Importance of Biopsy in Suspected Metastatic Breast Cancer

Why It Matters

In order to best understand this patient’s illness, a biopsy is important. A biopsy can give two important bits of information. First, it can tell us what the lesion is. Secondly, it can tell us the tumor biology of that particular lesion at that particular time. Imaging studies such as an MRI, CT or PET scan have revealed multiple sites of disease throughout her body including her bones, liver, lung, brain and lymph nodes. The question remains as to whether these represent metastases of her original breast cancer, a new primary tumor, a new infection or inflammation versus a benign process.

Even if diagnosis and initial treatment were carried out with full knowledge of the biology of the patient’s breast cancer, subsequent evolution of the disease can make a new tissue biopsy very useful. Prior therapy may have selected less responsive cancer cells and changes in the patient’s ER, PR or HER2 status from the time of diagnosis from the primary site to diagnosis from the metastatic site may have occurred. Many of the standard of care systemic therapies for breast and other cancers are directed based on these three markers and obtaining a contemporary biopsy can help to ensure that one is not “treating yesterday’s cancer for today’s cancer”.

Receptor alterations are common. Progesterone receptor (PR) alterations are noted more frequently than estrogen receptor (ER) or HER2 losses. Typically, the first pathology report guides the initial treatment, only to reveal misclassification of the metastatic disease several years later as additional reports are processed. HER2 status also may be found to change as better methods for evaluation have been incorporated and our understanding of the role of HER2 in different tumor subtypes has evolved.

Biomarker confirmation is not trivial in breast cancer as it can affect choice of therapy between different families of drugs. For hormone receptor positive (HR+) tumors endocrine therapy in combination with targeted therapies may be most effective, for HER2+ tumors HER2 targeted therapies will likely yield the best results, and for triple negative metastatic disease chemotherapy will be mainstay of treatment; selected cases may also benefit from immune or other targeted approaches based on further tumor characteristics.

As newer therapies are introduced for the treatment of breast cancer, accurate HER2 testing has become more important. Some of these new therapies are effective even in tumors with low levels of HER2 protein. As a result, the high quality handling and pathology evaluation of the biopsy, as well as accurate reporting of the biopsy results, is indispensible to determine if a patient may be benefited by these newer treatments. However, the patient may have already had HER2 testing performed prior to her diagnosis, possibly many years ago at another laboratory.

A biopsy is often needed to avoid a poor quality of life from resulting due to undertreatment or overtreatment. Specifically, it is important to determine whether a tumor has lost expression of the hormone receptors (such as estrogen receptor or progesterone receptor), meaning that continued endocrine therapy is time wasting with side effects worse than benefits. A biopsy is also critical in determining if a tumor has gained expression of the HER2 protein, which may indicate that the patient can benefit from additional HER2-targeted therapies that are currently not recommended. The biopsy is also needed to determine if the patient’s lesion is truly metastatic breast cancer, and not a different cancer or a benign process that has caused symptoms.

At some point fresh tissue is required for access to newer medications and clinical trials. Many targeted therapies and clinical trials require documentation of the biomarker status or evidence of a specific change having occurred in the cancer. Tissue can also be used for molecular profiling of new alterations that were not detected at the time of original diagnosis and can guide use of targeted therapies or inclusion in clinical trials.

A biopsy is indicated when the patient’s disease is not behaving as expected. An example might be the rapid progression of the disease; atypical involvement of organs or parts of the body; or solitary lesions that persist for years. A pathologic diagnosis is needed before misguided treatment is instituted to find out if the patient has a second primary disease, a change in behavior of the same disease, or an entirely different disease entity.

Repeating analysis of a tumour biopsy at the time of tumour progression can be helpful in understanding reason for treatment resistance and guiding treatment decisions for future therapy. Metastatic cancer is typically treated in a sequential manner; each therapy is active for a period of time prior to the induction of resistance. By repeating a biopsy, changes in tumour biology such as receptor conversion as well as new molecular alterations can be detected that may explain why a particular therapy has stopped working and help guide alternate therapy.

Tissue biopsy remains the gold standard for initial diagnosis and tumour characterisation. However, advances in technology are enabling the development of blood-based tests, which are emerging as useful complements to existing diagnostics. Next-Generation Sequencing (NGS) based tests are able to identify mutations present in circulating tumour DNA (ctDNA) in blood and monitor tumour progression, however they are not yet sufficient to enable lesions to be diagnosed solely from a blood test. They do not consistently provide the full receptor status information needed to select most targeted therapies.

Choosing the most informative lesion to biopsy is a process with potential risks and benefits. Superficial lymph nodes and skin or soft-tissue masses are often easy choices. Many liver lesions are easy diagnoses. Pulmonary masses and lesions can be diagnostic but may pose greater risk than lesions in other organs depending on their location. Bone and lymph node lesions can be difficult choices because the processing of the biopsy specimen can affect the accuracy of certain studies and the treating physician should coordinate with the pathologist to achieve the best results. Of all the lesions listed, bone is the one that is most often amenable for biopsy.

Techniques for performing image-guided biopsies have evolved as pathology and oncology have evolved to better enable safe and comfortable diagnosis and treatment planning for patients. Many metastatic diagnoses are established using ultrasound or CT guidance, and patients go home on the same day the biopsy is performed. As with any procedure, there is a chance of bleeding, infection, and significant pain at the biopsy site for which the patient needs to be informed. It is our feeling that patients have a right to understand these risks in simple terms.

Preservation of tissue quality can be optimized by strategic planning to avoid second interventions. Effective communication among the oncologist, interventional team, and pathologist is crucial to ensure that there is sufficient tissue for essential studies (ER, PR, and HER2 status) as well as for molecular profiling studies.

