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Understanding Metastatic Breast Cancer: An In-Depth Look

Metastatic breast cancer (MBC) or stage IV breast cancer is when cancer spreads beyond the breast and regional lymph nodes to distant sites like bones, liver, lungs or brain. Breast cancer cells travel through the blood stream and establish new tumors in various organs. This stage of breast cancer is a big clinical challenge as it's not curable in most cases. But with systemic therapy, targeted therapies and personalized treatment, many patients are living longer and better.

Despite all these advances, metastatic breast cancer still accounts for a big chunk of cancer morbidity and mortality worldwide. This article will go into the epidemiology, prognosis, metastatic patterns, treatment options and emerging trends, so clinicians can apply to patient care.

Table of Contents

Epidemiology and Prognosis

Globally, metastatic breast cancer diagnosed at initial presentation is 6-10% in high income countries. Over 685,000 women worldwide live with metastatic breast cancer, that's the burden of the disease and the growing number of patients who are living longer due to better treatments. But this percentage is higher in low and middle income countries because of delayed diagnosis and limited access to healthcare. Screening and early detection have reduced stage IV diagnosis in developed countries but metastatic recurrence is common even after treatment of earlier stage disease.

Prognosis

Prognosis for metastatic breast cancer is variable depending on factors like tumor subtype, metastatic site, response to treatment and extent of cancer growth:

70-80% of patients will die from the disease within 5 years of diagnosis. But survival rates vary greatly depending on tumor subtype. For example, patients with HER2 positive metastatic breast cancer do better because of HER2 targeted therapies and some patients can live more than 10 years. Patients with triple negative breast cancer (TNBC) have a more aggressive clinical course and shorter survival as there are limited treatment options outside of chemotherapy and immunotherapy.

But a subset of patients, especially those with specific biomarker profiles can live more than 10 years. For example, patients with HER2 positive disease have benefited a lot from HER2 targeted therapies.

Breast Cancer Progression

Breast cancer progression is when cancer cells break away from the primary tumor or nearby lymph nodes and enter the bloodstream or lymphatic system. These rogue cells can travel to other parts of the body and establish new tumors. This process is called metastasis and can happen at any stage of breast cancer but is more common in advanced stages. Understanding how cancer cells disseminate is key to developing treatment strategies and improving patient outcomes.

The pattern of metastatic spread in secondary breast cancer affects prognosis and treatment decisions. Common sites are:

Bone Metastases: Most common, 37.5-39.8% of cases. Imaging modalities like positron emission tomography (PET), magnetic resonance imaging (MRI) and bone scans are used to detect and characterize bone metastases. PET scans are very sensitive in detecting active metabolic lesions while MRI provides detailed visualization of bone marrow involvement. Bone only metastases means more indolent disease.

Visceral Metastases: Involvement of liver, lungs or other organs is seen in 21.9% of patients. These metastases means more aggressive disease.

Brain Metastases: Less common but more morbid site of spread, poor survival.

Multiple Metastases: 33% of patients present with multiple sites of disease.

Survival by Metastatic Site

Bone Metastases: OS is around 38 months, best prognosis among metastatic sites.

Visceral Metastases: OS is around 21 months.

Brain Metastases: Patients with brain metastases have the worst outcomes, median survival less than 12 months even with aggressive treatment.

Recognizing secondary breast cancer symptoms is important as symptoms can vary depending on the metastatic site and will lead to further testing and evaluation by healthcare professionals.

Symptoms and Diagnosis

Symptoms of metastatic breast cancer can vary greatly depending on where the cancer has spread. Common symptoms are:

Bone pain or tenderness: Means cancer has spread to the bones.

Fatigue or weakness: Feeling tired that doesn't go away with rest.

Weight loss or loss of appetite: Unintended weight loss or decrease in appetite.

Nausea or vomiting: Caused by cancer spreading to the liver or other organs.

Difficulty breathing: Lung involvement.

Coughing or wheezing: Persistent cough or wheezing means lung metastasis.

Abdominal pain or swelling: Liver or abdominal metastasis.

Headaches or seizures: Neurological symptoms if cancer has spread to the brain.

If you experience any of these symptoms, see a doctor immediately. Early detection and treatment of metastatic breast cancer can improve prognosis and quality of life.

TreatmentSystemic Therapy

Systemic therapy is the main stay of management for metastatic breast cancer patients. Treatment is tailored to the tumor biology, hormone receptor status, HER2 expression and genetic markers like BRCA mutations.

Hormone Therapy

For ER+ HER2- disease.

