Breast Cancer Treatment Protocol by Stage and Subtype

A breast cancer treatment protocol sequences care by stage, molecular subtype and whether the breast can be conserved. Dr. Rajesh Kumar Jain, Principal Director - Surgical Oncology, BLK-Max Super Speciality Hospital, New Delhi, India, treats triple-negative disease with chemotherapy first, starts most operable hormone-positive cancers with surgery, and gives every locally advanced case neoadjuvant chemotherapy, meaning chemotherapy before surgery.

The rest of his protocol follows from those three decisions. He calls this "the practical things": a compact protocol that a surgeon can apply whether or not a PET-CT scanner is down the corridor. This article sets it out step by step, from the first lump to the axilla, and closes with two cases doctors brought to the session. The wider themes of the masterclass, including robotic surgery, precision oncology and tumour boards, are in the complete guide to recent trends in surgical oncology.

How breast cancer presents: lump, pain or nipple discharge

Most patients with breast cancer present with a lump in the breast. Breast cancer is one of the commonest cancers worldwide and one of the commonest in Asia and India. A smaller group presents with vague breast pain, and some with nipple discharge, a presentation that needs its own work-up (covered later in this article).

The triple test for breast cancer diagnosis

Dr. Jain confirms the diagnosis with the triple test, three independent assessments that must agree:

• Clinical examination of both breasts and both axillae.
• Imaging: mammography for women over 40, and ultrasound for women under 40, whose denser breast tissue makes mammography less informative.
• Biopsy: a core needle (Tru-Cut) biopsy, which provides tissue for histology and for the receptor tests that follow.

Where the radiological picture remains uncertain after mammography and ultrasound, breast MRI is used in selected cases. It is a problem-solving tool, not a routine first step.

Breast cancer staging: matching the work-up to the risk

Staging answers one question: has the disease spread beyond the breast and axilla? Most of the time Dr. Jain stages with PET-CT, but he scales the investigation to the clinical risk.

• Early disease (T1 or T2) with no clinically involved nodes: a chest X-ray and an ultrasound of the abdomen are sufficient as a staging work-up.
• Palpable nodes or a larger primary tumour: PET-CT is preferred, because the probability of occult metastasis is high enough to justify it.

Low-cost alternatives to PET-CT, organ by organ

Many hospitals across sub-Saharan Africa have no PET-CT scanner. Dr. Jain's position is direct: if there is no PET-CT, there is no problem. Each organ that breast cancer commonly seeds has a cheaper substitute, arranged in a fallback order.

• Bone: a nuclear bone scan. If that is unavailable, a skeletal survey: plain X-rays of the spine, ribs, pelvis and the long bones of the limbs.
• Liver: a CT of the abdomen. If CT is also unavailable, an ultrasound of the abdomen, which he regards as a fair investigation.
• Lung: a CT of the chest. If CT is unavailable, a plain chest X-ray, which he considers sufficient to establish metastasis.

He adds one step that is easy to forget: an ultrasound of the pelvis in every breast cancer patient, to examine the uterus and ovaries. Its purpose is to detect Krukenberg tumours (metastatic deposits in the ovaries) and ovarian cancers that can occur alongside breast cancer. Ultrasound and plain X-ray are available almost everywhere. Less precise than PET-CT, they are still enough to establish metastatic staging and to decide whether treatment should aim at cure. Clinical stage groupings by tumour size and nodes are covered in the article on breast cancer staging without PET-CT, from Dr. Jain's earlier masterclass.

ER, PR and HER2 status: the molecular subtype

Once the diagnosis and stage are known, the next requirement is the molecular status of the tumour: oestrogen receptor (ER), progesterone receptor (PR) and HER2, a growth-signalling protein on the cancer cell surface. These three markers decide the order of treatment as much as the stage does.

Around 15 to 20 per cent of breast cancers are triple negative: ER, PR and HER2 are all negative. Most of the remainder are hormone-receptor positive, and a further group is HER2 positive.

