowship exam. I'm your host, Amanda Nikolic. We are on to our third episode of First Incision. Thanks so much for sticking around so far. If you thought the topics that we covered in the last two episodes were pretty in-depth, Be prepared for this episode. Getting into our team timeout for today, our patient is early breast cancer and the operation or topic we're going to be covering today include the following.
epidemiology, presentation and assessment, different classification systems, staging, the gene expression profiling, and also genetic breast cancers. And in our next segment, we'll go more into the treatment of early breast cancer. I guess it's time to get started. Specifically today, we're going to be focusing on early breast cancer. Early breast cancer is defined as tumors less than five centimeters in size.
with or without lymph nodes, with no local invasion or metastasis. More specifically, I'm referring to stage 1 or stage 2 breast cancer. So this includes tumors that are less than two centimeters with no spread to lymph nodes. These are stage one. Stage 2A, which are tumors that are less than two centimeters and spread to one to three auxiliary nodes.
Or tumors between 2 and 5 centimeters with no spread to lymph nodes. And stage 2B tumors, which includes tumors that are 2 to 5 centimeters with spread to 1 to 3 lymph nodes. Stage 2B tumors can also include tumors that are more than 5 centimeters, but because we're only talking about early cancers, we're talking about cancers that are less than 5 centimeters in size.
Early breast cancer may also encompass some stage 3A tumors. So these are tumors that are less than 5 centimeters but have spread to a higher number of lymph nodes, so 4 to 9 lymph nodes. Breast cancer is a very common pathology in the Western world. One in eight women will be diagnosed with breast cancer in their lifetime and it's more common as you age. So women over 40 are more likely to have breast cancer.
In addition, in Australia, there's approximately 150 men that are diagnosed with breast cancer each year. There's a number of risk factors we can talk about. Some of these are modifiable and some of these are non-modifiable. Modifiable risk factors include alcohol use, smoking, radiation exposure. Non-modifiable risk factors include being a female.
being older than 50, having a genetic predisposition, so a strong family history or a known genetic abnormality. And then other risk factors include those related to estrogen exposure. So patients who've had early menarche or late menopause, who've never had children or nulliparity, who've had a delayed first pregnancy. So their first pregnancy was when they were older.
are on hormone replacement or who didn't breastfeed are also at increased risk of breast cancer. Most breast cancers are thought to be sporadic, approximately 95%. are not related to a genetic predisposition or hereditary cancer. And the thought is that increased exposure to hormones, especially estrogen, will stimulate breast growth and cell cycle proliferation, which increases the risk those cells have of having DNA damage over time and therefore become...
a cancer. So how do we pick up early breast cancers? So patients can either be symptomatic or asymptomatic. In Australia, there is a breast cancer screening program that's run through Breast Screen Australia. This is a national program that offers free mammograms every two years to women aged between 50 and 74. And so you often will see patients referred to clinic with a screen-detected breast cancer.
Women less than 40 years old can also get a free mammogram, especially if they're concerned or have a family history, but they're not sent a letter inviting them to present for free screening. They have to seek this out themselves. In terms of symptomatic patients, patients may come complaining of a lump in the breast or the axilla. They may notice skin changes or tethering. There may be nipple discharge, bleeding or inversion.
breast asymmetry, a palpable auxiliary mass, or constitutional symptoms if they're presenting with a more advanced tumor such as fatigue, anorexia, or weight loss. This is more likely in those more advanced cases. When a patient does present with a lump, the classic teaching is that they should have a triple assessment. And what is a triple assessment? A triple assessment is a combination of number one, history and examination. Number two, imaging.
And number three, a biopsy or tissue diagnosis. So let's go into more detail about each of these points. History of these patients should... involve especially if they're symptomatic what they've noticed over what period of time where the lump is how long it's been there for whether it's changed in size those sorts of factors related to the lump
In addition, there should be a history of their risk. So some information should be gathered about their hormonal exposure and the number of years. So the history about when they had their menarche and whether they've gone through menopause. and what age that occurred, whether or not they've been on the contraceptive pill or on HRT, whether or not they've had any children and whether or not they breastfed those children and the age that they had those children.
There should also be a history of past history of breast disease, so whether or not they've previously been investigated for any breast lumps, diagnosed with any breast pathology, and specifically those benign breast disease we talked about that increase their risk. of having a malignancy.
In addition, family history should be taken to determine whether or not there may be an underlying genetic predisposition and specifically you should be asking them about first and second degree relatives with breast or ovarian cancer or other tumours that may seem... to run in the family. Other factors to consider are whether that patient has ever had any radiation therapy and a alcohol history should also be taken.
A breast examination is the next step in the triple assessment. This involves general inspection of the breast, looking for scars, any radiotherapy tattoos, previous portacath. looking for symmetry, whether there's any skin changes, any tethering, poda orange or inflammation, whether there's any puckering of the skin, and this is best done with the patient putting their hands on their hips. And also whether there's any tethering. So have the patient put their hands above their head.
An inspection should also be done of the nipple areola complex, looking for any inversion or discharge, as well as whether there's any evidence of lymphedema on the breast or in the arm. The next step after inspection is palpation. You can do this with the patient lying down or sitting up, but this should involve a systematic examination of the breast tissue being pushed against the chest wall, feeling for any masses.
