Treatment of Recurrent Breast Cancer

Cancer Connect

Medically reviewed by Dr. C.H. Weaver M.D. 10/2018​

Recurrent breast cancer is cancer that progresses during treatment or recurs after a remission. Although breast cancer may recur almost anywhere in the body, common locations include the liver, bones, lungs, brain, and skin. Treatment for recurrent breast cancer depends on prior treatment, hormonal and menopausal status, location of the recurrence, and whether a precision medicine can be applied.

Medicine has made—and continues to make—great strides in treating breast cancer and in making cancer treatment more tolerable, both physically and emotionally. The greatest recent advances are in Precision Medicine. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. By defining the consequences of these genetic abnormalities doctors can identify specific treatments directed against each genetic abnormality for each individual patient’s unique DNA profile. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of cells. 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.

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. Most patients who experience a recurrence of their cancer have disease that has metastasized, or spread, throughout the body. These patients require systemic treatment that can reach the cancer anywhere in the body; systemic therapy may consist of chemotherapy, hormonal therapy, or targeted therapy.

  • Hormone therapy is usually the first treatment for hormone receptor metastatic breast cancers. Hormone therapy drugs work by preventing the cancer cells from getting the estrogen they need to grow.
  • Chemotherapy is used for people with hormone receptor negative cancers, hormone receptor positive cancers that no longer respond to hormone therapy and in combination with targeted therapies such as those directed at HER2.
  • Treatment of Local-Regional Recurrence of Breast Cancer
  • Systemic Treatment for Recurrent Breast Cancer
  • Managing Bone Metastases
  • Strategies to Improve Treatment

Treatment of Local–Regional Recurrence of Breast Cancer

Following primary surgical treatment of breast cancer with mastectomy or breast-conserving surgery (lumpectomy plus radiation), patients may experience a local recurrence, which is defined as cancer recurring within the previously affected breast, chest wall, or skin over the breast. Patients may also experience a regional recurrence of cancer, which is defined as cancer involving the supraclavicular, internal mammary, or axillary lymph nodes.

Recurrence after mastectomy: Local recurrence of breast cancer following initial treatment with mastectomy may be effectively controlled with additional radiation treatment. Surgery prior to radiation therapy may also be beneficial in selected circumstances. Additional local recurrences may be preventable depending on the size of the cancer, the amount of radiation delivered, and the size of the radiation field (the amount of tissue irradiated).[1]

Despite effective local control with surgery and radiation, the majority of patients experiencing a local recurrence ultimately develop systemic recurrence of their cancer. For this reason, many doctors believe additional treatment with chemotherapy or hormonal therapy may be useful.

Recurrence after breast-conserving surgery: A recurrence following breast-conserving therapy that is limited to the local–regional area around the original cancer is typically treated with a mastectomy. With this approach, approximately 60-75% of patients are likely to survive five years or longer without another cancer recurrence. Mastectomy may be followed by radiation in some circumstances. Patients with regionally recurrent breast cancer are at a higher risk of a future systemic relapse[2] and may benefit most from the addition of radiation therapy or another treatment.

Systemic Therapy for Recurrent Breast Cancer

Most patients who experience a recurrence of breast cancer have disease that has metastasized, or spread, throughout the body. They require systemic treatment that can reach the cancer anywhere in the body; systemic therapy may consist of

  • Chemotherapy
  • Hormonal Therapy
  • Targeted therapy with Precision Cancer Medicines

If the first systemic therapy stops working and the cancer grows again, a second or third targeted treatment may be used. The first treatment is called “first-line” and additional therapy for cancer that has recurred is referred to as “second-line.” With the exception of instances where initial treatment may have been inadequate, second-line therapy is typically associated with lower response rates and a shorter duration of remission than first-line therapy. Thus, the goal of second-line therapy is to reduce symptoms, improve a patient’s quality of life, and improve survival. The type of second-line therapy that is selected and its effectiveness depends on which first-line therapy the patient received. Patients typically develop resistance to drugs that were previously used to treat their cancer.