Breast cancer treatment protocol by subtype and stage

In Dr. Jain's protocol, the subtype and stage decide what comes first: chemotherapy for triple-negative and locally advanced disease, surgery for operable hormone-positive disease, and systemic therapy for metastatic disease.

Triple-negative breast cancer

For triple-negative disease, Dr. Jain usually begins with neoadjuvant chemotherapy, followed by surgery and, lastly, radiation. Chemotherapy first treats possible micrometastatic disease early and shows how the tumour responds before the operation.

Operable early breast cancer that is ER or PR positive

For operable, early, hormone-receptor-positive cancer, treatment starts with surgery. The final histopathology report then determines the adjuvant (post-operative) treatment: chemotherapy, with or without hormone therapy, and radiotherapy where indicated.

Adjuvant systemic therapy

In his practice, the adjuvant plan is built mainly around chemotherapy, with additions defined by receptor status. Under international guidelines, whether hormone-receptor-positive early breast cancer needs adjuvant chemotherapy at all depends on tumour size, nodal status, grade and, increasingly, genomic risk scores.

• Hormone therapy for oestrogen-receptor-positive cancers.
• Trastuzumab, an antibody against HER2, as adjuvant targeted therapy for HER2-positive cancers.
• A second HER2-targeted agent added for some HER2-positive patients who can afford it.

Locally advanced breast cancer

Locally advanced breast cancer (LABC) is disease that is extensive in the breast or regional nodes but has not spread to distant organs. Dr. Jain includes:

• T4b disease: a bulky tumour with skin involvement, satellite skin nodules on the breast, fungation or ulceration.
• Nodal disease in the internal mammary nodes or the supraclavicular nodes only, without distant metastasis.

All of these patients are treated with neoadjuvant chemotherapy first. The response is assessed after neoadjuvant chemotherapy, and further local treatment (surgery and radiation) is then planned on that basis.

Metastatic breast cancer

When the disease has already spread, in his protocol, local therapy to the breast is not needed and treatment starts with chemotherapy. In hormone-positive, strongly ER-positive cases, hormone therapy is an option, chosen according to the patient's general condition, age and disease status. International guidelines (NCCN, ESMO) recommend endocrine therapy combined with a CDK4/6 inhibitor as the usual first-line treatment for hormone-receptor-positive, HER2-negative metastatic breast cancer, reserving chemotherapy first for rapidly progressive or life-threatening visceral disease.

Oligometastatic breast cancer: a category that is growing

One category Dr. Jain now sees quite frequently is oligometastatic breast cancer, meaning limited metastatic spread: a patient presenting with a single bone metastasis, or one or two bone metastases, or a single deposit elsewhere. These patients are treated aggressively, in the same way as locally advanced breast cancer. His experience over the years is that oligometastatic patients do very well when they are treated aggressively. Randomised evidence for aggressive local treatment of oligometastatic breast cancer is still limited and has not consistently shown a survival benefit, so the approach is decided case by case, ideally at a tumour board.

When radiotherapy is needed after breast cancer surgery

Every patient who undergoes breast conservation surgery must also receive adjuvant radiotherapy. After mastectomy, Dr. Jain adds radiation in three situations:

• Involved axillary lymph nodes: radiation is standard with four or more positive nodes and is recommended or strongly considered with one to three.
• A primary tumour of T3 size or larger (above 5 cm).
• Close or positive surgical margins.

Contraindications to breast conservation surgery

Dr. Jain's default is breast conservation surgery (BCS), which removes the tumour and keeps the breast, whenever there is no absolute contraindication. He prefers not to perform BCS in three groups:

• Pregnant patients. Conservation commits the patient to radiotherapy, which cannot be given during pregnancy.
• Patients with locally advanced disease at the time of surgery.
• Patients who decline radiotherapy, often because of logistics. Since BCS requires adjuvant radiation, a patient who cannot or will not complete it is better served by mastectomy.

The location of the tumour matters too. Disease in the central quadrant, behind the nipple and areola, generally favours mastectomy, as the first case below shows. The full choice between the two operations is set out in breast conservation surgery vs mastectomy, from his earlier masterclass.

