Zoledronic acid

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Zoledronic acid
Zoledronic acid.svg
Zoledronic-acid-from-xtal-2003-3D-balls.png
Clinical data
Trade names Reclast, Zometa, others [1]
Other nameszoledronate
AHFS/Drugs.com Monograph
MedlinePlus a605023
License data
Pregnancy
category
Routes of
administration 		Intravenous
Drug class Bisphosphonate [3]
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 22%
Metabolism Nil
Elimination half-life 146 hours
Excretion Kidney (partial)
Identifiers
  • [1-hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diyl]bis(phosphonic acid)
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
Formula C5H10N2O7P2
Molar mass 272.090 g·mol−1
3D model (JSmol)
  • O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
  • InChI=1S/C5H10N2O7P2/c8-5(15(9,10)11,16(12,13)14)3-7-2-1-6-4-7/h1-2,4,8H,3H2,(H2,9,10,11)(H2,12,13,14)
  • Key:XRASPMIURGNCCH-UHFFFAOYSA-N
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Zoledronic acid, also known as zoledronate and sold under the brand name Zometa among others, [7] by Novartis among others, is a medication used to treat a number of bone diseases. [3] These include osteoporosis, high blood calcium due to cancer, bone breakdown due to cancer, Paget's disease of bone [3] and Duchenne muscular dystrophy (DMD). It is given by injection into a vein. [3]

Contents

Common side effects include fever, joint pain, high blood pressure, diarrhea, and feeling tired. [3] Serious side effects may include kidney problems, low blood calcium, and osteonecrosis of the jaw. [3] Use during pregnancy may result in harm to the baby. [3] It is in the bisphosphonate family of medications. [3] It works by blocking the activity of osteoclast cells and thus decreases the breakdown of bone. [3]

Zoledronic acid was patented in 1986 and approved for medical use in the United States in 2001. [3] [8] It is on the World Health Organization's List of Essential Medicines. [9]

Medical uses

Zoledronic acid is indicated for the prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumor-induced hypercalcemia) in people with advanced malignancies involving bone; the treatment of adults with tumor-induced hypercalcemia (TIH). [5]

Zoledronic acid is also indicated for the treatment and prevention of postmenopausal osteoporosis; the treatment to increase bone mass in men with osteoporosis; the treatment and prevention of glucocorticoid-induced osteoporosis; the treatment of Paget’s disease of bone in men and women. [4] [6]

Bone complications of cancer

Zoledronic acid is used to prevent bone fractures in patients with cancers such as multiple myeloma and prostate cancer, as well as for treating osteoporosis. [10] It can also be used to treat hypercalcaemia of malignancy and can be helpful for treating pain from bone metastases. [11]

It can be given at home rather than in hospital. Such use has shown safety and quality-of-life benefits in people with breast cancer and bone metastases. [12]

Osteoporosis

Zoledronic acid is used for the treatment of osteoporosis in men and post-menopausal women at increased risk of fracture. [13] [14]

In 2007, the US Food and Drug Administration (FDA) approved zoledronic acid for the treatment of postmenopausal osteoporosis. [7] [15]

Other

Zoledronic acid may be used for treatment of osteogenesis imperfecta. [16]

Contraindications

Side effects

Side effects can include fatigue, anemia, muscle aches, fever, and/or swelling in the feet or legs. Flu-like symptoms are common after the first infusion, although not subsequent infusions, and are thought to occur because of its potential to activate human gamma delta T cell (γδ T cells).

Kidneys

There is a risk of severe renal impairment. Appropriate hydration is important before administration, as is adequate calcium and vitamin D intake before Aclasta therapy in patients with hypocalcaemia, and for ten days following Aclasta in patients with Paget's disease of the bone. Monitoring for other mineral metabolism disorders and the avoidance of invasive dental procedures for those who develop osteonecrosis of the jaw is recommended. [18]

Zoledronate is rapidly processed via the kidneys; consequently its administration is not recommended for patients with reduced renal function or kidney disease. [19] Some cases of acute kidney injury either requiring dialysis or having a fatal outcome following Reclast use have been reported to the U.S. Food and Drug Administration (FDA). [20] This assessment was confirmed by the European Medicines Agency (EMA), whose Committee for Medicinal Products for Human Use (CHMP) specified new contraindications for the medication on 15 December 2011, which include hypocalcaemia and severe renal impairment with a creatinine clearance of less than 35 ml/min. [21]

Bone

Osteonecrosis of the jaw

A rare complication that has been recently observed in cancer patients being treated with bisphosphonates is osteonecrosis of the jaw. This has mainly been seen in patients with multiple myeloma treated with zoledronic acid who have had dental extractions. [22]