Agents include aromatase inhibitors, SERMs and SERDs.

CDK4/6 inhibitors like palbociclib have improved outcomes when combined with hormone therapy. [3] However, resistance mechanisms like alterations in RB1 pathway, upregulation of cyclin E1 and activation of alternative pathways (e.G. PI3K/AKT/mTOR) can limit their long term efficacy. Emerging approaches to overcome resistance include combining CDK4/6 inhibitors with targeted agents like PI3K or mTOR inhibitors and next generation CDK inhibitors with broader activity. Ongoing trials are looking to define optimal sequencing to delay resistance and improve outcomes. [7]

Targeted Therapy

HER2 targeted therapies (e.G. Trastuzumab, pertuzumab, trastuzumab deruxtecan) have changed the landscape for HER2+ metastatic breast cancer and some patients can achieve long term remission. [9]

PARP inhibitors for BRCA mutated cancers. [5]

Newer agents like PI3K inhibitors (e.G. Alpelisib) target specific genetic alterations. [8]

Chemotherapy

Chemotherapy is the mainstay for triple negative breast cancer (TNBC) and visceral crisis.

Agents like sacituzumab govitecan have shown activity in heavily pretreated TNBC.

Local Therapy

While systemic therapy is first line, local therapy can provide palliation or address oligometastatic disease:

Surgery: Metastasectomy may be considered for isolated metastases in the liver or lungs. Note the SABR-COMET trial showed that stereotactic ablative radiotherapy (SABR) can improve overall survival in oligometastatic disease including breast cancer. [2] The MF07-01 trial also showed a survival benefit for patients who underwent locoregional surgery in de novo metastatic breast cancer. These trials suggest aggressive local therapy may be useful in selected patients but more trials are needed to confirm and define patient selection. [1]

Radiation Therapy: For symptom control of pain or spinal cord compression from bone metastases.

Locoregional Therapy: Treatment of the primary breast tumor in de novo metastatic disease is controversial but may provide local symptom relief.

Oligometastatic Disease

Oligometastatic disease is defined as limited metastatic burden, typically less than 5 sites. Survival outcomes for oligometastatic disease patients can vary greatly depending on the extent of treatment. For example the SABR-COMET trial showed a 13 month improvement in overall survival when stereotactic body radiotherapy (SBRT) was added to standard care, so there is potential for durable disease control in select patients. These studies emphasize the importance of precise imaging and multidisciplinary evaluation to identify patients for aggressive therapy. Precise imaging is key in metastatic breast cancer to identify patients for aggressive therapy. Aggressive approaches including surgery and stereotactic body radiotherapy (SBRT) have been explored to achieve durable control. But more trials are needed to confirm the benefit of these strategies.

Emerging Data and New Therapies

Early data suggests breast reconstruction in de novo metastatic disease patients may be associated with longer survival. But more data is needed to account for potential biases (healthier patients are more likely to get reconstructed).

Systemic therapies:

Antibody-drug conjugates (ADCs) trastuzumab deruxtecan

Immune checkpoint inhibitors: Pembrolizumab in PD-L1 positive TNBC [4]

New targets: Agents against Trop-2 and other emerging biomarkers.

Biomarker Driven Therapies for Breast Cancer Cells

Next generation sequencing (NGS) allows clinicians to identify actionable mutations and get patients into clinical trials of targeted therapy. Personalized medicine is becoming increasingly important in metastatic breast cancer management. [6]

Patient Care: Psychosocial Considerations

Living with metastatic breast cancer is mentally and emotionally challenging for patients. Common issues:

Anxiety and depression related to prognosis.

Financial toxicity from long treatment.

Social isolation and need for support networks.

Interdisciplinary teams including oncology social workers and mental health professionals are key to addressing these issues.

Palliative and End of Life Care

Since metastatic breast cancer is incurable for most patients, palliative care is important for:

Symptom management (e.G. Pain, fatigue, dyspnea).

Emotional and spiritual needs.

End of life discussions and advance care planning.

Closing Thoughts

While metastatic breast cancer remains a clinical challenge, treatment and personalized medicine have improved outcomes for many patients. Metastasis is when cancer cells travel to other parts of the body and create tumors. The prognosis of metastatic breast cancer varies based on the site of the tumors. Of the types of metastasis, bone metastasis has the best prognosis, while visceral and brain metastasis have the worst prognosis. The pattern and biology of the tumor, along with personalized medicine, drive the most positive outcomes.