If a mass is identified, the location of the mass as well as the size and characteristics, so whether it's tethered, lumpy, rubbery, hard, should be documented as well as the location, so what quadrant it's in. and a comparison made of the total breast size to the size of the lump. And the axilla should also be examined. I do this with the patient sitting up and taking the weight of their arm in my arm to help relax.
the muscles in the axilla and make sure that you're palpating the axilla against the chest wall as well as the lateral nodal groups to make sure that you're examining the whole axilla. Again, you're feeling for any rubbery or enlarged. or tethered nodes. The next step in the triple assessment is imaging. For most women especially those over 35 you would start with a mammogram and ultrasound.
The sensitivity of mammogram is reduced in patients with dense breasts and dense breast tissue is common in women under 35. And in those patients, you would consider just starting with an ultrasound rather than a mammogram. There is a classification system to classify breast density based on mammographic appearance. This gives you a score of A, B, C, or D, with A being an almost entirely fatty breast. B being scattered fibroglandular density.
C being heterogeneously dense with patches of density, which may obscure a small mass. And D is an extremely dense breast. And these breasts are very poor. candidates for mammography as it's very easy to miss lesions. Standard views you'll get for a mammogram are craniochordal and mediolateral oblique. And both of these should be looked at to try to give you a 3D picture of where a lesion may actually be.
When you're looking at a mammogram, a good approach is to firstly make sure that on the medial lateral oblique, you can see the pec major muscle so that you ensure that they've included enough of the breast. You're looking for symmetry, any architectural distortion or masses, whether there's any densities. You're looking at calcifications with macro calcifications, larger calcifications often being benign.
but micro calcifications being more concerning. You may also be able to see nipple retraction or skin involvement, and it's always a good idea to compare an old mammogram with a new mammogram. Suspicious or malignant lesions on a mammogram will typically appear speculated with architectural distortion.
And they may also be associated with microcalcifications that are smaller than 0.5 millimetres, are pleomorphic, so multiple shapes, and are often clustered in one area. Mammogram reports are... also often reported according to the BI-RADS classification. And this is a classification system that gives you a score between 0 and 6 about how suspicious a lesion that's seen on mammogram may be or how suspicious any lesion on the mammogram may be.
So a BI-RAD zero score shows an incomplete mammogram, which means that they either need additional imaging or additional views or an ultrasound or... may be given if previous mammogram is not available for comparison, so they want that first prior to giving a BI-RADS score. A BI-RADS 1 is a negative mammogram. So this shows a normal mammogram with no suspicious findings and this patient should be put back onto regular surveillance. BI-RADS 2 score is a benign.
mammogram. So this says that any lesions that are found have a 0% probability of malignancies. This may include things such as cysts. BI-RADS 3 is a probably benign mammogram. So less than 2% probability of a malignancy. And in these patients, you would consider organizing a shorter follow-up. So for example, organizing another mammogram in six months and comparing to make sure that those lesions that may be suspicious have not changed at all.
A BI-RADS-4 result is a suspicious for malignancy result. So this means there's between a 2% and 94% probability of malignancy. And these patients should have further imaging with an ultrasound and a biopsy should be considered for the findings. A BIRADS-5 is highly suggestive of malignancy. So this is where the radiologist is 95% sure that a lesion scene is a malignancy, and this should proceed to a biopsy.
And a BIRAD6 score is where there's a known malignant lesion. So it's already been biopsy proven as a cancer. An ultrasound is also often done for breast pathology. This is good to do with a mammogram, especially if there's lesions seen, as it gives you more information about that lesion. So for example, you'll be able to tell if a lesion is cystic or solid, and it also gives you more information.
be used to guide a biopsy. It's not great for screening because it only looks at small areas at a time and also doesn't give you a good picture of any calcifications. So findings on an ultrasound that would be suspicious for a cancer is a lesion that's taller than it is wide, that has posterior acoustic shadowing. that has poorly defined margins, that's invading through tissue planes or distorting architecture. They're usually hypoechoic. They may be lobulated and can have internal vascularity.
The ultrasound can also be used to investigate the axilla and have a look at lymph nodes. Lymph nodes that would be suspicious for being involved in tumours are ones that are enlarged, that are heterogeneous. have loss of their fatty hilum. That would have a thickened cortex. They may have calcifications in them. They may be round instead of an oval shape. They could be hypervascular.
and also can lose the quadomedullary differentiation. So all of those things would be concerning for an involved lymph node. And you can use ultrasound to guide core biopsy of a mass or ultrasound guided FNA of a lymph node. Talking about biopsy, that is the third step in our triple test. Typically for a mass in the breast, a core biopsy is preferable over a FNA.
The reason this is is because a lot of the lesions, as we talked about on the last podcast when we were talking about benign breast diseases, can be difficult to differentiate from each other and really the architecture of the lesion and whether or not it's invading through certain layers or not will determine how that lesion is classified. So you can't get that information on an FNA.
