HER2+ Breast Cancer

Overview and Staging

Being diagnosed with breast cancer is always overwhelming. Take a deep breath and learn all you can about HER2+ breast cancer to be better prepared for making treatment decisions with your medical team. They will guide you to understand this aggressive type of cancer that develop a resistance to treatment at some point.


Breast cancer is a complex disease characterized by mutations in genes and proteins that cause cells to grow out of control. HER2+ breast cancer exhibits a specific marker that requires a more targeted approach. Understanding the components of that approach and the details of your breast cancer diagnosis is important for making key decisions with your doctor.


Your doctor will consider the details of your breast cancer diagnosis, which includes the type (noninvasive or invasive) and the status of three main biomarkers: estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth receptor-2 (HER2).


The BReast CAncer 1 (BRCA1) and BReast CAncer 2 (BRCA2) genes are the most common hereditary susceptibility genes, and your doctor may test for others. Individuals that have inherited abnormalities in the BRCA1 or BRCA2 genes have an increased likelihood of developing breast cancer and/or ovarian cancer. Determining whether you have hereditary breast cancer is also important. Newly-diagnosed breast cancer patients found to have a BRCA mutation face an increased risk of another new breast cancer. As a result, the presence of inherited mutations in the BRCA1 and BRCA2 genes or other cancer-susceptibility genes may influence decisions regarding drugs for cancer prevention or prophylactic surgery to remove the breasts and/or ovaries, or lead to different systemic treatments.

More About HER2

Normal breast cells have two copies of the HER2 gene. Sometimes, breast cells grow and reproduce in an uncontrolled way, producing too many HER2 genes. HER2 is also a protein receptor found on the surface of breast cells.


Approximately 20 percent of all breast cancers make extra copies of HER2, which encodes a growth-promoting protein. Breast cancers with too much protein tend to grow and spread more aggressively. 


A diagnosis of HER2+ breast cancer means your breast cancer cells have too many HER2 genes or receptors or both. When breast cells have too many HER2 genes, it is referred to as HER2 amplification. When breast cells have too many HER2 receptors, it is known as HER2 overexpression.

Staging

Following your diagnosis, your doctor needs to determine the extent of the disease - a process called staging - to select the best treatment option for you. Staging determines the extent of your cancer, where it is located and whether it has metastasized (spread) to nearby organs, tissues or lymph nodes, or to other parts of your body.


All types of breast cancer, including HER2+ breast cancer, are classified according to the tumor, node, metastasis (TNM) system developed by the American Joint Committee on Cancer (AJCC). Once classified, they are given a stage (see Tables 1 and 2).


Table 1 - Stages of Breast Cancer

Stage T N M
0 Tis N0 M0
IA T1 N0 M0
IB T0 or T1 N1mi M0
IIA T0 or T1
T2
N1
N0
M0
M0
IIB T2
T3
N1
N0
M0
M0
IIIA T0-T3
T3
N2
N1
M0
M0
IIIB T4 N0-N2 M0
IIIC Any T N3 M0
IV Any T Any N M1
Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer Science+Business Media.

The T classification categories are the same for both clinical and pathologic staging and provide information on the size and extent of the tumor within the breast. Clinical T (described as cT) refers to the tumor size estimate based on physical/clinical examination and breast imaging; pathologic T (described as pT) refers to the size of the tumor when it has been removed and measured in the pathology laboratory.


Clinical staging for the N category (cN) describes the location and bulkiness of lymph nodes (usually in the axilla, under the arm) that seem to be malignant (from spread of the breast cancer) upon physical examination. Location and extent of any cancerous lymph nodes provide clues regarding the likelihood that the breast cancer might have spread to other organs. The pathologic N category (pN) is determined postoperatively and describes how many lymph nodes are involved.


The M category indicates whether the cancer has metastasized, or spread, to another part of the body beyond the breast and nearby lymph nodes.


Additionally, many other important factors are considered (and documented on your pathology report) before you receive your final stage: tumor grade; biomarkers, including your HER2, ER and PR status; molecular and genetic changes in cancer tissue; and results from multi-gene panels such as Mamma-Print, Oncotype DX, PAM 50 (Prosigna), EndoPredict and Breast Cancer Index.


As you talk with your doctor about the recommended treatment plan, consider seeking a second opinion from a doctor or cancer center with extensive experienced treating HER2+ breast cancer.

