Anjana Mohan and S. Ponnusankar*

Department of Pharmacy Practice, JSS College of Pharmacy, The Nilgiris, Ooty-643 001, India

Corresponding Author:
S. Ponnusankar
Department of Pharmacy Practice, JSS College of Pharmacy, The Nilgiris, Ooty-643 001, India
E-mail: ponnusankarsivas@gmail.com
Date of Submission 08 August 2011
Date of Revision 21 April 2013
Date of Acceptance 01 May 2013
Indian J Pharm Sci 2013;75(3):251-261  

 

DOI: 10.4103/0250-474X.117396

Abstract

Breast cancer is the foremost common malignancy among the female population around the world. Female breast cancer incidence rates have increased since 1980, slowed in 1990, the rate of increase have leveled off since 2001. In spite of the advances in the early detection, treatment, surgery and radiation support, almost 70% of the patients develop metastasis and die of the disease. Around 10% of the patients when diagnosed with breast cancer have metastases. Survival among the breast cancer patients have increased due to the introduction of novel single agent, combination of chemotherapeutic agents and targeted biologic agents, which is breast cancer specific. The staging of tumor-node-metastasis is significant for the prognosis and treatment. Predominantly the combination of chemotherapeutic regimen is given to improve the rate of clinical benefit and the overall survival rate. Novel mono-therapeutic options are being used often in metastatic setting as they will not be able to endure the toxicity of the combination regimen. Usually, endocrine therapy is recommended for hormone-responsive breast cancer due to efficacy and favorable side effect profile but chemotherapy becomes an option when endocrine therapy fails. This review summarizes the newer therapeutic options for early breast cancer and advanced breast cancer that are pretreated heavily on other chemotherapeutic agents. Further it provides monotherapies and other emerging novel combination regime which can be opted for first line or second line setting.

Keywords

Breast cancer, metastasis, novel monotherapy, combination regimen, clinical benefit rate

Breast cancer is a malignant proliferation of epithelial cell lining the ducts or lobules of the breast, which may have diverse outcomes and responses to treatment depending on the early diagnosis. This is the most common cancer in woman in many developed and developing countries. Breast cancer is the leading cause of cancer deaths in females between 20 and 59 years[1]. Early accurate diagnosis is important for optimizing the treatment and potential for cure. During the last decades, breast cancer survival has increased considerably[2,3] due to earlier diagnosis and increasing use of adjuvant and neoadjuvant therapies but around 30−70% of the patients eventually develop recurrence and die of metastasis every year. Improved treatment options offer a better prognosis for the patients with breast cancer.

The possibility of breast cancer is augmented with the increasing age, past medical history of uterus cancer, ovarian cancer, and family history of breast cancer. Postmenopausal hormone replacement therapy may also direct to breast cancer. Patients who had prior treatment for breast cancer have 30−50% chance of developing cancer in the contra lateral breast which can be reduced by adjuvant endocrine therapy for minimum 5 years. Several genetic, hormonal, and environmental factors are involved in the development of breast cancer.

Chemotherapy treatment during early stage breast cancer has shown to extend the survival. Chemotherapeutic option with anthracyclines or taxanes is considered to be the most effective in breast cancer. Almost 70% of the patients with metastatic breast cancer have human receptor (HR) positive tumors, which are responsive to adjuvant hormone therapy and helps in prolonging the disease free survival. Chemotherapy is the only treatment option for rapidly progressing metastatic breast cancer (MBC) and various classes of drugs along with their mechanism, available for the treatment as monotherapy is represented in fig. 1. Treatment failure in metastatic setting occurs due to the resistance to the chemotherapeutic agents which may be due to the prior exposure to these agents. No standard monotherapy or combination palliative chemotherapy is existing for patients who are pretreated with anthracyclines or taxanes. The median survival rate of the patient with metastasis is within the range of 3 years. When patients with metastasis are seen then the aim of the treatment is palliative care providing mental support and increasing the median survival. This article summarizes some of the newer therapeutic options currently available for the treatment of MBC.

Figure

Figure 1:Various drugs used in the treatment of metastatic breast cancer and their mechanism of action.