The other thing that's difficult is doing immunohistochemistry and getting hormone receptor statuses, often FNA, that often isn't enough material and it can't be fixed properly. biopsy of choice would be a core biopsy. This can be done in the room if you have a palpable lesion or an available ultrasound and appropriate skill or can be done by a radiologist. and typically involves using a 14 gauge needle and a local anesthetic to take multiple cause of the lesion.
You may get a number of results back on the core biopsy that could include it being inadequate or insufficient, benign, atypical or indeterminate. suspicious for malignancy or malignant and it's important that especially for concerning lesions with a result that doesn't marry up with the imaging findings that further biopsies are taken and it's discussed with a specialty breast unit or in an MDT.
Talking about triple assessment and imaging, there is a lot of research going on at the moment into the use of MRI in breast cancer. You may have seen this done for patients who are very young or have multiple tumors or lobular cancers. Basically, MRI is very sensitive in diagnosing cancers, but it does have a false... positive rate of 10 to 15%. It is rebated or funded in Australia for screening for asymptomatic women less than 50 years old who are high risk for development of breast cancer.
These include patients with a known genetic abnormality, such as those with BRCA gene, patients with more than three first or second degree relatives on the same side with breast or ovarian cancer. More than two first or second degree relatives on the same side with breast or ovarian cancer with an additional history of bilateral breast cancer in the family.
onset at less than 40 years old of breast cancer or less than 50 years old of ovarian cancer, both breast and ovarian cancer, male breast cancer, or patients of Ashkenazi Jewish ancestry. And also patients with one first or second degree relative with a diagnosis of breast cancer at less than 45 years old. And another first or second degree relative on the same side of the family with a bone or soft tissue sarcoma.
Breast MRI is also good for younger patients who may not be eligible for mammograms because they have quite dense breasts. as well as patients with implants. It's the best imaging modality to see the breast tissue around the implant and may also be useful in patients with previous breast surgery as well as patients presenting with an auxiliary node. Tumor with an unknown primary and also in patients with Paget's disease of the nipple who do not have an obvious underlying primary.
Before I move on to our next section, which is classifying breast cancer, I just want to briefly touch on the different molecular markers that we look at and their clinical significance. When I talk about molecular markers, I mean estrogen and progesterone receptors as well as HER2. So estrogen and progesterone are nuclear hormone receptors and they are located in the cytosol of target cells.
Oestrogen receptor is a ligand-dependent transcription factor and is composed of two receptors, ER-alpha and ER-beta, and approximately 70% to 80% of invasive cancers are ER-positive. PR is expressed in response to ER activation. 55% of tumours are both ER and PR positive. And of these tumors, about 70% of them will have a good response to endocrine therapy. If patients have ER positivity but PR negativity, then they have a worse prognosis and it's not really clear why that is.
And 50% of ER negative tumors will express PR receptors and some of these will respond to endocrine treatment. Another molecular marker that we talk a lot about is HER2. HER2 stands for Human Epidermal Growth Factor 2 and can also be called NEW or CERB2, C-ERB2. And this receptor is a tyrosine kinase receptor that sits on the surface of the cells. And when it is signaled or activated, it upregulates cell growth. And it's part of the epidermal growth factor receptor family.
It's encoded by the gene ERB2, and this is a proto-oncogene located on the long arm of chromosome 17. Gosh, proto-oncogenes, this is going back to medical school. So proto-oncogenes are genes that regulate cell proliferation and damage that... is done to the DNA that encodes a gene that's critical to the cell cycle regulation, changes a proto-oncogene into an oncogene. And only one mutation is required as these genes work in a dominant manner.
So going back to HER2, breast cancer cells can overexpress HER2 and therefore they get increased signals to divide and grow. When we're looking for HER2, we use immunohistochemistry, which stains for the actual protein or receptor that's on the cell surface.
There's different grading to say whether or not it's positive or negative. And this grading system is that if there's absolutely no staining observed or less than 10% of the cells have staining for the HER2 receptor, then it's scored as zero or negative for HER2. If there's a faint or barely perceptible staining in more than 10% of the tumor cells and only in part of the membrane, then it's scored as a 1+, and this is also classified as negative.
If there's weak to moderate staining, especially on the whole membrane in more than 10% of cells, then this is scored as 2+, and this is called weakly positive or equivocal. And if there's strong staining in more than 30% of cells, then this is three plus and is classified as positive. If you get an equivocal result, then the...
Tumor should be sent for FISH or CISH, so fluorescence in situ hybridization or silver in situ hybridization. And what this does is this actually looks at the number of copies of the gene on chromosome 17 in that. sell and if there's more than two copies then it's counted as positive. HER2 is clinically significant because overexpression of HER2 is a marker of a poor prognosis and also associated with a poor response to endocrine treatment.