Targeted Therapy With Precision Cancer Medicines

HER2-targeted therapy: Twenty to thirty percent of breast cancers over express (make too much of) a protein known as HER2.[3] Over expression of this protein leads to increased growth of cancer cells. Herceptin which targets the HER2 is one of the earliest targeted therapies and its success has led to the development of additional precision treatments that specifically target HER2-positive cells improving the outcomes among women with HER2-positive breast cancer.

  • Herceptin® (trastuzumab): Herceptin is an agent that recognizes and binds to HER2-positive cells. The effects of Herceptin are thought to include decreased cell growth and increased cell death.[4] Among women with HER2-positive breast cancer, Herceptin in combination with chemotherapy has been shown to increase response rates and prolong survival compared to treatment with either Herceptin or chemotherapy alone.[5],[6],[7] For women who have relapsed after prior chemotherapy for metastatic breast cancer, Herceptin can also be used alone. A study among women who had received extensive prior therapy for metastatic breast cancer reported that treatment with Herceptin alone resulted in a partial or complete disappearance of detectable cancer in 15% of the women.[8]
  • Perjeta (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 fact clinical studies demonstrate that the combination of Herceptin and Perjeta significantly improve survival for patients with HER2-positive metastatic breast cancer when added to chemotherapy In a comparative clinical study called the CLEOPATRA trial, the combination of Herceptin and Perjeta plus chemotherapy produced overall survival of 56 months versus just over 40 months for the Herceptin-only group.[9],[10]
  • Kadcyla™ (ado-trastuzumab emtansine, formerly known as T-DM1): Kadcyla 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. The TH3RESA study included 602 patients with advanced breast cancer previously treated with at least two HER2-directed therapies and compared Kadcyla to a physician’s Kadcyla treated patients had a near-doubling of progression-free survival and improved overall survival[11]
  • Tykerb® (lapatinib): Tykerb targets HER2 as well as a related protein known as the epidermal growth factor receptor (EGFR). Tykerb is approved for use in combination with Xeloda for the treatment of HER2-positive advanced or metastatic breast cancer that has progressed following prior therapy with an anthracycline, a taxane, and Herceptin. The combination of Tykerb with the chemotherapy drug Xeloda®(capecitabine) resulted in a longer time to cancer progression than Xeloda alone among women with HER2-positive, refractory advanced or metastatic breast cancer. Tykerb plus a taxane appears inferior to Herceptin plus a taxane when directly compared.[12]

Afinitor® (everolimus) is an oral medication that works by inhibiting a protein known as mTOR. The mTOR protein plays an important role in regulating cancer cell division and blood vessel growth. Studies suggest that Afinitor® plus Herceptin® and paclitaxel is effective for treatment of patients with advanced HER2-positive breast cancer that is hormone receptor (HR)-negative, but not HR positive.[13]

Chemotherapy for Recurrent Breast Cancer

Patients with recurrent cancer may have already received chemotherapy as their initial treatment or recently stopped responding to hormonal therapy. if the first chemotherapy drug (or combination of drugs) stops working and the cancer grows again, a second or third treatment regimen can be used. With the exception of instances where initial treatment may have been inadequate, second-line chemotherapy is typically associated with lower response rates and a shorter duration of remission than first-line therapy. Thus, the goal of second-line chemotherapy is to reduce symptoms, improve a patient’s quality of life, and improve survival.

The type of second-line therapy that is selected and its effectiveness depends on which first-line chemotherapy the patient received. In particular, whether or not a patient’s previous treatment contained doxorubicin or a taxane helps determine options for second-line treatment. Patients typically develop resistance to drugs that were previously used to treat their cancer.

Patients previously treated with a taxane: Abraxane®, a new way to deliver paclitaxel, Gemzar®(gemcitabine), or the oral chemotherapy drug Xeloda® (capecitabine) are treatment options for patients who have already been treated with a taxane.