Novel Monotherapeutic Options Available For The Treatment

Eribulin mesylate

Eribulin mesylate is a non−taxane, synthetic analog of halichondrin B isolated from a sea sponge. Eribulin has a mechanism of action that is distinct from those of the other tubulin targeting agents[4] and it inhibits the microtubule growth phase causing tubulin sequestration into the non−productive aggregates[5]. It causes irreversible mitotic block and apoptosis. It was hypothesized that Eribulin may be shown to have efficacy in cancer related to tubulin targeted agents. Eribulin is given to patients who are having metastatic breast cancer and pretreated with an anthracycline or a taxane. EMBRACE trial[5] was conducted to know the effect of Eribulin monotherapy versus the treatment of physician choice in patients with MBC, which concluded that the median progression free survival was 3.7 months, clinical benefit rate was 23%, overall survival rate was 58%. Cotes et al.[6] conducted a phase 2 study of the halichondrin B analog in patients with advanced MBC previously treated with an anthracyclines, taxanes, and capecitabine. The study results had reported that the objective response rate was 11.5% and clinical benefit rate of 17.2% with manageable tolerability profile (Table 1).

Fulvestrant

Name of the drug Name of the trial No. of patients Inclusion criteria Exclusion criteria Outcomes Reference
Eribulin mesylate EMBRACE Trial 2011 762 Age of 18 years and older, histologically confirmed with breast cancer, have taken 2-5 previous chemotherapeutic regimen like an anthracycline or a taxane, progression within 6 months of the last chemotherapy, adequate bone marrow, liver, renal function Previous participation in an Eribulin trial, use of any investigational drug within 4 weeks of the study, prior treatment with chemotherapy, radiation, trastuzumab or hormonal therapy within 3 weeks of the study, untreated brain metastasis, preexisting neuropathy of grade 2 or higher Significant improvement in overall survival, manageable toxic effects, significant improvement in the objective response rate, progression free survival Cortes et al.[5] 2011
Trastuzumab HERA trial 2011 5102 HER2 positive patients who had completed loco regional therapy, received at least 4 cycles of chemotherapy   Overall incidence of cardiac events is low, treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4 year median follow up Gianni et al.[12] 2011
NOAH trial 2010 334 Histologically proven locally advanced breast cancer, HER2 positive confirmed by immuno histochemical testing, at least one measurable lesion, adequate renal, hepatic, bone marrow function Metastasis, previous treatment for invasive malignant disease, previous or concurrent malignant disease other than basal cell carcinoma of the skin or in situ cervical cancer, pregnancy or lactation, use of other investigational drugs within 30 days, serious medical illness including cardiac failure Addition of 1 year of trastuzumab to neoadjuvant chemotherapy improved overall response rates, almost doubled rates of pathological complete response, and reduced risk of relapse, progression or death compared with patients who did not receive trastuzumab Gianni et al.[13] 2010
Fulvestrant CONFIRM trial 2010 736 Postmenopausal with locally advanced or metastatic breast cancer previous treatment with antiestrogen or an aromatase inhibitor as a first line therapy Liver or lung metastasis, brain-leptomeningeal metastasis more than one chemotherapy or endocrine therapy Fulvestrant 500 mg prolongs progression free survival over low dose. It did not cause increased clinical benefit rate Leo et al.[9] 2010
Eribulin Mesylate - 299 Age>18 years, histologically confirmed with breast cancer, 2-5 prior chemotherapeutic regimen with anthracyclines or paclitaxel, adequate liver, bone marrow, kidney function HER2 positive patients must have received trastuzumab, ER2 positive patients should have received endocrine therapy Hormonal therapy within 1 week, chemotherapy or radiation within 2 weeks of starting of Eribulin, prior treatment with Eribulin, mitomycin, nitrosourea, progression of brain metastasis cardiovascular impairment, neuropathy of grade 2, pregnancy, breast feeding, HIV, hypersensitivity to halichondrin B or derivatives Objective response rate, clinical benefit rate was noted Cortes et al.[6] 2010
Olaparib - 54 Patients of more than 18 years, MBC, mutation of BRCA1/BRCA2, ECOG performance scale of 0-2, life expectancy of 16 weeks Anticancer therapy in 28 days, brain or CNS metastasis, more than grade 2 toxicity Favorable therapeutic index in those who have genetic loss of function BRCA1, BRCA2 Tutt et al.[15] 2010
Pertuzumab - 79 Age of more than 18 years, performance status of 80%, MBC, adequate hematologic, renal, hepatic function Major surgery, pulmonary metastasis with lymphangitis or dyspnea at rest, LVEF less than 50%, pregnant, lactating The single agent Pertuzumab in HER2 negative breast cancer was not beneficial in the patients with metastasis Gianni et al.[18] 2010

Table 1: Monotherapy used in various trials for the treatment of metastatic breast cancer.

