When breast cancer spreads away from the breast to the bones, lungs, liver, brain, skin, or other organs it is said to be metastatic. The treatment goals for metastatic breast cancer are to prolong the duration and quality of life. Some women with metastatic disease have their cancer controlled with newer treatments for 10-20 years. Treatment for metastatic breast cancer depends on prior treatment, hormonal and menopausal status, location of the recurrence, and whether a precision medicine can be used.
Researchers continue to make great strides in treating breast cancer and in making cancer treatment more tolerable, both physically and emotionally. The greatest recent advances and focus of ongoing research are in Precision Cancer Medicines and Immunotherapy Standard chemotherapy typically destroys both normal and cancerous rapidly dividing cells in a wide range of tissues, often causing side effects by damaging normal cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
Breast cancers that are confined to the breast or area immediately surrounding the breast, are called local-regional recurrences, and are typically treated with surgery with or without radiation therapy. Most patients who experience a recurrence of breast cancer however have disease that has metastasized or spread to other locations in the body. These patients require systemic treatment that can reach the cancer anywhere in the body. Systemic therapy may consist of chemotherapy, hormonal therapy, precision cancer medicines or immunotherapy used alone or in combination.1,2 In general treatment for metastatic breast cancer falls into the following groups.
- Hormone Receptor Positive Cancers
- HER2 Positive Cancers and Other "Targetable Mutations"
- Triple Negative Breast Cancer
- Bone Metastases
Treatment of Hormone Receptor Positive Cancer
Endocrine or “hormone” therapy is usually the first treatment for hormone receptor positive metastatic breast cancer and chemotherapy is reserved for the treatment of cancers that no longer respond to endocrine therapy, hormone receptor negative cancers, or individuals requiring immediate shrinkage of the cancer.
Estrogen is an essential female hormone that is produced by the ovaries and adrenal glands. It serves many critical functions in the body, including developing the female sex organs in puberty, preparing the breasts and uterus for pregnancy in adulthood, and maintaining cardiovascular and bone health. Without estrogen, the female body is unable to sustain pregnancy and is susceptible to heart disease and osteoporosis.
Estrogen can also cause some cancers to grow. The breasts, uterus, and other female organs are composed of cells that contain estrogen receptors and estrogen circulating in the blood binds to these receptors and stimulates growth-related activities in the cell. When cells that have estrogen receptors become cancerous, exposure to estrogen increases the cancer’s growth. Cancer cells that have estrogen receptors are referred to as estrogen receptor-positive (ER-positive) cancers. The growth of some breast cancer cells can be prevented or slowed by reducing the exposure to estrogen. This is the goal of endocrine therapy.
Removal of the ovaries, the organ chiefly responsible for producing estrogen in premenopausal women, is one effective approach to eliminating estrogen production and is commonly used in many countries. Another approach is to utilize drugs that can accomplish a similar effect without removing the ovaries. These drugs include tamoxifen, aromatase inhibitors, and most recently cyclin-dependent kinase inhibitors (CDK).
Treatment for Hormone Receptor Positive Breast Cancer
Recommendations set forth by a convening Expert Panel specifically for women with HR-positive, metastatic breast cancer included the following.10 A combination of a CDK4/6 inhibitor and endocrine therapy is currently the first choice because the addition of CDK 4/6 inhibitors to endocrine therapy is associated with improved survival and maintained or improved quality of life compared to other endocrine therapies.3,4,5,6,7,8,9
- Patients whose cancer cells express any level of HR-positivity should be offered endocrine therapy as initial therapy.
- Sequential endocrine therapy (using one endocrine agent until the patient’s cancer progresses, then switching to a different endocrine agent until the cancer progresses again, etc.) is the preferred treatment of choice.
- Among postmenopausal women, aromatase inhibitors (AIs) are the initial treatment of choice, with or without the addition of the CDK inhibitor.11,12,13,14 For example a CDK inhibitor combined with an AI demonstrated a greater than 28-month median progression-free survival as initial endocrine-based therapy for metastatic disease compared to 14.8 months for treatment with an AI alone.