Atypical fractures

After approving the drug in July 2009, the European Medicines Agency conducted a class review of all bisphosphonates, including zoledronic acid, after several cases of atypical fractures were reported. [23] In 2008, the EMA's Pharmacovigilance Working Party (PhVWP) noted that alendronic acid was associated with an increased risk of atypical fracture of the femur that developed with low or no trauma. In April 2010, the PhVWP noted that further data from both the published literature and post-marketing reports were now available which suggested that atypical stress fractures of the femur may be a class effect. The European Medicines Agency then reviewed all case reports of stress fractures in patients treated with bisphosphonates, relevant data from the published literature, and data provided by the companies which market bisphosphonates. The Agency recommended that doctors who prescribe bisphosphonate-containing medicines should be aware that atypical fractures may occur rarely in the femur, especially after long-term use, and that doctors who are prescribing these medicines for the prevention or treatment of osteoporosis should regularly review the need for continued treatment, especially after five or more years of use. [23]

Pharmacology

As a nitrogenous bisphosphonate, zoledronic acid is a potent inhibitor of bone resorption, allowing the bone-forming cells time to rebuild normal bone and allowing bone remodeling. [24] [25]

Relative potency [26]
BisphosphonateRelative potency
Etidronate 1
Tiludronate 10
Pamidronate 100
Alendronate 100-500
Ibandronate 500-1000
Risedronate 1000
Zoledronate5000

Research

Zoledronic acid has been found to have a direct antitumor effect and to synergistically augment the effects of other antitumor agents in osteosarcoma cells. [27]

Zoledronic acid has shown significant benefits versus placebo over three years, with a reduced number of vertebral fractures and improved markers of bone density. [28] [15] An annual dose of zoledronic acid may also prevent recurring fractures in patients with a previous hip fracture. [14]

With hormone therapy for breast cancer

An increase in disease-free survival (DFS) was found in the ABCSG-12 trial, in which 1,803 premenopausal women with endocrine-responsive early breast cancer received anastrozole with zoledronic acid. [29] A retrospective analysis of the AZURE trial data revealed a DFS survival advantage, particularly where estrogen had been reduced. [30]

In a meta-analysis of trials where upfront zoledronic acid was given to prevent aromatase inhibitor-associated bone loss, active cancer recurrence appeared to be reduced. [31]

As of 2010 "The results of clinical studies of adjuvant treatment on early-stage hormone-receptor-positive breast-cancer patients under hormonal treatment – especially with the bisphosphonate zoledronic acid – caused excitement because they demonstrated an additive effect on decreasing disease relapses at bone or other sites. A number of clinical and in vitro and in vivo preclinical studies, which are either ongoing or have just ended, are investigating the mechanism of action and antitumoral activity of bisphosphonates." [32]

A 2010 review concluded that "adding zoledronic acid 4 mg intravenously every 6 months to endocrine therapy in premenopausal women with hormone receptor-positive early breast cancer ... is cost-effective from a US health care system perspective". [33]

Related Research Articles

<span class="mw-page-title-main">Osteoporosis</span> Skeletal disorder

Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in fracture risk.

<span class="mw-page-title-main">Hydrochlorothiazide</span> Diuretic medication

Hydrochlorothiazide, sold under the brand name Hydrodiuril among others, is a diuretic medication used to treat hypertension and swelling due to fluid build-up. Other uses include treating diabetes insipidus and renal tubular acidosis and to decrease the risk of kidney stones in those with a high calcium level in the urine. Hydrochlorothiazide is taken by mouth and may be combined with other blood pressure medications as a single pill to increase effectiveness. Hydrochlorothiazide is a thiazide medication which inhibits reabsorption of sodium and chloride ions from the distal convoluted tubules of the kidneys, causing a natriuresis. This initially increases urine volume and lowers blood volume. It is believed to reduce peripheral vascular resistance.

<span class="mw-page-title-main">Bisphosphonate</span> Pharmaceutical drugs for preventing bone loss

Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they have two phosphonate groups. They are thus also called diphosphonates.

<span class="mw-page-title-main">Paget's disease of bone</span> Disease affecting bone remodeling

Paget's disease of bone is a condition involving cellular remodeling and deformity of one or more bones. The affected bones show signs of dysregulated bone remodeling at the microscopic level, specifically excessive bone breakdown and subsequent disorganized new bone formation. These structural changes cause the bone to weaken, which may result in deformity, pain, fracture or arthritis of associated joints.