But it is a marker of good response to chemotherapy and specifically to anti-HER2 targeted therapies such as Herceptin or Trastuzumab, which in Australia we give in combination with chemotherapy. And it is a prognostic marker that's independent of the stage of the tumor, how many lymph nodes are involved, the grade, et cetera. So an important thing to know when we're talking about breast cancer.
there are a number of ways to classify or subtype breast cancers one of the ways that we do this is by looking at the molecular subtype of breast cancer This basically groups breast cancer into subtypes based on the genes that they express. And the different subtypes themselves act in different ways. They have different activity, biologic behavior.
and some are more aggressive than others. Although we don't... routinely test the genes of the tumor, we do use ERPR and HER2 receptor status as a surrogate to approximate these subtypes and guide our clinical decision making. The different subtypes include luminal A, luminal B, HER2 enriched, and basal or triple negative. So for luminal A tumours, we're talking about... ERPR positive tumors that are HER2 negative. They will often have a low grade and a low KI67 index. These tumors are...
typically not very aggressive and will have a good prognosis with treatment. They also do not respond well to chemotherapy. Luminal B. Tumors are slightly higher grade than luminal A. They are also ERPR positive, but they can be HER2 positive or negative. They often have a higher grade and a higher KI-67 index than a luminal A tumour and have a slightly worse prognosis. They also may not respond as well to chemotherapy.
HER2 enriched tumors are usually ERPR negative and HER2 positive. They have a high grade and a high KI67 index and are quite aggressive but do respond to targeted. therapies such as trastuzumab, which we'll talk about a little bit later. And triple negative tumors or basal-like tumors are ERPR negative and HER2 negative. They're typically high grade with a high KI-67 index. They have a poor prognosis and respond well to chemotherapy.
When we're talking about the grade, so high grade, low grade, there is a classification system which is used for determining this. This is based on the histological appearance of the tumor. And in Australia, we would often use the modified Bloom-Richardson grading system. And this looks at three areas and each of these areas are given a score between one and three.
It looks at the tubule formation, so what percentage of the tumor is made of normal appearing tubules. If it's got more than 75% that look pretty normal, you get one point. If it's 10% to 75%, you get two points. And if it's less than 10% tubule formation, then you get three points. It also looks at nuclear.
pleomorphism. So at the nuclei, are they small, uniform, do they look pretty similar, or are they very large, different in size, look quite bizarre, or somewhere in between. So you get one point if the nuclei... are small, uniform, similar size without many nucleoli. You get two points if the nuclei are enlarged and you get lots of nucleoli but are mostly the same size. And you get three if you have large, bizarre, pleomorphic with lots of prominent nucleoli.
And the last thing that we look at is mitotic figures. So how many mitotic figures can be found in 10 high-powered fields? You get one point if there's rare mitoses, so 0 to 9. You get two points if there's frequent mitoses, 10 to 19. And you get three points if there's lots and lots of mitoses, more than 20. And so if you get a score of three to five, then this is sort of a low-grade, well-differentiated grade one tumor. If the score is six to seven, then it's a grade two.
And if the score is eight to nine, then this is a poorly differentiated grade three tumor. Unfortunately, there is another way that we can classify. breast cancers. And this is by their histological subtype, which is essentially the way that the tumor looks under the microscope. This is important to know because certain histological subtypes behave differently and therefore the histological subtype will have prognostic information and prognostic value for that patient.
The most common histological subtype is invasive breast cancer of no special type. And this used to be called invasive ductal carcinoma, but the nomenclature is changing. This is the most common, with about 70-80% of breast cancers being an invasive breast cancer of no special type. And under the microscope will look pretty heterogeneous with diffuse sheets, nests, cords or single cells with a variable amount of ductal differentiation. This type is often associated with ductal carcinoma in situ.
The next most common histological subtype is the lobular subtype, and this is about 10% to 15% of breast cancers. The lobular subtype is characteristically negative for E-cadherin, which can be stained for using immunohistochemistry. E-cadherin is a protein on the surface of the cell that lets the cells stick to each other.
and loss of ecadherin means that the cells can spread out. So looking at a lobular cancer under the microscope, you may see what's called an Indian file arrangement of the tumor cells, which means they're lined up with, and they're more likely to be. multifocal or spread out. Typically, the cells are round and small and they don't stick to each other. They're labeled as non-cohesive and often have this single cell infiltration of the surrounding stroma.
These tumors are more likely to be hormone responsive and distinctly have a metastatic pattern that includes spread to the ovaries, gastrointestinal system. and peritoneum compared to invasive ductal carcinoma, which is more likely to metastasize to the liver and lung. Lobular carcinoma can also be subclassified into a number of types that include classic. pleomorphic, histiocytoid, signet ring or tubulolobular. The rest of the histological subtypes of breast cancer are much less common.
They account for about 10% of breast cancers. Some important ones to know include the medullary breast cancer. This is common in younger patients and patients with BRCA1 mutations, and it does have a better prognosis than ductal carcinoma. Classically on microscopy, you'll see sheets of tumor cells with scant stroma, a stromal lymphoid infiltration, and a pushing border.
And it's often a well-defined tuber mass, so it can be mistaken for solid tumors such as fibroadenomas. A mucinous subtype can also be called a colloid carcinoma. This is very rare, but is actually associated with a very good prognosis. It's common in the seventh decade of life. And under the microscope, you'll see a lot of mucin production, which is the hallmark of this tumor.
Another subtype is the tubular subtype. This is also very rare, but again, is associated with a really good prognosis. Under the microscope, you may see a single layer of epithelial cells. low-grade nuclei, and atypical cytoplasmic snoutings, which are arranged in tubules and glands. This has a very low incidence of lymph node involvement as well.