- If the cancer starts to progress on AIs, Faslodex® (fulvestrant) or combination therapy with a CDK inhibitor and an AI can further prolong survival. The CDK inhibitor Ibrance (palbociclib) when combined with Faslodex nearly doubles the duration of survival when compared to an AI alone.12
- Among premenopausal women, ovarian suppression or ablation should be included in the treatment strategy. The CDK inhibitor Kisqali in combination with tamoxifen or an AI plus goserelin improve time of survival without cancer progression to 23.8 months compared to 13 months for tamoxifen or an AI plus goserelin.15
Precision Cancer Medicines
Not all breast cancer cells are alike. They may differ from one another based on what genes have mutations. Through genomic-biomarker testing performed on a biopsy of the cancer or from a blood sample doctors are increasingly able to define the genomic alterations in a cancers DNA that is driving the growth of a specific cancer. Once a genetic abnormality is identified, a precision medicine can be designed to target a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
Laboratory evaluation for targetable mutations can be performed on tissue and in the blood and is evolving rapidly. It is not uncommon to get different test results from different laboratories so patients should consider having their testing reviewed and perhaps repeated by a breast cancer expert with expertise in NGS testing for breast cancer.
HER2 Positive Cancers – Twenty to thirty percent of breast cancers over express (make too much of) a protein known as HER2. Over expression of this protein leads to increased growth of cancer cells. There are several precision medicines that specifically target HER2-positive cells, and these have significantly improved outcomes among women with HER2-positive breast cancers. Optimal sequencing of these medications is increasingly complicated and new anti-HER2 therapies continue to become available leading to improved outcomes. Currently the NCCN recommends the following treatments.
- Herceptin® (trastuzumab) recognizes and binds to HER2-positive cells and was the first precision medicine developed for the treatment of breast cancer. Among women with HER2-positive breast cancer, Herceptin is often used in combination with Perjeta as the initial treatment for metastatic disease.16,17,18,19,20
- Perjeta (perjeta) targets a different part of the HER2 protein than Herceptin. Since the two drugs target different regions of HER2, they are believed to work in a way that is complementary to each other. In a comparative clinical study called the CLEOPATRA trial, the combination of Herceptin and Perjeta plus chemotherapy improved survival compared to treatment with Herceptin alone and this combination is often the initial therapy for metastatic disease.29,30
If cancer returns after initial treatment, there are several additional medications available that specifically target HER2 and others being evaluated in clinical trials. The presence of cancer spread to the brain is a key determinant in subsequent therapy and patients should discuss whether a MRI of the brain is necessary – 15% of patients will have asymptomatic brain metastases.
- Tukysa (tucatinib) is a highly selective oral tyrosine kinase inhibitor that targets HER2 and appears to have the best activity against brain metastases. The HER2CLIMB clinical trial demonstrated that Tukysa added to Herceptin and Xeloda reduced the risk of disease progression and improved survival, even in women with brain metastases. The Tukysa regimen is well tolerated and associated with minimal hair loss.26,27,28
- Kadcyla (ado-trastuzumab emtansine, formerly known as T-DM1) is an antibody-drug conjugate that combines Herceptin and a chemotherapy drug (DM1) that interferes with cancer cell growth. Kadcyla delivers Herceptin and DM1 directly to HER2-positive cells, and limits exposure of the rest of the body to the chemotherapy. Kadcyla has been demonstrated to delay cancer progression and prolong survival compared to Tykerb plus Xeloda (capecitabine) and Herceptin plus docetaxel in women with recurrent metastatic, HER2-over expressed breast cancer. Kadcyla has also been evaluated as the initial treatment for metastatic HER2 + breast cancer and found to produce similar outcomes as Herceptin plus taxane or T-DM1 plus Perjeta.21,22,23,24,25 Kadcyla may cause interstitial lung disease and patients should discuss the potential complication with their physician.
- Neratinib targets several other HER2 proteins in addition to HER2 and can often be helpful when resistance to HER2 targeted therapies occurs.
- Tykerb (lapatinib) also targets HER2 as well as a related protein known as the epidermal growth factor receptor (EGFR).19,20
BRCA Mutations – About 3% of breast cancers are in people who inherited BRCA mutations. BRCA1 and BRCA2 are tumor-suppressor genes that encode proteins involved in DNA repair through the homologous recombination repair pathway. Mutations in the BRCA gene raise the risk of cancer because they make the body less likely to repair damage to its DNA, making the mutations that lead to cancer more likely. Poly ADP-ribose polymerase (PARP) inhibitors block enzymes involved in repairing damaged DNA. By disrupting a cancer cells’ ability to repair itself PARP inhibitors slow uncontrolled growth and replication of cancer cells.31,32 There are several PARP inhibitors in development.
- Lynparza (olaparib) is the first PARP inhibitor approved for use in breast cancer. Lynparza was demonstrated to be superior to chemotherapy for treatment of HER2-negative advanced breast cancer patients who have a BRCA mutation.31
- Women with BRCA positive breast cancers have hereditary breast cancers and related individuals may be at increased risk of breast cancer and should be evaluated.