<span class="mw-page-title-main">Teriparatide</span> Pharmaceutical drug for treating osteoporosis

Teriparatide, sold under the brand name Forteo, is a form of parathyroid hormone (PTH) consisting of the first (N-terminus) 34 amino acids, which is the bioactive portion of the hormone. It is an effective anabolic agent used in the treatment of some forms of osteoporosis. Teriparatide is a recombinant human parathyroid hormone analog. It has an identical sequence to the 34 N-terminal amino acids of the 84-amino acid human parathyroid hormone.

<span class="mw-page-title-main">Alendronic acid</span> Chemical compound

Alendronic acid, sold under the brand name Fosamax among others, is a bisphosphonate medication used to treat osteoporosis and Paget's disease of bone. It is taken by mouth. Use is often recommended together with vitamin D, calcium supplementation, and lifestyle changes.

<span class="mw-page-title-main">Aromatase inhibitor</span> Class of drugs

Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when supplementing testosterone exogenously. They may also be used for chemoprevention in women at high risk for breast cancer.

<span class="mw-page-title-main">Raloxifene</span> Chemical compound

Raloxifene, sold under the brand name Evista among others, is a medication used to prevent and treat osteoporosis in postmenopausal women and those on glucocorticoids. For osteoporosis it is less preferred than bisphosphonates. It is also used to reduce the risk of breast cancer in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">Osteopenia</span> Abnormally low bone mineral density

Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density is low. Because their bones are weaker, people with osteopenia may have a higher risk of fractures, and some people may go on to develop osteoporosis. In 2010, 43 million older adults in the US had osteopenia. Unlike osteoporosis, osteopenia does not usually cause symptoms, and losing bone density in itself does not cause pain.

<span class="mw-page-title-main">Bazedoxifene</span> Chemical compound

Bazedoxifene, used as bazedoxifene acetate, is a medication for bone problems and possibly for cancer. It is a third-generation selective estrogen receptor modulator (SERM). Since late 2013 it has had U.S. FDA approval for bazedoxifene as part of the combination drug Duavee in the prevention of postmenopausal osteoporosis. It is also being studied for possible treatment of breast cancer and pancreatic cancer.

<span class="mw-page-title-main">RANKL</span> Mammalian protein found in Homo sapiens

Receptor activator of nuclear factor kappa-Β ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF), is a protein that in humans is encoded by the TNFSF11 gene.

<span class="mw-page-title-main">Ibandronic acid</span> Chemical compound

Ibandronic acid is a bisphosphonate medication used in the prevention and treatment of osteoporosis and metastasis-associated skeletal fractures in people with cancer. It may also be used to treat hypercalcemia. It is typically formulated as its sodium salt ibandronate sodium.

<span class="mw-page-title-main">Osteonecrosis of the jaw</span> Medical condition

Osteonecrosis of the jaw (ONJ) is a severe bone disease (osteonecrosis) that affects the jaws. Various forms of ONJ have been described since 1861, and a number of causes have been suggested in the literature.

<span class="mw-page-title-main">Denosumab</span> Human monoclonal antibody

Denosumab, sold under the brand names Prolia among others, is a human monoclonal antibody used for the treatment of osteoporosis, treatment-induced bone loss, metastases to bone, and giant cell tumor of bone.

<span class="mw-page-title-main">Strontium ranelate</span> Chemical compound

Strontium ranelate, a strontium(II) salt of ranelic acid, is a medication for osteoporosis marketed as Protelos or Protos by Servier. Studies indicate it can also slow the course of osteoarthritis of the knee. The drug is unusual in that it both increases deposition of new bone by osteoblasts and reduces the resorption of bone by osteoclasts. It is therefore promoted as a "dual action bone agent" (DABA).

<span class="mw-page-title-main">Lasofoxifene</span> Chemical compound

Lasofoxifene, sold under the brand name Fablyn, is a nonsteroidal selective estrogen receptor modulator (SERM) which is marketed by Pfizer in Lithuania and Portugal for the prevention and treatment of osteoporosis and for the treatment of vaginal atrophy, and the result of an exclusive research collaboration with Ligand Pharmaceuticals (LGND). It also appears to have had a statistically significant effect of reducing breast cancer in women according to a study published in The Journal of the National Cancer Institute.

Senile osteoporosis has been recently recognized as a geriatric syndrome with a particular pathophysiology. There are different classification of osteoporosis: primary, in which bone loss is a result of aging and secondary, in which bone loss occurs from various clinical and lifestyle factors. Primary, or involuntary osteoporosis, can further be classified into Type I or Type II. Type I refers to postmenopausal osteoporosis and is caused by the deficiency of estrogen. While senile osteoporosis is categorized as an involuntary, Type II, and primary osteoporosis, which affects both men and women over the age of 70 years. It is accompanied by vitamin D deficiency, body's failure to absorb calcium, and increased parathyroid hormone.