There are further subtypes, but these are super rare. These include papillary, so invasive papillary carcinoma is one of these types. There's also an invasive micropapillary carcinoma. And this is much more aggressive than invasive papillary carcinoma. It has a high rate of lymph node metastases and a much worse outcome and survival than invasive ductal carcinoma. And this also compares to an invasive papillary carcinoma, which has a better prognosis than invasive ductal carcinoma.
It's very rare and is usually centrally located. As you can imagine, it's thought to be associated with papillomas and atypical papillomas and is often ERPR positive. Apocrine is another histological subtype. This is very rare and has prominent apocrine differentiation. This is often high grade with poor prognosis. You can get neuroendocrine tumors in the breast. These are also very rare.
Like all neuroendocrine tumors, a neuroendocrine tumor itself is a much better prognosis than a neuroendocrine carcinoma. So it's classified as per neuroendocrine tumors elsewhere in the body and will have positive staining for synapse. and chromogranin A markers. Another histological subtype is the adenoid cystic. This is a low-grade, good prognosis tumour.
and can be seen as similar to a salivary tumor on microscopy. It can be found in a wide range of ages of patients, so between 25 and 80 years old, but it's most common post-menopause. Metaplastic breast cancer also is worth a mention. This is a super rare, less than 1% of breast cancers, but it's a very aggressive breast cancer. And it includes a number of subtypes, so spindle cell carcinoma.
carcinosarcoma, squamous cell carcinoma of ductal origin, adenosquamous carcinoma, and carcinoma with pseudosarcomatous metaplasia. They are often very large, grow rapidly. Commonly node negative as they spread more like a sarcoma via hematogenous spread. There are others with the WHO classification recognising at least 17 distinct. histological special types, but those are the ones that I have chosen to talk about today, but feel free to do some reading.
Moving on now to breast cancer staging, the American College of Surgeons published the eighth edition of the AJCC Cancer Staging Manual, which has a lot of detail about breast cancer staging. This is worth having a look at, but it does go into a lot more detail than I think is required for the exam. And so I'm just going to do a summary of the salient points of the TNAM staging system.
The first thing to know is that there is different staging depending on whether the patient is pre-op, post-op or pre- or post neoadjuvant treatment. So for example... You would put a small C in front of the staging classification if this was clinical staging. So this is using information that you have before surgery or any neoadjuvant treatment.
You would put a small P in front of the staging if you were using pathological information that you've gathered post-surgery, so using the pathology report. And if the patient has had neoadjuvant systemic therapy... prior to surgery, then you would use the designation YP to indicate that that patient had had neoadjuvant treatment. So we'll start with the T stage. This stands for tumor. So this is looking at the primary tumor. The first T stage you may come across is...
TIS, which means tumor in situ. And this can be either DCIS, ductal carcinoma in situ, or Paget's disease of the nipple, which is not associated with any underlying cancer. or DCIS. If this was, then it should be referred to according to the underlying tumor. T1 are tumors that are less than or equal to 20 millimeters in size. This can be split into T1. MI, which is a less than one millimeter in size tumor. T1A, which are tumors that are one to five millimeters in size.
T1B, which are tumors that are 5 to 10 millimeters in size, or T1C, which are tumors that are 10 to 20 millimeters in size. T2 tumors are 20 to 50 millimeters. T3 tumors are greater than 50 millimeters. And T4 tumors are tumors of any size but that have direct extension into the chest wall or into the skin. And this can be subclassified into AB. C and D. So T4A is extension into the chest wall, such as invasion into the pectoralis muscle.
T4B is ulceration or satellite nodules or edema including poda orange of the skin that doesn't meet the classification for inflammatory breast cancer. T4C is where both T4A and T4B are present. And T4D is inflammatory breast cancer. Moving on to N, which is looking at the nodal status of the tumor. N0 is no regional lymph node metastases or only isolated tumor cells found. With isolated tumor cells, meaning the largest contiguous tumor deposit is not larger than 0.2.
millimeters. N1 is micrometastases or macrometastases found. Micrometastases being at least one contiguous tumor deposit larger than 0.2 millimeters and less than two millimeters, with a macrometastasis being a tumor deposit greater than two millimeters in size. N1 is classified as micro or macrometastasis in one to three auxiliary lymph nodes. N2 is four to nine axillary lymph nodes. And N3 is 10 or more axillary lymph nodes.
There is further classification under N1, N2, N3 that involve whether or not the internal mammary lymph nodes are involved radiologically, as well as whether there is involvement of the level 3 auxiliary lymph nodes, which are the... infraclavicular nodes and it's worth having a look at the AJCC staging manual to look at that in more detail.
It's also worth noting that the supraclavicular lymph nodes are not considered regional nodes. And therefore, if they are involved, then they're considered distant metastases. So that brings us to the M part of the TNM staging, with M being distant metastases. And this one's quite easy. M0 is no clinical or radiological evidence of any distant metastases.
M1 is evidence of distant metastases, and that can include, as I've mentioned, supraclavicular lymph nodes or metastases in the liver, lung, or elsewhere. This does bring us to the role of other imaging in early breast cancer, specifically looking at CT scan, bone scans and PET scans. This comes into staging of breast cancer and really patients with early breast cancer should be considered for staging if they have any evidence of local invasion or involved auxiliary lymph nodes.