  • Abraxane™ (nanoparticle albumin-bound paclitaxel): Abraxane employs a new technique for delivering the anti-cancer drug, paclitaxel. It utilizes albumin, the most abundant protein in the body, to deliver the paclitaxel directly to cancer cells. Albumin is a blood protein that is used by the body to transport nutrients and energy to tissues throughout the body. Once the albumin reaches the tissues of the body, it binds to receptors on the surface of the blood vessel and is taken into the tissues, where it delivers its cargo to the surrounding cells. In the case of Abraxane, that cargo is the anti-cancer drug, paclitaxel.Results of a clinical trial indicate patients with breast cancer that has progressed with taxanes may respond to treatment with Abraxane. Among 75 patients with taxane-refractory disease, half experienced anti-cancer responses with Abraxane treatment. The cancer was stabilized, meaning it didn’t progress, in 40% of patients. While some patients experienced side effects of treatment, three-quarters were able to receive full doses of Abraxane. Severe loss of sensation in hands and feet occurred in 17% of patients, but this condition did not halt treatment for these patients; 77% were able to continue treatment with lower doses of Abraxane.[14]
  • Gemzar® (gemcitabine): Clinical studies indicate that Gemzar is an active anti-cancer agent in the treatment of patients with recurrent breast cancer that has previously been treated with a taxane. In clinical trials that have evaluated Gemzar as a second-line treatment for breast cancer, approximately one-third of patients had an anti-cancer response. These patients survived an average of 12-18 months.[15],[16]
  • Xeloda® (capecitabine): Xeloda 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.[17]

Patients not previously treated with a taxane: For patients not previously treated with docetaxel (Taxotere®) or paclitaxel (Taxol®), clinical studies suggest that treatment with one of these drugs, either as a single agent or in combination with other chemotherapy drugs, can reduce cancer symptoms and prolong a patient’s survival compared to other treatments.

Patients with anthracycline-resistant disease: Patients who have stopped responding to anthracyclines, a class of drugs that includes doxorubicin, are said to be anthracycline-resistant. Treatment options for these patients typically include a taxane alone or in combination with another chemotherapy drug.

  • Abraxane: A clinical trial that directly compared Abraxane to Taxol in the treatment of 460 patients with metastatic breast cancer, more than three-quarters of whom had received prior therapy that included an anthracycline, demonstrated improved outcomes with Abraxane. Abraxane doubled anti-cancer response rates and significantly delayed disease progression with fewer side effects.[18] The group of patients who had received prior therapy experienced the greatest improvement, living 10 weeks longer than those treated with paclitaxel (56 weeks versus 46 weeks).[19]
  • Taxotere: Results from a large clinical trial indicate that Taxotere produces longer progression-free and overall survival, and more anti-cancer responses compared to Taxol in the treatment of recurrent breast cancer.[20] Taxotere also appears to be as effective as 5-FU/Navelbine, while producing fewer side effects, in the treatment of patients with metastatic breast cancer whose cancer has progressed following anthracycline-based therapy.[21]
  • Taxotere/Paraplatin: Results of a clinical trial indicate that 61% of patients with anthracycline-resistant disease treated with Taxotere/Paraplatin responded to treatment, and 66% lived one year or more. On average, the cancer progressed 10 months after treatment.[22]
  • Taxotere/Xeloda: Results of a clinical trial indicate that patients who received Taxotere plus Xeloda treatment had more anti-cancer responses, lived longer, and experienced a longer time before their cancer progressed compared to patients who were treated with Taxotere alone.[23] The results from this trial prompted the Food and Drug Administration (FDA) to approve the combination of Taxotere plus Xeloda for the treatment of metastatic breast cancer that has stopped responding to anthracyclines.

Patients not previously treated with doxorubicin: The chemotherapy drug doxorubicin is one of the most active chemotherapy agents used for the treatment of breast cancer—most patients receive it as part of their initial treatment for breast cancer. However, an individual can only receive a limited number of doxorubicin due to the risk of damage to the heart with increased exposure.[24]

Doxorubicin administered alone or in combination with a taxane may be an effective second-line treatment for patients not previously treated with this drug. Patients who have been previously treated with doxorubicin can receive additional doxorubicin treatment in selected circumstances, depending upon how much prior doxorubicin therapy was administered. Because doxorubicin is known to cause damage to the heart, patients may wish to have their heart function evaluated before electing to receive continued doxorubicin therapy.[25]

Patients resistant to anthracyclines, taxanes, and Xeloda: The chemotherapy drug Ixempra™(ixabepilone) has been approved as a single agent for the treatment of metastatic or locally advanced breast cancer that is resistant to anthracyclines, taxanes, and Xeloda. Ixempra is also approved in combination with Xeloda for patients who are resistant to anthracyclines and taxanes, and for patients who are resistant to taxanes and cannot tolerate further anthracycline treatment.