It is an estrogen receptor (ER) antagonist that down regulates the circulating ERs[7]. It is currently used in the treatment of postmenopausal women with advanced breast cancer even with prior endocrine treatment[8]. It acts by ER dimerization causing rapid degradation leading to the loss of cellular ER. The drug was approved by USFDA in 2002. CONFIRM trial[9] conducted in 2010 concluded that the median progression free survival was 6.5 months in the group of patients administered with 500 mg and 5.5 months in 250 mg group. The median duration of response was 19.4 months for 500 mg and 16.4 months for 250 mg of fulvestrant (Table 1).

Trastuzumab

It is a humanized monoclonal antibody directed against extracellular domains of the HER2 receptor and it dramatically improved the outcomes in patients with HER2 over expressing (HER2 positive) breast cancer[10]. It binds to an epitope in the HER2 receptor that cause uncoupling of HER2–HER3 heterodimers thereby inhibiting antibody dependent cell−mediated cytotoxicity[11]. It is the first antiHER2 therapy approved by USFDA in 1998. Recently concluded HERA trial (2011) reported that disease free survival in the patients treated with 1 year trastuzumab was 78.6% as compared with the observation group 72.2% while there was no significant difference in the overall survival rate in the both groups[12]. NOAH Trial reported the addition of trastuzumab as neoadjuvant significantly improved the event free survival in HER2 positive breast cancer patients by 71% versus 56% without trastuzumab[13] (Table 1).

Olaparib

It acts by inhibiting enzyme poly ADP ribose polymerase. It is one of the first PARP inhibitor[14]. Olaparib 400 mg twice daily was found to be active in patients with BRCA1 or BRCA2 mutations, MBC which was resistant to conventional chemotherapy. Tutt et al.[15] concluded that olaparib 400 mg twice daily had better progression free survival, the objective response rate than 100 mg twice daily. The objective response rate with 400 mg olaparib group was 41% and with 100 mg group was 22% (Table 1).

Pertuzumab

It binds to HER2 at the dimerization domain[16], thereby inhibiting its ability to form dimmers, bind competitively to the intracellular adenosine tri phosphate binding site of HER[17]. Gianni et al. [18] concluded that in patients treated with loading dose of pertuzumab (arm A) the median duration of clinical benefit was 36.5 weeks and those treated with no loading dose of pertuzumab (arm B) the median duration of clinical benefit was 33-36 weeks. Median time to treatment failure was 6.3 weeks in arm A and 6 weeks in arm B (Table 1).

Current Combination Regimen(S) For The Treatment Of Breast Cancer

Bevacizumab and taxanes

Bevacizumab is humanized monoclonal antibody that specifically inhibits vascular endothelial growth factor. It is a key mediator of angiogenesis[19,20]. Bevacizumab is used for the treatment of metastatic breast cancer, colorectal cancer, and non−small cell lung cancer. It is approved as the first line treatment in glioblastoma multiforme. It was approved by USFDA in 2004. It was also granted approval to be used in combination with interferon alfa for the treatment of metastatic renal cell carcinoma. Smith et al.[21] reported the overall response rate of 47% and median time to progression of 7.2 months with median overall survival of 19.5 months. Smith et al.[21] reported that this combination regimen has improved the time to progression, overall response rate and had less adverse event (Table 2). Miles et al.[22] reported that the regimen increased the progression free survival when combined with docetaxel.

Bevacizumab, everolimus, and lapatinib

Everolimus inhibits mammalian target of rapamycin complex 1 (mTORC1) which plays an essential role in protein synthesis thereby reducing cell proliferation, tumor growth, and angiogenesis[23]. It is also approved for treating patients with progressive neuroendocrine tumors in the pancreas, which cannot be surgically removed and in metastatic pancreatic cancer. Lapatinib is a 4−anilinoquinazoline kinase inhibitor of intracellular tyrosine kinase domains of epidermal growth factor receptor. It also inhibits HER2 and HER1 receptor tyrosine kinase[24,25] and it was approved in 2007 by USFDA. Minkwitz et al.[26] reported the treatment of chemotherapy with bevacizumab had 19.4% discontinuations with everolimus the discontinuation was 24.1% and with lapatinib the discontinuation was 34.5%. Treatment was discontinued in patients with lapatinib 1250 mg due to the side effects (Table 3).