In these patients, it's worth doing a CT chest abjopelvis, and this is quite good for picking up metastases in the lung, liver, and potentially pleura or peritoneum. A bone scan is used to evaluate the skeleton for bony mets. And again, this is good for patients with a high risk of systemic spread at diagnosis or those with bony pain. If a bone scan is not available or you have access to a spec to CT with 3D imaging, this can also be used.
In Australia, PET scans are now funded for staging of locally advanced breast cancer, so stage three. This doesn't necessarily come in under early breast cancer and can also be funded for evaluation of suspected metastatic. or locally or regionally recurrent breast cancer. But this is relatively new. So we'll be seen being used a lot more, I think, in the future. Talking about things that may be used a lot more in the future.
There is also gene expression profiling tests. These may also be called prognostic tools or molecular risk tools. These are relatively newly developed and being used in the assessment and management of breast cancer. genetic assays looking at the gene expression of the tumor to determine a risk of recurrence of breast cancer. So they actually get a slide of the tumor itself and run these tests on that tissue. The clinical use of this is developing.
There are a number of different tests that can be used in different ways, but it seems like they could be used. in patients who you're unsure whether or not they may need or not need neoadjuvant chemo or adjuvant chemo and can also be used to determine whether or not you should be using endocrine treatment and for how long. So examples of this include one of the most commonly used, which is the Oncotype DX test. And this is used to predict the risk of recurrence of early breast cancer.
That's ER positive and node negative. And also to determine how likely a woman might be to benefit from adjuvant chemotherapy. It can also be used, and the only one that I've found, that can be used to look at the risk of recurrence of DCIS and also how likely a patient is to benefit from radiotherapy after DCIS surgery.
And this test looks at 21 genes and gives a recurrence score between 0 and 100. And the cutoffs for whether these are low risk or high risk depends on whether a patient is postmenopausal or premenopausal. And this has the sort of strongest research behind it. Other tests include the mammoprint test. And this is used on stage one and stage two early tumors that are less than five centimeters in size and have less than three lymph nodes involved that are ERPR positive as well as...
negative tumors. And these look at 70 genes and calculates a recurrence of tumor, recurrence of cancer risk score. There's also the endopredict. And this is used to predict the risk of distant recurrence of early stage hormone positive HER2 negative breast cancer with less than four lymph nodes involved. And again, you get a high or a low risk result of that breast cancer. And this considers 12 genes, but also looks at the size of the cancer and the lymph node status. Another one is the...
ProCigna breast cancer prognostic gene signature assay. And this was previously the PAM50, which was much easier to say and remember. But this is used to produce the... Predict the risk of distance recurrence in postmenopausal women within 10 years of diagnosis of an early stage hormone receptor positive disease with less than four lymph nodes. And it should be done after five years of hormone therapy.
And this guides whether or not five years of hormone therapy is enough or whether 10 years of treatment should be done. And this looks at 58 genes. There's also other online prognostic calculators that you can use to formulate a risk assessment to help guide decision making. And this includes the...
predict breast cancer tool and adjuvant online score. Some of these I have seen used in clinical practice. There was one patient who had what looked like quite a good... prognostic tumor with ER positive HER2 negative but she went on to have one of these tests which identified that she had a high risk of recurrence and so she went on to have neoadjuvant chemotherapy. And my understanding is that...
these genes help to classify the tumors into those molecular subtypes slightly better. Remember that we're using the ERPR and HER2 status as a surrogate to put tumors into those molecular subtype boxes. But because they're actually testing the genes, you can get a better picture for the behavior or predicted behavior of those cancers.
In Australia, I think at the moment, women have to self-subsidise or pay for these tests themselves, but that may change as they gain further evidence. So watch this space. The last topic I'm going to be talking about today for early breast cancer, because we have covered a lot, is the genetic breast cancers. So approximately 5% to 10% of breast cancers are thought to have some sort of genetic or hereditary component.
When you're taking a history from a patient who's concerned that they have a family history or may have a predisposition for breast cancer, the following are... factors that would increase their risk or associated with a higher risk of having an underlying genetic abnormality. This includes a blood relative who has had breast cancer diagnosed at less than 50 years of age.
Breast and ovarian cancer on the same side of the family or in the same person. A relative with a triple negative breast cancer. Other cancers that run in the family, including prostate, melanoma. pancreatic, gastric, uterine, thyroid, colonic, and or sarcomas. Women in the family having had cancer in both breasts. patients with an Ashkenazi Jewish heritage, a patient who's had a man in their family who've had breast cancer, or obviously patients in families that have a known abnormal gene.