References

[1] Soran, A., Ozmen, V., Ozbas, S., Karanlik, H., Muslumanoglu, M., Igci, A., Canturk, Z., Utkan, Z., Ozaslan, C., Evrensel, T., Uras, C., Aksaz, E., Soyder, A., Ugurlu, U., Col, C., Cabioglu, N., Bozkurt, B., Uzunkoy, A., Koksal, N., Gulluoglu, B. M., … Johnson, R. (2018). Randomized Trial Comparing Resection of Primary Tumor with No Surgery in Stage IV Breast Cancer at Presentation: Protocol MF07-01. Annals of surgical oncology, 25(11), 3141–3149. Https://doi.Org/10.1245/s10434-018-6494-6

[2] Palma, D. A., Olson, R., Harrow, S., Gaede, S., Louie, A. V., Haasbeek, C., Mulroy, L., Lock, M., Rodrigues, G. B., Yaremko, B. P., Schellenberg, D., Ahmad, B., Senthi, S., Swaminath, A., Kopek, N., Liu, M., Moore, K., Currie, S., Schlijper, R., Bauman, G. S., … Senan, S. (2020). Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 38(25), 2830–2838. Https://doi.Org/10.1200/JCO.20.00818

[3] Turner, N. C., Slamon, D. J., Ro, J., Bondarenko, I., Im, S. A., Masuda, N., Colleoni, M., DeMichele, A., Loi, S., Verma, S., Iwata, H., Harbeck, N., Loibl, S., André, F., Puyana Theall, K., Huang, X., Giorgetti, C., Huang Bartlett, C., & Cristofanilli, M. (2018). Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. The New England journal of medicine, 379(20), 1926–1936. Https://doi.Org/10.1056/NEJMoa1810527

[4] Schmid, P., Adams, S., Rugo, H. S., Schneeweiss, A., Barrios, C. H., Iwata, H., Diéras, V., Hegg, R., Im, S. A., Shaw Wright, G., Henschel, V., Molinero, L., Chui, S. Y., Funke, R., Husain, A., Winer, E. P., Loi, S., Emens, L. A., & IMpassion130 Trial Investigators (2018). Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. The New England journal of medicine, 379(22), 2108–2121. Https://doi.Org/10.1056/NEJMoa1809615

[5] Robson, M., Im, S. A., Senkus, E., Xu, B., Domchek, S. M., Masuda, N., Delaloge, S., Li, W., Tung, N., Armstrong, A., Wu, W., Goessl, C., Runswick, S., & Conte, P. (2017). Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. The New England journal of medicine, 377(6), 523–533. Https://doi.Org/10.1056/NEJMoa1706450

[6] Harbeck, N., & Gnant, M. (2017). Breast cancer. Lancet (London, England), 389(10074), 1134–1150. Https://doi.Org/10.1016/S0140-6736(16)31891-8

[7] Sledge, G. W., Jr, Toi, M., Neven, P., Sohn, J., Inoue, K., Pivot, X., Burdaeva, O., Okera, M., Masuda, N., Kaufman, P. A., Koh, H., Grischke, E. M., Frenzel, M., Lin, Y., Barriga, S., Smith, I. C., Bourayou, N., & Llombart-Cussac, A. (2017). MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 35(25), 2875–2884. Https://doi.Org/10.1200/JCO.2017.73.7585

[8] André, F., Ciruelos, E., Rubovszky, G., Campone, M., Loibl, S., Rugo, H. S., Iwata, H., Conte, P., Mayer, I. A., Kaufman, B., Yamashita, T., Lu, Y. S., Inoue, K., Takahashi, M., Pápai, Z., Longin, A. S., Mills, D., Wilke, C., Hirawat, S., Juric, D., … SOLAR-1 Study Group (2019). Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. The New England journal of medicine, 380(20), 1929–1940. Https://doi.Org/10.1056/NEJMoa1813904

[9] Litton, J. K., Rugo, H. S., Ettl, J., Hurvitz, S. A., Gonçalves, A., Lee, K. H., Fehrenbacher, L., Yerushalmi, R., Mina, L. A., Martin, M., Roché, H., Im, Y. H., Quek, R. G. W., Markova, D., Tudor, I. C., Hannah, A. L., Eiermann, W., & Blum, J. L. (2018). Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. The New England journal of medicine, 379(8), 753–763. Https://doi.Org/10.1056/NEJMoa1802905

Ovarian Cancer Symptoms: Early Warning Signs Every Woman Should Know

Ovarian cancer is often diagnosed late because its symptoms resemble those of less serious conditions.

As a result, only 20% of patients are diagnosed early when treatment is more effective.