Cabazitaxel and capecitabine

Cabazitaxel is a novel tubulin binding taxoid. It has a safety profile in docetaxel or paclitaxel resistant breast cancer[27]. Recently in the year 2010, this drug was approved by USFDA for the treatment of metastatic breast cancer patients. It is also used in the treatment of metastatic hormone refractory prostrate cancer. Villannueva et al.[28] reported that the median duration of response was 3.1 months and the median time to progression was 4.9 months (Table 2).

Name of the
regimen		 Name of
the trial		 No of
patients 		Inclusion criteria Exclusion criteria Outcome Reference
Capecitabine and
vinorelbine		 − 50 Women aged 18−75,
histologically confirmed
with breast cancer,
previously treated with
anthracyclines or a taxane,
adequate renal, hepatic,
hematologic function, prior
hormonal therapy or prior
radiation therapy 		Pregnant, lactating, history
of other cancer within past
5 years except non melanoma
skin cancer, in situ carcinoma
of the cervix 		Combination chemotherapy is effective and safe previously treated with
anthracyclines, taxanes.
Safe and tolerable as a
second line treatment
in the patients with
metastatic breast cancer
The overall response
rate was 23.8%. It
showed activity and
favorable safety profile in
patients pretreated with
anthracyclines or taxanes
across all dose levels 		Mao et al.[33] 2011
Cabazitaxel and
capecitabine		 − 33 Age of above 18 years,
histologically confirmed
breast cancer, adequate
renal, hepatic,
hematological function,
at least one measurable
lesion, prior exposure to
anthracyclines or taxanes 		The overall response
rate was 23.8%. It
showed activity and
favorable safety profile in
patients pretreated with
anthracyclines or taxanes
across all dose levels 		Villanueva
et al.[28]
2011
Trastuzumab with
vinorelbine and
Trastuzumab with
docetaxel		 HERNATA
study
2011		 284 Eligible patients with
the age of 18−75 years,
histologically confirmed
with breast cancer, HER2
positive, measurable or
non measureable disease,
performance status of
less than 2, adequate
bone marrow, renal, liver,
cardiac function, life
expectancy of more than
12 weeks 		Brain metastasis, dyspnea,
second primary malignancy,
serious concomitant illness 		The trial didn’t show
any superiority of any
drug in terms of efficacy.
The combination with
vinorelbine had fewer
toxicity profiles as
compared with the
docetaxel. Median time
to treatment failure for
docetaxel was 5.6 months
versus 7.7 months for
Vinorelbine 		Anderson
et al.[56]
2011
Trastuzumab and
docetaxel with
trastuzumab,
docetaxel,
carboplatin		 BCIRG
007
Study		 263 MBC patients with HER2
positive, between age
limit of 18−75, karnofsky
performance status of
more than 60%, adequate
liver, renal, cardiac,
hematological function,
prior taxane−based or
trastuzumab−based or
anthracycline−based
adjuvant therapy 		Brain or leptomeningeal
metastasis, prior congestive
heart failure, myocardial
infection in the preceding
year, unstable angina,
grade 3 cardiac arrhythmia,
uncontrolled hypertension,
active infection, active peptic
ulcer, unstable diabetes
mellitus, peripheral neuropathy,
chronic corticosteroid therapy,
serious medical illness,
psychiatric condition, invasive
malignancy for the past
10 years 		Both regimens in the
study were highly
active and each having
a response rate of 72%,
time to progression of
approximately 10 months
and median overall survival
exceeding 3 years. Both
regimens have similar
safety profile, active
regimens for patients with
HER2 amplified disease 		Valero
et al.[58]
2010
Pegylated liposomal doxorubicin and cyclophosphamide 29 Patients with stage 2-3 of age more than 66 years adequate bone marrow, renal, hepatic function, left ventricular ejection fraction of more than 55% ECOG performance status of 0-2, measurable lesions DellaAll patients had clinical response with partial response of 62.1%, pathological complete response 3.4%. Treatmentwas well tolerated with no grade 3, 4 toxicities, but have limited activity in pre operative setting Dellapasqua et al.[52] 2011
Paclitaxel and
uracil−tegafur		 TEGATAX
trial
2011		 31 Metastatic or locally
advanced breast cancer
patients of the age more
than 18, who are HER2
negative resistant to
anthracyclines, at least
one radiological measurable
lesion, less than 2 regimens
during metastasis 		Prior treatment with
paclitaxel, tegafur,
capecitabine, brain
metastasis, peripheral
neuropathy of more than
grade 2 		The combination therapy have a significant role in  40%, response duration