Table 2 - AJCC TNM System for Classifying Breast Cancer

Category Definition
Tumor (T)
TX Primary tumor cannot be assessed.
T0 No evidence of primary tumor.
Tis (DCIS) Ductal carcinoma in situ.
Tis (Paget) Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS) in the underlying breast parenchyma (tissue).
T1
  T1mi
  T1a
  T1b
  T1c
Tumor ? (not more than) 20 mm in greatest dimension.
Tumor ? (not more than) 1 mm in greatest dimension.
Tumor > (more than) 1 mm but ? (not more than) 5 mm in greatest dimension.
Tumor > (more than) 5 mm but ? (not more than) 10 mm in greatest dimension.
Tumor > (more than) 10 mm but ? (not more than) 20 mm in greatest dimension.
T2 Tumor > (more than) 20 mm but ? (not more than) 50 mm in greatest dimension.
T3 Tumor > (more than) 50 mm in greatest dimension.
T4

  T4a
  T4b

  T4c
  T4d
Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or macroscopic nodules).
Extension to the chest wall.
Ulceration and/or ipsilateral (on the same side) macroscopic satellite nodules and/or edema (including peau d’orange) of the skin that does not meet the criteria for inflammatory carcinoma.
Both T4a and T4b are present.
Inflammatory carcinoma.
Node (N)
pNX Regional lymph nodes cannot be assessed.
pN0
  pN0(i+)

  pN0(mol+)
No regional lymph node metastasis identified or ITCs (isolated tumor cells) only.
ITCs (isolated tumor cells) only (malignant cell clusters no larger than 0.2 mm) in regional lymph node(s).
Positive molecular findings by reverse transcriptase polymerase chain reaction (RT-PCR); no ITCs (isolated tumor cells) detected.
pN1


  pN1mi
  pN1a
  pN1b
  
  pN1c
Micrometastases; or metastases in 1-3 axillary (armpit) lymph nodes; and/or clinically negative internal mammary nodes with micrometastases or macrometastases by sentinel lymph node biopsy.
Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm).
Metastases in 1-3 axillary (armpit) lymph nodes, at least one metastasis larger than 2.0 mm.
Metastases in ipsilateral (on the same side) internal mammary sentinel nodes, excluding ITCs (isolated tumor cells).
pN1a and pN1b combined.
pN2
  
  pN2a
  pN2b
Metastases in 4-9 axillary (armpit) lymph nodes; or positive ipsilateral (on the same side) internal mammary lymph nodes by imaging in the absence of axillary lymph node metastases.
Metastases in 4-9 axillary (armpit) lymph nodes (at least one tumor deposit larger than 2.0 mm).
Metastases in clinically detected internal mammary lymph nodes with or without microscopic confirmation; with pathologically negative axillary (armpit) nodes.
pN3






  pN3a
  
  
  pN3b
  
  pN3c
Metastases in 10 or more axillary (armpit) lymph nodes;
or in infraclavicular (below the clavicle) (Level III axillary) lymph nodes;
or positive ipsilateral (on the same side) internal mammary lymph nodes by imaging in the presence of one or more positive Level I, II axillary lymph nodes;
or in more than three axillary lymph nodes and micrometastases or macrometastases by sentinel lymph node biopsy in clinically negative ipsilateral internal mammary lymph nodes;
or in ipsilateral supraclavicular (above the clavicle) lymph nodes.
Metastases in 10 or more axillary (armpit) lymph nodes (at least one tumor deposit larger than 2.0 mm);
or metastases to the infraclavicular (below the clavicle) (Level III axillary) lymph nodes.
pN1a or pN2a in the presence of cN2b (positive internal mammary nodes by imaging);
or pN2a in the presence of pN1b.
Metastases in ipsilateral (on the same side) supraclavicular (above the clavicle) lymph nodes.
Note: (sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or FNA/core needle biopsy respectively, with NO further resection of nodes.
Metastasis ( M)
M0
  cM0(i+)


No clinical or radiographic evidence of distant metastases.
No clinical or radiographic evidence of distant metastases in the presence of tumor cells or deposits no larger than 0.2 mm detected microscopically or by molecular techniques in circulating blood, bone marrow, or other nonregional nodal tissue in a patient without symptoms or signs of metastases.
cM1 Distant metastases detected by clinical and radiographic means.
pM1 Any histologically proven metastases in distant organs; or if in nonregional nodes, metastases greater than 0.2 mm.

Guiding Treatment Decisions

With HER2+ breast cancer, it is common to use anti-HER2 targeted therapy to slow or stop the growth of the cancer (see Treatment Planning). Anti-HER2 drugs are approved for all stages of HER2+ breast cancer, and they are often used along with other treatments. 


It is common to begin one targeted therapy and then be switched to a different one. Because HER2+ breast cancer is characterized by multiple mutations, the cancer may become resistant to treatment. This means the cancer stops responding to therapy and begins to grow again, requiring a change of treatment. In HER2+ breast cancer, this has been reported with some types of chemotherapy and targeted therapy. Research is ongoing to determine what causes resistance so that it can be prevented.