Two clinical trials prompted the FDA approval of Ixempra. The first trial evaluated Ixempra as a single agent. This trial included 126 patients with advanced breast cancer who had stopped responding to treatment with an anthracycline, a taxane, and Xeloda. Patients who had HER2-positive cancer had received prior therapy with Herceptin® (trastuzumab) and had stopped responding. Anticancer responses with Ixempra occurred in 12% of patients.[26]

The second trial compared Ixempra plus Xeloda to Xeloda alone in 752 patients who had stopped responding to anthracyclines and taxanes.[27] Treatment with Ixempra plus Xeloda significantly improved progression-free survival compared with Xeloda alone in this group of patients.

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.

XGEVA® (Denosumab) is indicated for the prevention of skeletal-related events in patients with bone metastases from breast cancer and other solid tumors. XGEVA targets a protein known as the RANK ligand. This protein regulates the activity of osteoclasts (cells that break down bone). In patients with bone metastases, increased RANK ligand production can cause destruction of bone. XGEVA has been directly compared with the bisphosphonate drug Zometa and shown to be more effective at delaying skeletal complications such as fracture, spinal cord compression, surgery to the bone, and radiation to the bone.[27],[28]

Bisphosphonates: 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.[29],[30]

Strategies to Improve Treatment

The development of more effective cancer treatments requires that new and innovative therapies are evaluated with cancer patients. Clinical trials are studies that measure the effectiveness of new drugs or treatment strategies. Areas of active investigation aimed at improving the treatment of recurrent breast cancer include the following:

PARP inhibitors: Poly (ADP-ribose) polymerase (PARP) inhibitors are a class of drugs under study for many types of cancer, including breast cancer. PARP is an enzyme involved in DNA repair. At this time, PARP inhibitors are only offered in clinical trials for people with metastatic breast cancer. Early findings suggest PARP inhibitors hold the most promise for people with metastatic breast cancer who have a BRCA1or BRCA2 gene mutation.

Immunotherapy: Drugs that help the body’s immune system attack cancer cells are now used to treat many cancers (including melanoma and lung cancer). These drugs “take the brakes off” the natural factors that limit how the immune system can control tumor cells. For this reason, they are sometimes called “checkpoint inhibitors.” Many types of immunotherapy drugs and other immune mediated strategies are currently being evaluated in breast cancer.

PI3 kinase inhibitors: PI3 kinase is an enzyme important in cell growth. The PIK3CA gene helps control PI3 kinase enzyme activity. Some breast cancers have a mutation in the PIK3CA gene (this gene mutation is in the genes of breast cancer, not the person). This mutation can affect PI3 kinase and cause the tumor to grow. Aberrant activation of the PI3K pathway has been widely implicated in many types of cancer, including breast cancer and lung cancer. Additionally, increased activity of the PI3K pathway is often associated with resistance to cancer therapies.[31],[32] Pictilisib (GDC-0941) is a novel, oral, highly specific, small-molecule, ATP-competitive class I PI3K inhibitor.[33] In preclinical studies in a range of cancer models, combinations of pictilisib with cytotoxic agents or other targeted agents achieved synergistic antitumor activity compared with the chemotherapy or anticancer agent alone.[34],[35]

Pictilisib may benefit women with advanced breast Cancer. The addition of pictilisib to Faslodex® has been demonstrated to delay the time to cancer recurrence in women with advanced breast cancer who are positive for both estrogen receptor (ER) and progesterone receptor (PR) and have previously failed treatment with an aromatase inhibitor. In this clinical study 168 postmenopausal patients with ER-positive, HER2-negative, advanced or metastatic breast cancer who had relapsed or progressed following or during treatment with an aromatase inhibitor were enrolled in a clinical study and treated with either Faslodex® and pictilisib or Faslodex® alone and directly compared.[36] For ER and PR- positive patients, the addition of pictilisib resulted in a significant doubling of progression-free survival, from 3.7 months to 7.4 months.