of more than 8 months,

clinical benefit of 59%,

median survival of 23.5

months, time to disease

progression of 9.5 months 		Villanueva et al.[49] 2011
Motesanib and
paclitaxel		 282 HER2 negative locally advanced or metastatic breast cancer patients over 18 years with the ECOG performance of 0−1, adequate organ, hematological function No significant difference in the objective response rate between motesanib and the placebo group, clinical benefit rate was 66% for motesanib group. a significant improvement of 14%. The combination regimen is not more effective than placebo with paclitaxel for HER2 negative advanced breast cancer Martin
et al.[45]
2011
Iniparib plus
chemotherapy		 123 Metastatic breast cancer female patients of age more than 18 years, ER negative, PR negative, ECOG performance of 0−5, adequate bone marrow, renal, hepatic function, clinically stable brain metastasis In iniparib group the clinical benefit rate was 56% which is greater than chemotherapy group. Progression free survival was 5.9 months in iniparib group and 3.6 months in chemotherapy alone. Overall survival was 12.3 months in iniparib group and 7.7 months in chemotherapy alone group. In patients with advancer triple negative breast cancer the addition of Iniparib to the chemotherapy improved the clinical benefit rate and the overall survival Shaughnessy
et al.[41]
2011
Tamoxifen and
exemestane		 TEAM
trial
2011		 9779 Histologically confirmed estrogen receptor positive, progesterone positive breast cancer who had completed local treatment, invasive tumor with all size without axillary lymph node involvement , no metastasis Cardiac disease, any other
malignancy 		No significant difference 
in the overall survival and  
the diseases free survival  

was noted in the patients

treated with both regimen 		Velde et al.[39] 2011
Bevacizumab and
taxane		 2251 Histologically confirmed
HER 2 negative metastatic
breast cancer patients of
more than 18 years, ECOG
of 0−2, adequate hepatic,
renal, hematologic function 		Previous chemotherapy for
metastatic breast cancer,
peripheral neuropathy of
more than grade 2, increased
peripheral neuropathy, minor
surgery within 24 h, active
peptic ulcer, hypertension,
pregnancy, lactation 		Time to progression
was 9.5 months; overall
response rate was
52%. The combination
chemotherapy is well
tolerated and had less
adverse event 		Smith
et al.[21]
2011
Capecitabine and
vinorelbine		 72 Age of >18 years,
histological confirmation
of breast cancer, previous
chemotherapy with
anthracyclines or taxanes
adequate renal, hepatic,
cardiac function 		Hypersensitivity to
fluoropyrimidines more
than grade 2 of peripheral
neuropathy, serious illness
organ allograft, GI disorder,
pregnant, lactating women 		Response rates varied from
39−70%, suitable treatment
regimen for elderly patient
of more than 65 years with
MBC, acceptable toxicity
and efficacy profile 		Fan et al.[34]
2010
Ixabepilone and
capecitabine with
capecitabine		 1221 Metastatic advanced
disease, performance
scale of more than
70%, life expectancy of
more than 12 weeks,
prior pretreatment with
anthracyclines or taxanes 		Pregnancy, lactation, serious
illness 		Improved progression
free survival and overall
response rate, safety
profile was manageable
with appropriate dose
modification 		Sparano
et al.[36]
2010
Bevacizumab and
taxanes		 736 Histologically confirmed HER2 negative, age of more than 18 years ECOG performance status of 0−2, adequate renal, hepatic, hematologic function Previously treated disease Clinical benefit was
seen after lapatinib
monotherapy for 14 days
after pretreatment with
paclitaxel and lapatinib 		Boussen
et al.[43]
2010
Paclitaxel and
bevacizumab
with or without
sunitinib		 SABRE−B HER2 negative MBC with
no prior chemotherapy,
any prior adjuvant
chemotherapy, brain
metastasis, ECOG of 0−1,
adequate organ function 		Uncontrolled hypertension, heart failure, proteinuria, open biopsy, major surgery, significant injury within

28 days of the enrollment 		Addition of sunitinib to bevacizumab and paclitaxel is not feasible due to the side effects
 Mayer et al.[47] 2010

Table 2: Combination regimens used in various trial for the treatment of MBC and its outcome.