Hormone Receptor–Negative Breast Cancer
The treatment for hormone receptor–negative breast cancer consists of systemic therapy with chemotherapy and/or immunotherapy. Patients with breast cancer that does not have estrogen/progesterone receptors, those not responding to hormonal treatment, and individuals requiring symptomatic relief from progressive breast cancer may also benefit from treatment with chemotherapy.
There are currently several standard chemotherapy drugs and treatment regimens available, and approximately 25% of patients who undergo chemotherapy will experience a complete remission of their cancer. Patients should discuss their goals of treatment with their physician and consider participation in a clinical study as their initial treatment.
- Taxanes Taxotere (docetaxel) and Taxol (paclitaxel) are both taxanes that, when used in combination or sequentially with other chemotherapy drugs, appear to have more anti-cancer activity than non-taxane chemotherapy for the treatment of metastatic breast cancer.
- Abraxane (nanoparticle albumin-bound paclitaxel): A technique for delivering anti-cancer drugs is called nanoparticle albumin-bound (nab) technology. Abraxane is a treatment that delivers the anti-cancer drug paclitaxel using nab technology. This technique utilizes albumin, the most abundant protein in the body, to deliver the paclitaxel directly to cancer cells. With Abraxane 50% more drug can be administered, more active drug is transported into the cancer cells, and patients experience fewer side effects.33
- Xeloda (capecitabine) is a well-tolerated, oral chemotherapy drug that can be taken at home for treatment of breast cancer. Research indicates that 20-30% of patients experience a measurable shrinkage of their cancer following treatment with Xeloda. Xeloda is well-tolerated, and the average duration of survival of patients treated with Xeloda is almost 13 months.
Triple Negative Breast Cancer (TNBC)
Approximately 12-15% of all breast cancers are triple negative, meaning that they are estrogen and progesterone-receptor negative, and human epidermal growth factor receptor 2-negative (HER2-). This means that TNBC is not stimulated to grow from exposure to the female hormones, estrogen or progesterone, nor through an overactive HER2 pathway.
- Trodelvy (sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate comprised of an antibody that attaches to specific receptors called Trop-2 receptors and delivers an attached drug that kills cancer cells, called SN-38. By targeting Trop-2 receptors, larger amounts of chemotherapy can be delivered to the cancer cells because healthy cells are largely spared from the cancer-killing effects of the treatment. Trodelv was approved by the U.S. FDA for the treatment of patients with TNBC on April 5th, 2020.39
Checkpoint Inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 receptor these drugs restore an immune cells’ ability to recognize and fight the breast cancer cells. A diagnostic test to measure the level of PD-L1 is available.
- Tecentriq (atezolizumb) The combination of Tecentriq and Abraxane improved average survival duration from 15.5 months among patients with PD-L1–positive tumors to 25 months leading to accelerated FDA approval in 2020.34,35,36
- Keytruda (pembroluzumab) Patients were treated with Keytruda plus chemotherapy or chemotherapy alone and directly compared. In patients with the highest CPS of 10 or greater the addition of Keytruda to chemotherapy significantly prolonged survival without cancer progression.38
Managing Bone Metastases
Recurrent breast cancer often includes cancer that has spread to the bones, called bone metastases. Cancer can spread to the bones when individual cancer cells break off from the original tumor and travel in the circulatory or lymph system until they get lodged in a small vessel in a new area. The cell then grows into another tumor. Management of bone metastases may include a RANK ligand inhibitor or a bisphosphonate drug, and the use of bone-modifying therapy to reduce skeletal morbidity in patients with bone metastases should be considered.39,40,41,42
- XGEVA (denosumab) is indicated for the prevention of skeletal-related events in patients with bone metastases from breast cancer.39,40
- Bisphosphonates are a class of drugs that decrease the rate of bone destruction in patients with cancer. Clinical studies have shown that bisphosphonate therapy can prevent or delay bone destruction, including fractures and related pain, in women with breast cancer that has spread to the bone.41,42
- Strontium89 is a radionuclide therapy that is used to alleviate pain caused by bone metastases. Strontium89 delivers radiation directly to the boney cancerous sites and has been shown to provide pain relief from bone with a single injection.43
Treatment of Locally Recurrent Breast Cancer
Recurrent breast cancers that are confined to the breast or area immediately surrounding the breast, called local-regional recurrences, are typically treated with surgery with or without radiation therapy.46,47
Surgery may be indicated for certain situations
For example, patients may need surgery if the following issues occur:
- Fungating/painful breast lesions (mastectomy).
- Brain or vertebral metastases with spinal cord compression.
- Isolated lung metastases.
- Pathologic (or impending) fractures.
- Pleural or pericardial effusions.