Abemaciclib is a cyclin-dependant kinase. Cyclin-dependent kinases play a key role in regulating the replication and growth of cells. In many cancers, uncontrolled cell growth occurs because there is a loss of control in regulating the cell cycle due to increased signaling from CDK 4 and 6. Abemaciclib was designed to block the growth of cancer cells by specifically inhibiting CDK 4 and 6. Although abemaciclib inhibits both CDK 4 and CDK 6.

Abemaciclib is being developed by Lilly Oncology, which has an active clinical development program studying abemaciclib in breast cancer. MONARCH 1 is a Phase II clinical trial evaluating the use of abemaciclib as single therapy in women with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer. In addition, Lilly is evaluating abemaciclib in two Phase III clinical trials: MONARCH 2 to evaluate the combination of abemaciclib and fulvestrant in postmenopausal patients with HR+, HER2- advanced or metastatic breast cancer, and MONARCH 3 to evaluate the combination of abemaciclib and a nonsteroidal aromatase inhibitor in patients with HR+, HER2- locoregionally recurrent or metastatic breast cancer.

Avastin (Bevacizumab) and other anti-angiogenesis drugs. Anti-angiogenesis drugs, such as Avastin block the growth of new blood vessels. The loss of blood supply prevents the cancer from growing. Early studies suggested that Avastin benefited some women with metastatic breast cancer but longer-term follow-up data did not confirm these findings causing the FDA to reverse its approval for the use of Avastin in the treatment of metastatic breast cancer. Avastin and other anti-angiogenic drugs are still being evaluated in clinical studies and Avastin remains FDA-approved for use in other cancers.


[1] Recht A, Hayes DF, Everlein TJ, Sadowsky NL. In: Harris JR, Lippman ME, Morrow M, Hellman S, eds. Diseases of the Breast. Philadelphia: Lippincott-Raven Publishers; 1996:649-667.

[2] Doyle T, Schultz DJ, Peters C, et al. Long-term results of local recurrence after breast conservation treatment for invasive breast cancer. International Journal of Radiation Oncology, Biology and Physics. 2001;51:74-80.

[3] National Cancer Institute FactSheet. Herceptin® (Trastuzumab): Questions and Answers. Available here. Accessed October 11, 2007.

[4] Hobday TJ, Perez EA. Molecularly targeted therapies for breast cancer. Cancer Control. 2005;73-81.

[5] Pegram MD, Slamon DJ. Combination therapy with trastuzumab (Herceptin) and cisplatin for chemoresistant metastatic breast cancer: Evidence for receptor-enhanced chemosensitivity. Seminars in Oncology. 1999;26:89-95.

[6] 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.

[7] 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 #555t.

[8] 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.

[9] CLEOPATRA Trial Changes Standard Therapy for Metastatic HER2 Positive Breast Cancer [press release]. European Society for Medical Oncology (ESMO) Congress 2014. Available here. Accessed October 4, 2014.

[10] FDA approves new treatment for late-stage breast cancer. [FDA News Release]. U.S. Food and Drug Administration website. Available here

[11] Wildiers H, Kim SB, Gonzalez-Martin A, et al. T-DM1 for HER2-positive metastatic breast cancer (MBC): Primary results from TH3RESA, a phase 3 study of T-DM1 vs treatment of physician’s choice. Presented at the 38th Congress of the European Society for Medical Oncology (ESMO), Amsterdam, Netherlands, September 27-October 1, 2013. Abstract 15.

[12] Hurvitz SA, Andre F, Jiang Z, et al. Phase 3, Randomized, Double-Blind, Placebo-Controlled Multicenter Trial of Daily Everolimus plus Weekly Trastuzumab and Paclitaxel as First-Line Therapy in Women with HER2+ Advanced Breast Cancer: BOLERO-1. Program and Abstracts of the 2014 San Antonio Breast Cancer Symposium; December 9–13, 2014; San Antonio, Texas. Abstract S6-01.