Name of the combination Name of the trial No of patients Inclusion criteria Exclusion criteria Outcome Reference
Bevacizumab,
everolimus,
lapatinib and
neoadjuvant
chemotherapy		 Gepar
Quinto trial
2011		 270 Healthy female patients
with unilateral or bilateral
untreated breast cancer,
cT4 or cT3 cN+ disease for
HER2 negative disease, all
tumor stages if the tumor
is estrogen receptor or
progesterone negative,
restricted to cT2 tumors
with clinically positive
lymph nodes , cT1 tumors
with positive sentinel node
biopsy if the tumour was ER
or PR positive		   Bevacizumab with EC-D was
well tolerated (26%) with
chemotherapy alone (21.5%).
Everolimus and P after EC
pretreatment did not have
significant difference in
the toxic effects. Adding
bevacizumab and everolimus
to chemotherapy appeared
feasible		 Minkwitz
et al.[26]
2011
Doxorubicin plus
pemetrexed
followed by
docetaxel verses
doxorubicin plus
cyclophosphamide
followed by
docetaxel		 276 Histologically confirmed
primary invasive breast
cancer, HER 2 over
expressing patients with
age 18-70 years, staging
T2-4a N0-2M0, tumor
size of more than 2 cm,
adequate cardiac function,
life expectancy of more
than 6 months		 An experimental
drug if used within
30 days of study,
prior anthracycline
or antitumor therapy,
second primary
malignancy of cervix,
serious concomitant
disorder		 AP-D had a CR rate of 14.5%
and a PR rate of 45%. AC-D
had a complete response
rate of17.6% and a PR of
50.4%. Pathological complete
response for AP-D and
AC-D was 16.5 and 20.2%,
respectively. Both the
chemotherapeutic regimen
is well tolerated, active as
neoadjuvant chemotherapy
in early breast cancer. AC-D
is active against HR negative
tumors than HR positive tumor
while the other regimen have
almost same efficacy in HR
positive and negative tumor		 Schneeweiss
et al.[55]
2010
Doxorubicin plus
cyclophosphamide
followed by
paclitaxel
compared with
doxorubicin
plus paclitaxel
followed by
weekly paclitaxel		 1830 Stage 1-3A, T1or T2 disease
with one sentinel node with
micro metastasis less than
2 mm, prior treatment with
mastectomy within 84 days
of the study		 T4 stage, previously
received any prior
treatment for breast
cancer, history of
other malignancy
within 5 years,
prior anthracyclines
or anthracyclines
therapy, cardiac
dysfunction		 There was no significant
difference in the 6 year
survival for the two arms. the
substitution of paclitaxel for
cyclophosphamide has shown
to be more effective for high
risk breast cancer patients		 Loesch
et al.[59]
2010

Table 3: Multiple Newer Regimens On Recent Trials And Its Outcome.

Capecitabine and vinorelbine

Vinorelbine is third generation vinca alkaloid that has significant activity against advanced breast cancer in the first line setting[29]. Capecitabine is an oral fluoropyrimidines precursor which is orally administered prodrug activated in liver and converted to 5−fluorouracil at the tumor site via a three−phase enzymatic cascade[30]. After two intermediate steps involving carboxyl esterase I the liver and cytidine deaminase in the liver/tumor tissue, the final metabolite is converted to 5-fluorouracil by thymidine phosphorylase[31]. It has shown its efficacy in patients who are heavily pretreated with anthracycline or a taxane[30]. Due to its favorable toxicity and efficacy profile it is used frequently in clinical trial of novel drugs as control treatment. Capecitabine can be used as a single agent in patients with advanced breast cancer who are pretreated with anthracycline or taxanes. Capecitabine monotherapy has time to progression (3.1−4.9 months) and the response rate of 20-28% approximately[32]. Mao et al.[33] have reported that the overall clinical benefit rate was 72% and the objective response rate was 26% with median time to progression of 5 months. Fan et al.[34] reported that median time to progression was 7.7 months, median survival of 26.1 months and response rate of 53.8% (Table 2).