A useful online tool to use is the FRA-BOC, Familial Risk Assessment, Breast and Ovarian Cancer. online tool that can be used by doctors to provide an estimation of the risks of developing breast or ovarian cancer. Using a tool like this can be useful for giving the patient information about their risk and also can guide
which patients should be referred to a familial genetic counsellor for genetic testing. So there are a number of well-known mutations that are associated with an increased risk of breast cancer. Most of these mutations are inherited in an autosomal dominant pattern, which is easy because you only have to remember that for them all. I'll briefly run through some of the ones that are
most associated with breast cancer risk. So the ones that have the highest risk of the development of breast cancer over the woman's lifetime include the very well-known BRCA1 and BRCA2 mutations. So the BRCA genes are genes that help to repair cell damage and they keep breast, ovarian and other cells growing normally. So they are responsible for DNA repair and cell cycle checkpoint responses, and they're known as tumor suppressor genes. BRCA gene 1 is located on chromosome 17.
and BRCA2 is located on chromosome 13. And having a mutation of one of these genes mean that they don't work normally. So if they're a tumor suppressor gene and they're not working normally, they're not going to help suppress the development of tumors. And most tumors in these patients will have lost a second functional allele. So they carry the mutation, but then they get a second hit that knocks out the other gene to then develop a breast cancer.
The risk of breast cancer development in the lifetime of the patient is approximately 85% for patients with a BRCA1 mutation and 55% for a BRCA2 mutation. Patients with BRCA mutations are most likely, or about 80% of the breast cancers that develop, will be triple negative breast cancers. And these patients also have risks of the development of other cancers, including ovarian, colonic.
pancreatic, prostate in men, and melanomas. Another gene that is associated with a high risk of breast cancer is the PALB2 gene. And this gene encodes a protein that actually works with the BRCA2 protein to repair damaged DNA. So therefore, the BRCA gene can't work properly. And patients with a mutation in the PALB2 gene have a 58% risk of developing breast cancer by the age of 70 years old. Another gene that's associated with an increased risk of breast cancer is the
PTEN gene or the PTEN gene. And this is another tumor suppressor that helps to regulate cell growth, apoptosis, angiogenesis, adhesion and cell movement. Abnormal inheritance of this gene leads to something called Cowden syndrome. And the other name for this is multiple hematoma syndrome. It's autosomal dominant inheritance, as all of them are, and is located on chromosome 10.
Patients with Cowden syndrome have a higher risk of breast cancers, between 30% to 50% risk of developing a breast cancer over their lifetime. And they also have approximately 5% risk of thyroid cancer, which is usually a follicular. cancer, central nervous system tumors, specifically a cerebellar gangliocytoma, and also endometrial cancer. These patients will also develop benign features that are Good for spot.
spots on the examination. So have a look at some pictures of Cowden syndrome. So this includes mucocutaneous lesions, such as mucocutaneous papillomatous papules on the tongue and in the mouth, for example. They can also develop hematomasis polyps in the small and large bowel and fibrocystic disease of the breast and adenomas or multinodular goiters in the thyroid. So that's a good one to look into. Another gene to talk about is the TP53 gene or P53 gene.
Everybody knows about this gene. It was taught in length at medical school and the P53 gene provides instructions for a protein that stops tumor growth. So it's another tumor suppressor gene. An inheritance of an abnormal P53 gene causes Lee-Fraumeni syndrome. And this is associated with a wide range of malignancies that will develop at quite an early age. The most common being breast cancer, of which 80% of patients with a P53 gene mutation will develop breast cancer.
and other associated tumours include soft tissue sarcomas, brain tumours and adrenal carcinomas. And that's why we often ask about sarcomas when we're talking about family history. Two genes that are associated with a moderate to high risk of the development of breast cancer. First one is the ATM gene. The ATM gene codes a protein that repairs damaged DNA. So again, a tumor suppression.
suppressor gene. Inheritance of two abnormal copies of this gene causes a syndrome called ataxia telangiectasia. And one abnormal coffee is associated with an increased rate of breast and pancreatic cancer development with approximately a 30% to 38% lifetime risk of the development of breast cancer. The other one is the CDH1 gene. You may have heard of this before as it is known as the hereditary diffuse gastric cancer syndrome.
The CDH1 gene encodes for e-cadherin, so these patients develop quite an aggressive form of gastric cancer. at an early age, and it's also associated with a 40% to 50% lifetime risk of the development of an invasive lobular breast cancer, remembering that the characteristic feature of a lobular breast cancer is that it lacks the e-cadherin gene. or expression of e-cadherin. Some other ones that are associated with a moderate risk of breast cancer development is the CHECK2.
CHEK2 gene. So this gene is a cell cycle checkpoint regulator, another tumor suppressor gene. And in these patients with an abnormal inheritance of this gene, they have a 28% to 37% lifetime risk of the development of breast cancer, so about double relative risk to the general population.
and this may be higher if they have other family members that have already developed breast cancer. NBN gene encodes a protein called Nibrin, and this helps to... repair damaged DNA and these patients have an increased risk of breast cancer and patients with an Neurofibromatosis 1, it's an abnormal inheritance of the NF1 gene, also have an increased risk of breast cancer.
Patients with STK11 gene abnormalities, this is Piotr's-Jager syndrome, are also at high risk of the development of breast cancer in these patients. have that typical appearance of freckles around the eyes, nose, mouth and inside the mouth and have approximately a 45% lifetime risk of breast cancer. And others include Lynch syndrome and Farconee anemia.
When we look at this group of patients who have an increased risk of development of breast cancer there's a few things we need to consider. The first one is trying to calculate what their risk may be. The second is screening. And the third is trying to reduce their risk of breast cancer.