[13] O’Shaughnessy JA, Blum JL, Sandbach JF, Savin MA, Fenske E, Hawkins MJ, Baylor-Charles A: Weekly nanoparticle albumin paclitaxel (Abraxane) results in long-term disease control in patients with taxane-refractory metastatic breast cancer San Antonio Breast Cancer Symposium, San Antonio, TX. 2004; Abstract #1070.

[14] Spielmann M, Llombart-Cussac A, Kalla S, et al. Single-agent gemcitabine is active in previously treated metastatic breast cancer. Oncology. 2001; 60:303-307.

[15] Carmichael J, Possinger K, Phillip P, et al. Advanced breast cancer: A phase II trial with gemcitabine.Journal of Clinical Oncology. 1995;13:2731-2736.

[16] Blum JL, Jones SE, Buzdar AU, et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. Classic Papers and Current Comments. 2001;5:790-799.

[17] 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 Antonio Breast Cancer Symposium ( 12/3/03 ), Abstract #44.

[18] New Antitubulin Agents. Proceedings from the 22nd annual Miami Breast Cancer Conference. Presented by Dr. Perez. Friday February 25, 2005. 2:45 pm. Miami, Florida.

[19] Jones SE, Overmoyer EB, Budd GT, et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. Journal of Clinical Oncology. 2005;23:5542-5551.

[20] Bonneterre J, Roché H, Monnier A et al. Docetaxel vs. 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure. British Journal of Cancer. 2002;87:1210-1215.

[21] Mavroudis D, Alexopoulos A, Malamos N, et al. Salvage treatment of metastatic breast cancer with docetaxel and carboplatin. A multicenter phase II trial. Oncology. International Journal of Cancer Research and Treatment. 2003;63:207-212.

[22] O’Shaughnessy J, Miles D, Vukelja S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. Journal of Clinical Oncology. 2002:20:2812-2813.

[23] Buzdar AU, Marcus C, Smith TL, et al. Early and delayed clinical cardiotoxicity of doxorubicin. Cancer. 1985;55:2761.

[24] FDA. FDA Oncology Tools Product Label Details in Conventional Order for Doxorubicin. Accessed March 29,2002.

[25] Perez E, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a Phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. Journal of Clinical Oncology. 2007;25:3407-3414.

[26] Vahdat LT, Thomas E, Li R, et al. Phase III trial of ixabepilone plus capecitabine compared to capecitabine alone in patients with metastatic breast cancer previously treated or resistant to an anthracycline and resistant to taxanes. Proceedings from the 2007 annual meeting of the American Society of Clinical Oncology. 2007;25:abstract 1006.

[27] 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.

[28] 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.

[29] 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.

[30] 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.

[31] Myers AP, Cantley LC. Targeting a common collaborator in cancer development. Sci Transl Med. 2010;2:48ps45.

[32] McCubrey JA, Steelman LS, Franklin RA, et al. Targeting the RAF/MEK/ERK, PI3K/AKT and p53 pathways in hematopoietic drug resistance. Adv Enzyme Regul. 2007;47:64-103.

[33] Folkes AJ, Ahmadi K, Alderton WK, et al. The identification of 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem. 2008;51:5522-5532.

[34] Sampath D, Belvin M, Guan J, et al. Combination of class I PI3K inhibitor, GDC-0941, with standard of care therapeutics results in enhanced anti-tumor responses in human cancer models in vitro and in vivo. Presented at: 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; October 21-24, 2008; Geneva, Switzerland. Poster 220.

[35] Wallin JJ, Guan J, Prior WW, et al. Nuclear phospho-Akt increase predicts synergy of PI3K inhibition and doxorubicin in breast and ovarian cancer. Sci Transl Med. 2010;2:48ra66.

[36] Krop IE, Johnston S, Mayer IA, et al. The FERGI phase II study of the PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant vs fulvestrant plus placebo in patients with ER+, aromatase inhibitor (AI)-resistant advanced or metastatic breast cancer – Part I results Abstract #S2-02. Presented at: San Antonio Breast Cancer Symposium; Dec. 9-13, 2014; San Antonio.