<span class="mw-page-title-main">Medication-related osteonecrosis of the jaw</span> Medical condition

Medication-related osteonecrosis of the jaw is progressive death of the jawbone in a person exposed to a medication known to increase the risk of disease, in the absence of a previous radiation treatment. It may lead to surgical complication in the form of impaired wound healing following oral and maxillofacial surgery, periodontal surgery, or endodontic therapy.

Jane A. Cauley is a Distinguished Professor in the Department of Epidemiology and an Associate Dean for Research at the University of Pittsburgh.

<span class="mw-page-title-main">Osteolytic lesion</span> Softened section of a bone

An osteolytic lesion is a softened section of a patient's bone formed as a symptom of specific diseases, including breast cancer and multiple myeloma. This softened area appears as a hole on X-ray scans due to decreased bone density, although many other diseases are associated with this symptom. Osteolytic lesions can cause pain, increased risk of bone fracture, and spinal cord compression. These lesions can be treated using bisphosphonates or radiation, though new solutions are being tested in clinical trials.

References

  1. ↑ "International trade names for zoledronic acid". Drugs.com. Archived from the original on 4 March 2016. Retrieved 14 January 2015.
  2. ↑ "Zoledronic acid Use During Pregnancy". Drugs.com. 1 June 2020. Archived from the original on 16 November 2021. Retrieved 19 October 2020.
  3. 1 2 3 4 5 6 7 8 9 10 "Zoledronic Acid". The American Society of Health-System Pharmacists. Archived from the original on 15 December 2017. Retrieved 8 December 2017.
  4. 1 2 "Reclast- zoledronic acid injection, solution". DailyMed. 7 July 2022. Retrieved 10 August 2024.
  5. 1 2 "Zometa EPAR". European Medicines Agency. 20 March 2001. Archived from the original on 7 June 2023. Retrieved 5 July 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. 1 2 "Aclasta EPAR". European Medicines Agency (EMA). 15 April 2005. Retrieved 10 August 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  7. 1 2 "Novartis's Reclast Receives FDA Approval for Women With Postmenopausal Osteoporosis". FierceBiotech (Press release). 20 August 2007. Archived from the original on 28 March 2018. Retrieved 2 September 2021.
  8. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 524. ISBN   9783527607495. Archived from the original on 14 January 2023. Retrieved 2 June 2020.
  9. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
  10. ↑ National Prescribing Service (2009). "Zoledronic Acid for Osteoporosis". Medicines Update, Available at "Zoledronic acid (Aclasta) for osteoporosis: National Prescribing Service Ltd NPS". Archived from the original on 23 April 2010. Retrieved 20 January 2010.
  11. ↑ "Zomera prescribing information" (PDF). Novartis Pharmaceuticals Corporation. U.S. Food and Drug Administration. April 2014. Archived (PDF) from the original on 19 June 2022. Retrieved 10 October 2023.
  12. ↑ Wardley A, Davidson N, Barrett-Lee P, Hong A, Mansi J, Dodwell D, et al. (May 2005). "Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: a randomised, crossover study of community vs hospital bisphosphonate administration". British Journal of Cancer. 92 (10): 1869–1876. doi:10.1038/sj.bjc.6602551. PMC   2361764 . PMID   15870721.{{cite journal}}: CS1 maint: overridden setting (link)
  13. ↑ Dhillon S (November 2016). "Zoledronic Acid (Reclast, Aclasta): A Review in Osteoporosis". Drugs. 76 (17): 1683–1697. doi:10.1007/s40265-016-0662-4. PMID   27864686. S2CID   22079489.
  14. 1 2 Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, et al. (November 2007). "Zoledronic acid and clinical fractures and mortality after hip fracture". The New England Journal of Medicine. 357 (18): 1799–1809. doi:10.1056/NEJMoa074941. PMC   2324066 . PMID   17878149.{{cite journal}}: CS1 maint: overridden setting (link)
  15. 1 2 Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, et al. (May 2007). "Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis". The New England Journal of Medicine. 356 (18): 1809–1822. doi: 10.1056/nejmoa067312 . PMID   17476007. S2CID   71443125.{{cite journal}}: CS1 maint: overridden setting (link)