Capecitabine and ixabepilone

Ixabepilone is a semisynthetic analog of epothilone analog which acts by binding to β tubulin subunits of microtubules leading to induction of tubulin polymerization and disruption of chromosomal segregation that is needed for the completion of mitosis. It ultimately induces apoptosis[35]. It has low susceptibility to common resistance mechanism that is related to anthracyclines or taxanes. Combination of this regimen is mainly used in advanced breast cancer and those patients who are treated prior with anthracycline or taxanes. Sparano et al.[36] reported that the overall response rate of the combination regimen was 43%, time to response was 6.6 weeks, median progression free survival was 6.24 months for the combination as compared with 4.4 months for capecitabine alone (Table 2).

Exemestane and tamoxifen

Exemestane is a third generation steroidal aromatase inhibitor used for metastatic breast cancer. Exemestane has more efficacy as compared with tamoxifen given alone[37]. Exemestane has currently emerged as the first line treatment option for metastatic breast cancer after a phase 2 randomized trial conducted by the European organization for research and treatment of cancer (EORTC)[38]. Exemestane is mainly used in postmenopausal women with early or advanced breast cancer. Velde et al.[39] reported that when 5 years data were taken, no difference was noted in the disease free survival and overall survival in patients with HR positive breast cancer treated with exemestane and tamoxifen but musculoskeletal adverse events were increased with exemestane therapy alone.

Iniparib plus chemotherapy

Iniparib is a poly adenosine diphosphate−ribose polymerase 1 (PARP1) inhibitor. PARP1 regulates the DNA base−excision repair. Now iniparib is recommended for triple negative breast cancer. Iniparib synergize the cytotoxic and antiproliferative effects of gemcitabine and carboplatin[40]. Shaughnessy et al.[41] reported that when iniparib was added to gemcitabine and carboplatin the clinical benefit rate improved from 34 to 56%, median overall survival from 7.7 months to 12.3 months with median progression free survival from 3.6 to 5.9 months (Table 2).

Lapatinib and paclitaxel

It is a tyrosine kinase inhibitor and inhibits the cellular proliferation which is overexpressed with HER1 or HER2. It acts intracellularly, binds with cytoplasmic ATP binding site thereby blocking the phosphorylation and the activation leading to apoptosis[42]. Boussen, et al.[43] concluded that clinical response rate was 78.6% in cohort A (tumors overexpressing with HER2 without coexpression of EGFR) patients. In cohort B (tumors expressing EGFR without HER2 overexpression) the clinical response rate was 71.4%.

Motesanib and paclitaxel

Motesanib is a vascular endothelial growth factor tyrosine kinase inhibitor (VEGFRTKI). VEGF plays an important role in angiogenesis. It is also acting as an antagonist at VEGFR1, VEGFR2, and VEGFR3. The inhibition of kinase is different from that of other VEGFR inhibitors[44]. Martin et al.[45] has reported the overall response rate for motesanib group was 49% and for placebo was 41%, the median progression free survival for motesanib group was 9.5 months versus 9.0 months, clinical benefit rate for motesanib was 66%, and for placebo was 18% (Table 2).

Paclitaxel, bevacizumab, and sunitinib

Sunitinib is an oral multi kinase inhibitor that blocks multiple molecular targets that is affecting the growth, proliferation, and metastatic progression of cancer. It increases the circulating vascular endothelial growth factor[46]. Mayer et al.[47] concluded that patients receiving the three drug regimen had unacceptable high level toxicity with discontinuations. Poor tolerability was noted in the regimen with paclitaxel, bevacizumab, and sunitinib.

Paclitaxel and tegafur

Tegafur is a derivative of 5−fluorouracil that inhibits dihydropyrimidine dehydrogenase. Combination therapy or monotherapy with tegafur have a response rate of 6-28%[48]. Villanueva et al.[49] reported that the response duration was 8.4 months, median time to progression was 9.5 months, median overall survival was 23.5 months (Table 2).