Radiation therapy has a major role in the palliation of localized symptomatic metastases. Indications for external-beam radiation therapy include the following:
- Painful bony metastases.
- Unresectable central nervous system metastases (i.e., brain, meninges, and spinal cord).
- Bronchial obstruction.
- Fungating/painful breast or chest wall lesions.
- After surgery for decompression of intracranial or spinal cord metastases.
- After fixation of pathologic fractures.
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2 Seidman AD, Bordeleau L, Fehrenbacher L, et al.: National Cancer Institute Breast Cancer Steering Committee Working Group Report on Meaningful and Appropriate End Points for Clinical Trials in Metastatic Breast Cancer. J Clin Oncol 36 (32): 3259-3268, 2018.
3 Rugo HS, Diéras V, Gelmon KA, et al.: Impact of palbociclib plus letrozole on patient-reported health-related quality of life: results from the PALOMA-2 trial. Ann Oncol 29 (4): 888-894, 2018.
4 Rugo HS, Finn RS, Diéras V, et al.: Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up. Breast Cancer Res Treat 174 (3): 719-729, 2019.
5 Turner NC, Ro J, André F, et al.: Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med 373 (3): 209-19, 2015.
6 Verma S, O’Shaughnessy J, Burris HA, et al.: Health-related quality of life of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treated with ribociclib + letrozole: results from MONALEESA-2. Breast Cancer Res Treat 170 (3): 535-545, 2018.
7 Janni W, Alba E, Bachelot T, et al.: First-line ribociclib plus letrozole in postmenopausal women with HR+ , HER2- advanced breast cancer: Tumor response and pain reduction in the phase 3 MONALEESA-2 trial. Breast Cancer Res Treat 169 (3): 469-479, 2018.
8 Kaufman PA, Toi M, Neven P, et al.: Health-Related Quality of Life in MONARCH 2: Abemaciclib plus Fulvestrant in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer After Endocrine Therapy. Oncologist 25 (2): e243-e251, 2020.
9 Gao JJ, Cheng J, Bloomquist E, et al.: CDK4/6 inhibitor treatment for patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US Food and Drug Administration pooled analysis. Lancet Oncol 21 (2): 250-260, 2020.
10 Rugo H, Rumble R, Macrae E, et al. Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology Guideline. Journal of Clinical Oncology. 2016; 34 (25): 3069-3103. doi:10.1200/JCO.2016.67.1487JCO**.**
11 Tripathy D, Sohn J, Im S, et al. First-line ribociclib or placebo combined with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the randomized Phase III MONALEESA-7 trial. Presented at the San Antonio Breast Cancer Symposium (SABCS), December 6, 2017, San Antonio, Texas (abstract#S2-05).
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17 Gori S, Colozza M, Mosconi AM, et al. Phase II Study of weekly Paclitaxel and Trastuzumab in Anthracycline-and Taxane-Pretreated Patients with HER2 Overexpressing Metastatic Breast Cancer. British Journal of Cancer. 2004;90:36-40.
18 Extra J, Cognetti F, Maraninchi D, et al. Long-term survival demonstrated with trastuzumab plus docetaxel: 24 month data from a randomized trial (M77001) in HER2-positive metastatic breast cancer. Proceedings from the 41st Annual Meeting of the American Society of Clinical Oncology. Orlando FL. 2005; Abstract 555.
19 Cobleigh MA, Vogel CL, Tripathy D et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Journal of Clinical Oncology. 1999;17:2639-2648.
20 CLEOPATRA Trial Changes Standard Therapy for Metastatic HER2 Positive Breast Cancer [press release]. European Society for Medical Oncology (ESMO) Congress 2014. Available at esmo.org/Conferences/ESMO-2014-Congress/Press-Media/CLEOPATRA-Trial-Changes-Standard-Therapy-for-Metastatic-HER2-Positive-Breast-Cancer. Accessed October 4, 2014.
21 Hurvitz SA, Dirix L, Kocsis J, et al.: Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol 31 (9): 1157-63, 2013.
22 Krop IE, Kim SB, González-Martín A, et al.: Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol 15 (7): 689-99, 2014.
23 Krop IE, Kim SB, Martin AG, et al.: Trastuzumab emtansine versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol 18 (6): 743-754, 2017.
24 Perez EA, Barrios C, Eiermann W, et al.: Trastuzumab Emtansine With or Without Pertuzumab Versus Trastuzumab Plus Taxane for Human Epidermal Growth Factor Receptor 2-Positive, Advanced Breast Cancer: Primary Results From the Phase III MARIANNE Study. J Clin Oncol 35 (2): 141-148, 2017.