Time to result is crucial for this test- a few day delay can translate into days of unnecessary symptoms and stress. The standard workflow for our lab is to return diagnosis confirmation first, followed by the receptor results, and then any additional molecular testing with an estimate of time to result. The patient needs to know what their next steps are as soon as treatment can safely and appropriately be initiated.

Informing your patients as to why a biopsy is necessary, and how it will aid in their management and care can alleviate a considerable amount of their anxiety. Informing them that a biopsy can confirm a diagnosis, measure glycemic control, or gain access to treatment that can alter the course or management of their disease is often all a patient needs to know to alleviate a considerable amount of anxiety. Further relief can be achieved by informing your patients of when they can expect results and what their next course of action will be.

Who It Affects

For the patient with a new suspicious image, or symptoms of spread of the disease, a new biopsy result can change the treatment plan entirely. The tissue results can change the course of treatment to a targeted therapy approach, shift management to an endocrine therapy approach, necessitate chemotherapy, alter the radiation plan for symptom control, and reveal that the suspicious lesion is not related to metastatic breast cancer and therefore treatment can be redirected in a different pathway.

Patients with an interval of time of greater than 1 year since their initial cancer diagnosis and treatment for that cancer may be considered for re-biopsy. A cancer may change in behavior over time to continue to grow and avoid destruction under pressure of therapy. The levels of key target receptors for cancer therapies may increase or decrease making the difference between beneficial and ineffective cancer therapies.

Patients with the spread of cancer to unusual sites or patterns of spread are a high-stakes group for diagnosis by tissue. Patients with a single lesion, an atypical site of organ involvement, or a pattern of disease spread that is not consistent with prior disease behavior are a high-stakes group for diagnosis by tissue. A biopsy diagnosis may shorten time to correct pathologic diagnosis and avert longer-term ineffective and toxic systemic therapy.

Patients with a bone-predominant disease require a thoughtful approach to both the initial biopsy as well as subsequent monitoring of their disease. Although bone metastases are frequent, they can be more challenging to obtain a diagnostic biopsy from than their soft tissue counterparts. Special consideration needs to be given to optimally utilizing the limited amount of tissue obtained from a bone biopsy to provide the most relevant biomarker information. Decisions as to whether the best lesion to biopsy includes a soft-tissue component, as well as test prioritization, will also be addressed.

The biopsy results are crucial to the medical oncologists and to the rest of the multidisciplinary care team. The medical oncologists rely on the receptor and molecular information obtained from the biopsy to select the appropriate systemic therapy for the patient, and to educate the patient and their families as to the expected benefit versus toxicity of the proposed treatment. The radiologists and interventionalists strive to select the appropriate target lesion for biopsy, obtaining adequate tissue in a safe and expedient manner. The pathologists strive to confirm a diagnosis and run the indicated biomarker studies in a timely and standardized fashion.

Downstream effects on health systems and payers include ensuring ability to perform the biopsy, the classes of targeted therapies for which patients will be considered eligible for coverage, image guided biopsy services and pathology capability to perform tests, and turnaround time for results. Decisions about repeat receptor studies and molecular profiling studies to support diagnosis for cancer also have significant effects on diagnostic strategies and patients’ access to certain medications for which biomarker information is crucial.

There is a need to improve outcomes for all patients with head and neck cancer and address the inequity in current service configuration with long waits for biopsy, inadequate local pathology capacity and long distances to tests for many patients. Improved referral pathways, regional testing networks and better use of telepathology are also required.

What Changes

• Confirm diagnosis before changing systemic therapy, because tissue distinguishes metastatic breast cancer from other conditions and prevents inappropriate treatment. Biopsy is particularly important when imaging is ambiguous, when disease is limited to one site, or when the clinical picture is unusual.
• Reassess tumor biology at the diagnosis of metastatic disease and at progression, because receptor status and actionable targets can change. Repeat testing can reveal loss or gain of ER, PR, or HER2 and other clinically meaningful changes that alter therapy selection.
• Use tissue and blood testing in a complementary way rather than as substitutes. Tissue biopsy remains essential for confirming histology and for full receptor testing, while circulating tumor DNA can add value for monitoring and for detecting certain resistance mutations over time.
• Build workflows that reduce delays and protect tissue quality. Rapid biopsy referral pathways, standard biomarker panels for suspected recurrence, and clear processes for communicating results can shorten time to treatment and reduce repeat procedures.
• Improve informed consent and preparation so the biopsy experience is safer and less stressful. Patients benefit when clinicians explain why the tissue is needed, what will be tested, and how the results could change care. Simple guidance about medications that affect bleeding risk, expected soreness, and warning signs after the procedure can improve safety and confidence.
• Strengthen reporting and interpretation so results lead to the right action. When biomarkers differ from prior results, teams should interpret them in context and confirm that testing quality was appropriate. When results are borderline or unexpected, repeat testing or additional pathology review may be appropriate to avoid misclassification.
• Plan for equitable access by investing in biopsy capacity and modern pathology services. Expanding image-guided biopsy services, strengthening regional pathology networks, and supporting telepathology can reduce delays and travel burden, especially for patients outside major centers.
• Add patient navigation support so high-value testing does not get lost in the system. Coordinators can help schedule biopsies quickly, ensure pathology requests include all needed assays, track pending results, and arrange follow-up appointments for treatment decisions. This support is especially helpful for patients who must travel for procedures or who face language, transportation, or financial barriers.
• In suspected metastatic breast cancer, biopsy is not a formality; it is a decision point that shapes treatment, access, and patient experience. Prioritizing timely biopsy and high-quality pathology supports precise care, avoids ineffective therapy, and helps patients navigate complex decisions.

References:

https://pmc.ncbi.nlm.nih.gov/articles/PMC3986435/ https://pmc.ncbi.nlm.nih.gov/articles/PMC5210262/