Axillary management: dissection or sentinel node biopsy

The axillary plan, for the lymph nodes in the armpit, depends on whether the nodes are clinically involved.

• Palpable nodes: level 1 and level 2 lymph nodes are always dissected. If level 2 nodes are found to be involved on the table, level 3 is cleared as well.
• Clinically node-negative (N0) disease: a sentinel lymph node biopsy, removal of the first node or nodes draining the tumour, is performed during axillary surgery, with frozen section (rapid microscopic examination during the operation). If the sentinel node is negative, axillary dissection is generally avoided, sparing the patient the arm swelling and stiffness that a full clearance can cause.

Case: two periareolar masses with invasive ductal carcinoma

A doctor from Ethiopia described a patient with two masses in the right breast near the areola, measuring 3 cm and 4 cm and joined by fibrous tissue on mammography. Core needle biopsy showed invasive ductal carcinoma. The questions were how to proceed and whether breast conservation was possible.

Dr. Jain's answer follows the protocol exactly:

1. Complete the staging first. The biopsy only establishes that this is breast cancer. At minimum, obtain a chest X-ray and an ultrasound of the abdomen, and if possible a skeletal survey or bone scan, to establish whether there is metastasis.
2. Establish ER, PR and HER2 status.
3. If the disease is localised and ER or PR positive, proceed to surgery. Review the mammogram: conservation could be considered if the rest of the breast is normal and the two lumps are confined to one area.
4. Weigh the location. Periareolar disease is central quadrant disease, and here he judges that mastectomy with axillary clearance is the better operation.
5. If metastases are found in the lung, liver or bone, start treatment with chemotherapy instead.

Bloody nipple discharge without a lump: causes and work-up

A gynaecologist and obstetrician from Tanzania asked about a patient with bloody discharge from the breast, no lump and no palpable lymph nodes. Haemorrhagic nipple discharge means there is a problem inside a duct, and Dr. Jain sets out three common causes.

Duct papilloma

The most common cause is a duct papilloma, a benign growth inside the duct. Because a papilloma can harbour or progress to papillary carcinoma, it is excised rather than observed.

The first and best investigation for any nipple discharge is an ultrasound of the breast, which shows the ducts and any content inside them. If a papilloma is found, the affected duct is localised under ultrasound guidance with a needle or wire and removed: an operation called microdochectomy. Histopathology follows within two or three days. If the lesion is a papilloma, treatment is complete. If it is papillary carcinoma, the patient is treated as a breast cancer patient and undergoes further surgery, mastectomy or breast conservation according to the case.

Breast cancer presenting with discharge

The second cause is breast cancer itself, usually invasive ductal carcinoma. In Dr. Jain's figure, around 10 per cent of breast cancer patients present with nipple discharge, bloody or otherwise abnormal in colour, and some have no palpable lump at all.

Duct ectasia

The third cause is duct ectasia, a condition of perimenopausal women, mostly between about 45 and 57 years of age, which typically produces a brownish discharge. In his approach, the treatment is again excision of the affected duct. Many cases of duct ectasia settle without surgery; excision is generally reserved for persistent or bloodstained discharge. Infection or mastitis can also cause discharge, and is usually clear clinically.

The work-up

Beyond ultrasound, smears of the discharge are prepared on slides and sent for cytology. In most cases, however, a microdochectomy is what finally establishes the diagnosis: if benign, nothing more is needed; if malignant, the patient is treated for cancer.

Where this protocol fits

The exchanges behind both cases are on the masterclass Live Discussion. This protocol is the breast half of a masterclass on breast and gastrointestinal surgical oncology. The gastrointestinal half, the symptoms that should make any doctor suspect cancer early, is in the article on the early warning signs of cancer, organ by organ. Dr. Jain's earlier masterclass covered breast cancer imaging, reconstruction and genomic testing in greater depth; it is summarised in the complete guide to breast cancer diagnosis and surgical management.