93% of women diagnosed early survive for more than five years, whereas survival drops to just 13% for those diagnosed later when the cancer has spread.

Dr Alex Missick, a family doctor from UK Meds, emphasizes that women can lower their risk of late-stage diagnosis by recognizing both common and lesser-known symptoms, as per Daily Mail.

She lists common signs like bloating, pelvic pain, feeling full quickly and frequent urination.

Additionally, she mentions six less obvious symptoms that many women may not associate with ovarian cancer.

Certain lesser-known symptoms such as pain during sex, leg swelling and pain, extreme fatigue, bowel habit changes, back pain and menstrual irregularities could indicate ovarian cancer.

As per the reports, certain factors, like aging and family history, increase the risk of ovarian cancer.

Additionally, mutations in the BRCA1 and BRCA2 genes can raise the risk of both ovarian and breast cancer.

Being overweight is another risk factor for developing the disease.

Dr Missick advices that if these symptoms persist and occur alongside more common ovarian cancer signs, women should consult a doctor.

Treatment options typically include surgery to remove cancer, chemotherapy to shrink tumours and hormone therapy to help control the disease.

Doctor Shares Ovarian Cancer Symptom You Should Look Out For When Eating

Ovarian cancer is the sixth most common form of cancer in women in the UK - and four symptoms could be signs. One symptom can be spotted when you're eating The doctor warned people about four key symptoms (

Image: Chinnapong via Getty Images)

A medical expert is sounding the alarm over four potential symptoms of ovarian cancer people should look out for, especially around meal times. Dubbed the 'silent killer', ovarian cancer ranks as the UK's sixth most common cancer among women.

Each year in the UK, there are approximately 7,500 new cases – that's about 21 diagnoses every day. March marks Ovarian Cancer Awareness Month, a crucial period for boosting our collective knowledge on the disease's signs and rallying support for those affected.

Dr Suraj Kukadia is drawing attention to four telltale signs of ovarian cancer that shouldn't be ignored. "Anyone with ovaries can get ovarian cancer," he informs, noting that it predominantly strikes those aged 50 and older.

Despite often vague symptoms, Doctor Sooj highlights several red flags to watch out for. You can read more about them below.

There are five main types of gynaecological cancer – cervical, ovarian, vaginal, vulvar and uterine (

Image:

Getty Images) Bloating

A persistently "swollen or bloated tummy" could point to ovarian cancer, says Doctor Suraj. However, the NHS clarifies that while bloating is a widespread issue with numerous causes, it doesn't necessarily mean one has ovarian cancer.

"The most common reason for bloating is having a lot of gas in your gut," explains an NHS statement, listing certain foods, fizzy drinks and swallowed air during eating as typical culprits.

Bloating, constipation, food intolerances, coeliac disease and irritable bowel syndrome (IBS) can all lead to bloating. If you're frequently experiencing bloating, it might be worth popping in to see your GP.

Pelvic pain

Pelvic pain is another symptom of ovarian cancer, according to Doctor Suraj, who said "pain or tenderness in the pelvic region" could be a sign. However, like bloating, pelvic pain is quite common and doesn't necessarily mean you have ovarian cancer.

The NHS reassures people that "most causes of pelvic pain are not serious". Conditions such as constipation, IBS, urinary tract infections (UTIs), sexually transmitted infections (STIs), appendicitis and peritonitis can all cause pelvic pain.

Loss of appetite

Loss of appetite is another symptom to look out for, particularly noticeable at mealtimes. Doctor Suraj explained that a loss of appetite or "feeling really full really quickly" could both indicate ovarian cancer.

It's worth noting that loss of appetite can be a symptom of many types of cancer, as well as other conditions. As we get older, our appetite naturally decreases too.

Changes to toilet habits

Changes to toilet habits, such as needing to pee more often or having an urgent need to pee frequently, can also be a symptom of ovarian cancer, according to Doctor Suraj. He added that a change in bowel habits could also signal the condition.

The medical expert highlighted that if certain symptoms occur "roughly 12 or more times a month," it's advisable to see your GP. He mentioned that other "non-specific" symptoms to watch out for are persistent back pain, unexplained weight loss, and constant fatigue.

The NHS adds that signs of ovarian cancer can also manifest as indigestion, changes in bowel habits like constipation or diarrhoea, and post-menopausal vaginal bleeding. It's crucial to remember that these non-specific symptoms aren't exclusive to any one illness, so experiencing them doesn't automatically mean you have ovarian cancer.

However, if you're worried, don't hesitate to consult with your doctor. For further details on ovarian cancer, the NHS website is a reliable source of information.

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