  16. ↑ Dwan K, Phillipi CA, Steiner RD, Basel D (October 2016). "Bisphosphonate therapy for osteogenesis imperfecta". The Cochrane Database of Systematic Reviews. 2016 (10): CD005088. doi:10.1002/14651858.CD005088.pub4. PMC   6611487 . PMID   27760454.
  17. ↑ Vondracek SF (April 2010). "Managing osteoporosis in postmenopausal women". American Journal of Health-System Pharmacy. 67 (7 Suppl 3): S9-19. doi:10.2146/ajhp100076. PMID   20332498.
  18. ↑ "NPS MedicineWise" (PDF). Archived from the original (PDF) on 4 March 2016. Retrieved 25 January 2014.
  19. ↑ "Zometa 4mg/5ml Concentrate for Solution for Infusion". medicines.org.uk. Archived from the original on 24 February 2010. Retrieved 24 February 2010.
  20. ↑ "FDA Alert: Reclast (zoledronic acid): Drug Safety Communication - New Contraindication and Updated Warning on Kidney Impairment". drugs.com. Archived from the original on 3 March 2016. Retrieved 23 January 2018.
  21. ↑ "European Medicines Agency - Human medicines". europa.eu. Archived from the original on 25 September 2015. Retrieved 3 April 2012.
  22. ↑ Durie BG, Katz M, Crowley J (July 2005). "Osteonecrosis of the jaw and bisphosphonates" (PDF). The New England Journal of Medicine. 353 (1): 99–102, discussion 99–102. doi:10.1056/NEJM200507073530120. PMID   16000365. Archived (PDF) from the original on 21 August 2023. Retrieved 25 June 2023.
  23. 1 2 "European Medicines Agency - Human medicines". europa.eu. Archived from the original on 19 January 2013. Retrieved 3 April 2012.
  24. ↑ "Aclasta label- Australia" (PDF). Archived from the original (PDF) on 4 March 2016. Retrieved 25 January 2014.
  25. ↑ "Bisphosphonates". International Osteoporosis Foundation. Retrieved 30 July 2022.[ permanent dead link ]
  26. ↑ Tripathi KD (30 September 2013). Essentials of medical pharmacology (Seventh ed.). New Delhi: Jaypee Brothers Medical Publishers, Ltd. ISBN   9789350259375. OCLC   868299888.
  27. ↑ Koto K, Murata H, Kimura S, Horie N, Matsui T, Nishigaki Y, et al. (July 2010). "Zoledronic acid inhibits proliferation of human fibrosarcoma cells with induction of apoptosis, and shows combined effects with other anticancer agents". Oncology Reports. 24 (1): 233–239. doi: 10.3892/or_00000851 . PMID   20514467.{{cite journal}}: CS1 maint: overridden setting (link)
  28. ↑ Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U, et al. (February 2002). "Intravenous zoledronic acid in postmenopausal women with low bone mineral density". The New England Journal of Medicine. 346 (9): 653–661. doi: 10.1056/NEJMoa011807 . PMID   11870242.{{cite journal}}: CS1 maint: overridden setting (link)
  29. ↑ Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Pöstlberger S, Menzel C, et al. (February 2009). "Endocrine therapy plus zoledronic acid in premenopausal breast cancer". The New England Journal of Medicine. 360 (7): 679–691. doi: 10.1056/NEJMoa0806285 . PMID   19213681.{{cite journal}}: CS1 maint: overridden setting (link)
  30. ↑ Coleman RE, Winter MC, Cameron D, Bell R, Dodwell D, Keane MM, et al. (March 2010). "The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer". British Journal of Cancer. 102 (7): 1099–1105. doi:10.1038/sj.bjc.6605604. PMC   2853093 . PMID   20234364.{{cite journal}}: CS1 maint: overridden setting (link)
  31. ↑ Brufsky A, Bundred N, Coleman R, Lambert-Falls R, Mena R, Hadji P, et al. (May 2008). "Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole". The Oncologist. 13 (5): 503–514. doi:10.1634/theoncologist.2007-0206. PMID   18515735. S2CID   23710758.{{cite journal}}: CS1 maint: overridden setting (link)
  32. ↑ Tonyali O, Arslan C, Altundag K (November 2010). "The role of zoledronic acid in the adjuvant treatment of breast cancer: current perspectives". Expert Opinion on Pharmacotherapy. 11 (16): 2715–2725. doi:10.1517/14656566.2010.523699. PMID   20977404. S2CID   26073229.
  33. ↑ Delea TE, Taneja C, Sofrygin O, Kaura S, Gnant M (August 2010). "Cost-effectiveness of zoledronic acid plus endocrine therapy in premenopausal women with hormone-responsive early breast cancer". Clinical Breast Cancer. 10 (4): 267–274. doi:10.3816/CBC.2010.n.034. PMID   20705558.
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