So the first thing to think about is what is their actual risk of developing cancer over their lifetime? And this is important when you're talking to a patient so that they can have this information to be able to make a decision about what they want to do. terms of risk reduction. There are a number of tools that can be used to try to calculate someone's risk.
In Australia, we use the Familial Risk Assessment Breast and Ovarian Cancer Screening Tool, which can be found on the canceraustralia.gov.au website. And this can be used to assess... the risk a woman has of developing breast cancer, as well as can be a guide to when to refer for genetic counselling.
There's a number of other risk prediction tools online. I came across the Gale model quite a lot and there's others that include the Klaus model and the... B-O-A-D-I-C-E-A which are calculation tools you can use online to put in certain factors that will give you a number or a percentage risk of that patient developing cancer over the next five years or over their lifetime, depending on the tool.
Screening is something else that should be thought about. It's a little bit confusing looking through the literature about what age to start screening, who should have earlier screening and who should have screening with MRI. In Australia, I couldn't really find a clear guideline or a clear program for screening. There are some in other countries, especially I came across the NHS high-risk screening program. But basically...
Patients who have a known mutation and patients who, using one of those previous risk scores I talked about, have a more than 20% to 30% lifetime risk of developing cancer should be screened. They should be screened probably at an earlier age and that should be tailored according to the type of mutation they have and also the age of relatives that they have that have developed breast cancer. So if those relatives were very young, you may start.
screening younger than you would in somebody whose relatives were older. And most of the screening programs for these high-risk patients would include an MRI scan as well as mammogram once the patient is over 35 or 40.
And in Australia, MRI is subsidised for high-risk patients. So that's something to be aware of. When we're talking about BRCA carriers, Probably these patients should be screened earlier from the age of about 25 to 30 with an MRI and adding in mammogram once they get older than 35 or 40. And in patients with TP53 genetic abnormalities, they should probably be starting earlier, probably from 20 years old. And other high-risk groups could be screened from 30 years onwards.
In regards to risk reduction interventions, there are both surgical and non-surgical interventions we can consider. Non-surgical includes surveillance, which we just talked about, but also include chemo prevention. So this is using medications such as tamoxifen to reduce the risk of that patient developing a cancer. Again, it was very difficult to find a clear guideline about when we should be using these drugs or whether we should be using them at all.
It's especially controversial because there doesn't appear to be any trials showing a survival advantage, although the trials do show that there is a reduced risk of the development of breast cancer. And obviously, these drugs themselves have side effects. So for example, CIRMs and aromatase inhibitors will reduce the risk mostly of...
hormone receptor positive tumors. If patients are pre-menopausal, then you would suggest tamoxifen. And if they're post-menopausal, you would suggest an aromatase inhibitor. They shouldn't be started before women have completed their childbearing. And side effects of tamoxifen, for example, include thromboembolism, hot flushes and increased risk of endometrial cancer.
and aromatase inhibitors such as anastrozole have side effects of joint pain, hot flushes, and osteoporosis or loss of bone density. The other thing that can be done is to stop the ovarian synthesis of estrogen. either with a surgical oophorectomy or with the use of GnRH agonists, although these are not routinely used at this moment in risk reduction.
An oophrectomy or salpingo oophrectomy may be a good option in a patient who has a BRCA gene who's also at higher risk of a development of ovarian cancer as this will decrease her risk of breast cancer due to the... Reduce production of estrogen as well as reduce her risk of the development of an ovarian cancer. If it was going to be considered, it should be after the completion of childbearing, obviously.
has its own side effects. So these include early menopause and the symptoms and issues that come along with that and requires close monitoring with DEXA scans to make sure the patient doesn't become osteoporotic. When we are talking about
risk reducing surgery, we do need to touch on bilateral mastectomy. This should be... a discussion with the patient about their level of risk and should include a multidisciplinary team that involves consideration of the patient and their risk and what the patient themselves want because this is an irreversible decision.
An MRI should be performed within three months of surgery to make sure there isn't any already existing underlying malignancy as these are often found in mastectomy specimens for this reason. It's also important to remember that bilateral mastectomy doesn't completely reduce the patient's risk of developing breast cancer because every mastectomy will leave some breast tissue, but it does reduce it.
to quite a large degree. There are a number of surgical options which include skin sparing or nipple and skin sparing mastectomy. And obviously, there are various reconstructive options, including immediate and delayed. And these may be either tissue or implant-based reconstructions. Wow, I am exhausted. What a huge topic.
Hopefully you got something out of that. I definitely learned a lot reading about all of those different aspects of early breast cancer. Lucky for us, a lot of this will cross over into locally advanced and advanced breast cancer, which are also covered in the surgical. curriculum. So we've done a lot of the hard work today. My next podcast will be going a bit more into the detail of management of early breast cancer. This is going to be very controversial and there is a lot.
that isn't really clear. So hopefully at some point, we will also be able to get a specialist on the podcast to ask them about some of these questions that we are not clear on. It's time to close up. Thanks for listening to First Incision. If you have any comments or feedback, send us a message at firstincisionpodcast at gmail.com or follow us on Instagram at firstincision. Happy studying!