Pegylated liposomal doxorubicin and cyclophosphamide

Pegylated liposomal doxorubicin is a formulation of doxorubicin in polyethylene glycol coated liposome. Pegylated formulation prolongs the circulation time and accumulation in the tumor tissues. It helps in the reduction of the side effects as compared with free doxorubicin[50]. Metronomic chemotherapy is the chronic administration of low doses of chemotherapeutic drugs at regular intervals[51]. Dellapasqua et al.[52] have reported that the partial response rate was 62.1% and no grade four toxicity was reported (Table 2).

Pemetrexed plus doxorubicin followed by docetaxel verses doxorubicin plus cyclophosphamide followed by docetaxel

Pemetrexed is a folate antimetabolite, which inhibits thymidylate synthase and dihydrofolate reductase. In pretreated metastatic breast cancer single agent pemetrexed with or without vitamin supplementation provided the response rate of 8-28%[53]. Pemetrexed is transported into the cell by the reduced folate carrier and membrane folate binding protein transport systems. In the cell it is converted into the polyglutamated forms which are then retained in the cell[54]. The polyglutamated metabolites have prolonged action in the malignant cells. The drug was approved by USFDA in the year 2010. It is also approved by FDA for maintenance treatment of patients with nonsquamous non−small cell lung cancer whose disease has not progressed after four cycle of first line chemotherapy with platinum based agents. Schneeweiss et al.[55] reported that the pathological complete response with the regimen doxorubicin, pemetrexed, docetaxel was 16.5% and with the regimen doxorubicin, cyclophosphamide, docetaxel was 20.2%. Response rate of doxorubicin, cyclophosphamide was 43.7%, and with doxorubicin, pemetrexed was 40.5% which shows almost similar activity (Table 3).

Trastuzumab plus docetaxel with trastuzumab plus vinorelbine

Vinorelbine is a vinca alkaloid chemotherapeutic drug. It acts synergistically when given in combination with trastuzumab. The antitumor activity of vinorelbine is due to the inhibition of mitosis at the metaphase. It may also interfere with the cyclic AMP, nucleic acid biosynthesis, and inhibit mitotic microtubule formation. Trastuzumab is now approved to be used in combination with cisplatin and fluoropyrimidines for treatment of HER2 over expressing metastatic gastric or gastroesophageal junction adenocarcinoma, who have not received prior treatment for metastatic disease. HERNATA trial concluded in 2011 reported that there was not much difference on overall survival and median time to progression, response rate between the two treatment arms[56] (Table 2).

Trastuzumab and docetaxel with trastuzumab, docetaxel, carboplatin

A pivotal phase 3 study conducted by Salmon et al. demonstrated that the combination of trastuzumab and chemotherapy significantly prolonged time to progression and overall survival compared with chemotherapy alone in patients with HER2 positive MBC. Carboplatin predominantly cause interstrand DNA cross links[57]. It nonspecifically affects the cell cycle. Carboplatin is used as first line agent in recurrent ovarian carcinoma. It was approved in 2005 by USFDA. Valero et al.[58] reported that there was no significant difference between docetaxel, trastuzumab (TH) and docetaxel, trastuzumab, carboplatin (TCH). Time to progression in TH regimen was 11.1 months and in TCH was 10.4 months. Response rate in the both regimen was 72%, overall survival rate was 37.1 month in TH regimen, and 37.4 in TCH regimen (Table 2).

Conclusion

There are several treatment options for breast cancer like chemotherapy, hormonal therapy, targeted anti−HER2 therapy, antiangiogenic therapies are available. Now adjuvant and neoadjuvant chemotherapy is advancing as it cures the micro−metastasis leading to better outcomes. There is a significant improvement in the overall survival rate and progression free survival after the introduction of novel drugs. When selecting a treatment option, the tolerability, efficacy, and mechanism of overcoming resistance have to be considered. The single agent eribulin is a choice of monotherapy for third line monotherapy in advanced breast cancer. Certain drugs like eribulin, ixabepilone with capecitabine, vinorelbine with capecitabine are approved in breast cancer resistant to anthracyclines and taxanes. Fulvestrant a novel single agent drug have considerable progression free survival in ER positive breast cancer. Iniparib in combination with gemcitabine and carboplatin have shown the efficacy in triple negative breast cancer. In HER2 positive breast cancer addition of trastuzumab to neoadjuvant chemotherapy improved overall response rate, reduced progression, relapse and death. Several other treatment options are coming up with maximum clinical efficacy and minimum toxicity level.

References