25 Modi S, Saura C, Yamashita T, et al.: Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med 382 (7):610-621, 2020.
26 Lin NU, Murthy RK, Anders CK, et al, Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). Presented at: ASCO20 Virtual Scientific Program. J Clin Oncol. 2020;38(suppl):abstr 1005.
27 Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-Positive metastatic breast cancer. N Engl J Med. 2020;382:597-609.
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29 Cobleigh MA, Vogel CL, Tripathy D et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Journal of Clinical Oncology. 1999;17:2639-2648.
30 CLEOPATRA Trial Changes Standard Therapy for Metastatic HER2 Positive Breast Cancer [press release]. European Society for Medical Oncology (ESMO) Congress 2014. Available at esmo.org/Conferences/ESMO-2014-Congress/Press-Media/CLEOPATRA-Trial-Changes-Standard-Therapy-for-Metastatic-HER2-Positive-Breast-Cancer. Accessed October 4, 2014
31 Robson M, Im SA, Senkus E, et al.: Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med 377 (6): 523-533, 2017.
32 Litton JK, Rugo HS, Ettl J, et al.: Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med 379 (8): 753-763, 2018.
33 O’Shaughnessy J, Tjulandin S, Davidson N, et al. ABI-007 (Abraxane®), a nanoparticle albumin-bound paclitaxel demonstrates superior efficacy vs. taxol in MBC: a phase III trial (Abstract #44). Proceedings from the 26th annual San AntonioBreast Cancer Symposium ( 12/3/03 ), Abstract #44.
34 N Engl J Med. Published on October 20, 2018. Abstract
35 Schmid P, Adams S, Rugo HS, et al. IMpassion130: updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, Phase III study of atezolizumab (atezo) + nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC). Presented at: the 2019 ASCO Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 1003.
36 Schmid P, Cortés J, Dent R, et al: KEYNOTE-522: Phase III study of pembrolizumab + chemotherapy vs placebo + chemo as neoadjuvant treatment, followed by pembrolizumab vs placebo as adjuvant treatment for early triple-negative breast cancer. ESMO Congress 2019. esmo.org/Conferences/ESMO-Congress-2019/Abstracts Abstract LBA8_PR. Presented September 29, 2019.
37 Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. Presented at: ASCO20 Virtual Scientific Program. J Clin Oncol. 2020;38(suppl):abstr 1000.
38 Bardia A, Mayer IA, Vahdat LT, et al.: Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. N Engl J Med 380 (8): 741-751, 2019.
39 Lipton A, Siena S, Rader M et al. Comparison of denosumab versus zoledronic acid (ZA) for treatment of bone metastases in advanced cancer patients: An integrated analysis of 3 pivotal trials. Presented at the 35th European Society for Medical Oncology (ESMO) Congress, Milan, Italy, October 8-12, 2010. Abstract 1249P.
40 Cleeland CS, Patrick DL, Fallowfield L et al. Effects of denosumab vs zoledronic acid (ZA) on pain in patients (pts) with advanced cancer and bone metastases: An integrated analysis of 3 pivotal trials. Presented at the 35th European Society for Medical Oncology (ESMO) Congress, Milan, Italy, October 8-12, 2010. Abstract 1248P.
41 Ross JR, Saunders Y, Edmonds PM, et al. Systematic Review of Role of Bisphosphonates on Skeletal Morbidity in Metastatic Cancer. British Medical Journal. 2003;327:469-471.
42 Lipton A, Theriault RL, Hortobagyi GN, et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: Long term follow-up of two randomized, placebo-controlled trials. Cancer. 2000; 88(5):1082-1090.
43 Nilsson S, Strang P, Ginman C, et al. Palliation of Bone Pain in Prostate Cancer Using Chemotherapy and Stontium-89. A Randomized Phase IIStudy. Journal of Pain and Symptom Management. 2005; 29: 352-357
44 Rugo HS, Lerebours F, Ciruelos E, et al. Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results. Presented at: ASCO20 Virtual Scientific Program. J Clin Oncol. 2020;38(suppl):abstr 1006.
45 André F, Ciruelos E, Rubovsky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor positive advanced breast cancer. N Engl J Med. 2019;380:1929-1940.
46 Darby S, McGale P, Correa C, et al.: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomized trials. Lancet 378 (9804): 1707-16, 2011.
47 Wapnir IL, Price KN, Anderson SJ, et al.: Efficacy of Chemotherapy for ER-Negative and ER-Positive Isolated Locoregional Recurrence of Breast Cancer: Final Analysis of the CALOR Trial. J Clin Oncol 36 (11): 1073-1079, 2018.
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