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  Table of Contents  
ONCOLOGY GOLD STANDARD CONSENSUS RECOMMENDATION
Year : 2014  |  Volume : 51  |  Issue : 1  |  Page : 73-79
 

ICON 2013: Practical consensus recommendations for hormone receptor-positive Her2-negative advanced or metastatic breastcancer


On behalf of Breast Cancer Expert Group of Indian Cooperative Oncology Network (ICON Trust)

Date of Web Publication18-Jun-2014

Correspondence Address:
P M Parikh
On behalf of Breast Cancer Expert Group of Indian Cooperative Oncology Network (ICON Trust)

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.134650

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 » Abstract 

The management of hormone receptor-positive Her2-negative breast cancer patients with advanced or metastatic disease is a common problem in India and other countries in this region. This expert group used data from published literature, practical experience, and opinion of a large group of academic oncologists, to arrive at practical consensus recommendations for use by the community oncologists.


Keywords: Chemotherapy, developing countries, endocrine therapy, guidelines, women


How to cite this article:
Parikh P M, Gupta S, Dawood S, Rugo H, Bhattacharyya G S, Agarwal A, Chacko R, Sahoo T P, Babu G, Agarwal S, Munshi A, Goswami C, Smruti B K, Bondarde S, Desai C, Rajappa S, Somani N, Singh M, Nimmagadda R, Pavitran K, Mehta A, Parmar V, Desai S, Nair R, Doval D. ICON 2013: Practical consensus recommendations for hormone receptor-positive Her2-negative advanced or metastatic breastcancer. Indian J Cancer 2014;51:73-9

How to cite this URL:
Parikh P M, Gupta S, Dawood S, Rugo H, Bhattacharyya G S, Agarwal A, Chacko R, Sahoo T P, Babu G, Agarwal S, Munshi A, Goswami C, Smruti B K, Bondarde S, Desai C, Rajappa S, Somani N, Singh M, Nimmagadda R, Pavitran K, Mehta A, Parmar V, Desai S, Nair R, Doval D. ICON 2013: Practical consensus recommendations for hormone receptor-positive Her2-negative advanced or metastatic breastcancer. Indian J Cancer [serial online] 2014 [cited 2017 Aug 21];51:73-9. Available from: http://www.indianjcancer.com/text.asp?2014/51/1/73/134650



 » Introduction Top


The Indian Cooperative Oncology Network (ICON Trust) Expert Group met to discuss and arrive at a consensus statement to provide community oncologists practical guidelines on the management of hormone receptor-positive Her2-negative breast cancer patients with advanced or metastatic disease. While the discussions will take the scenario as exists in India as a representative country with limited resources, the final manuscript is applicable globally. [1],[2]

The discussion was based on domain expertise of the international faculty, published evidence and practical experience in real life management of such patients. Opinion of the 300 participants in the 28 th meeting of ICON Trust was also taken into consideration by the expert panel. The expert group was chaired by Dr Sudeep Gupta whereas the discussions were moderated by Dr Shaheenah Dawood and Dr Purvish Parikh.

The core expert group discussed over several sessions about the possible methodologies. It was decided to use a series of questions on key practical issues and management challenges with each question answerable in the form of selection from multiple choice options. The consensus answers were used as the basis of formulating the consensus statement providing community oncologists with ready-to-use practical recommendations.

As part of the background work, the best existing evidence was compiled and provided to the expert group panel members for review in preparation of the expert group meeting. [3],[4],[5] The national and international experts invited to this meeting were also provided the data on the voting by the audience delegates from the 28 th ICON Trust meeting. Members of the panel were also allowed to share their personal experiences, make comments and record dissent while voting for the consensus statements.

A total of seven broad question categories were part of the expert group discussions [Table 1].
Table 1: Question categories addressed by the ICON trust expert group

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This manuscript is the outcome of the expert group discussion and consensus arrived at in 2013.

Defining clinical cohort and practice of expert group panel members

The primary objective was to provide a consensus statement for community oncologists that could be applicable as ready-to-use practical recommendations. Hence, the applicable setting was outlined by defining the clinical cohort and current practice of the participating delegates and expert group panel members - on the basis of which this document was prepared.

Breast cancer is the commonest cancer among women in India, the age-adjusted incidence being 32.4 per 100,000 in Maharashtra in the year 2010 with a 2.5% increase predicted annually upto 2021. [5]

To the question , what is the fraction of advanced/metastatic breast cancer patients with ER +ve/Her2 -ve phenotype disease in their practice, the answers were as follows [Table 2].
Table 2: Question 1 (i): What is the fraction of advanced/metastatic breast cancer patients with HR +ve/Her2 −ve phenotype in your practice?

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In one study of 11,780 breast tumors (age range 18 to 102 years), hormone receptor positivity was 53.9%. [6] A total of 41.8% tumors were positive for both estrogen and progesterone receptors, 10.6% positive for estrogen receptors alone and 3.4% positive for progesterone receptors alone. Overall hormone receptor positivity increased steadily with age, it being 10% in patients less than 19 years of age and 90% in those 71 years or older. As far as grade of tumor was concerned, there was an inverse correlation with respect to the hormone receptor positivity, it being 93% for grade 1 tumors and 39.5% for grade 3 tumors. With the median age of breast cancer in India being 49 years, the majority tend to be in the pre-menopausal group. [5] This is a significant difference from patients seen in the western world. [7]

Triple negative phenotype is 42% at initial presentation for all comers. In advanced and metastatic setting will be less since they have better prognosis and less chance of relapse. In a study of 2001 patients, Her2 positivity by IHC was seen in 498 (24.8%) patients and triple negative breast cancers formed 29.8% (n = 596) of all invasive cancers. [8] HER2 over-expression did not differ significantly with age (incidence being 17.7% for those below the age of 35 years and 17.0% for those above, P = 0.825). On the other hand hormone receptor expression (ER and/or PR) increases and triple negative phenotype decreases with increasing age.

To the question regarding the fraction of above patients with visceral involvement, the expert group agreed with the polls that it is between 20 and 40% of hormone-sensitive Her2-negative patients have visceral involvement when they present with metastatic disease. In tier 2 cities, where access to oncology centers may be a challenge, this incidence is slightly higher. This is applicable to the one fifth of the poll participants who are seeing visceral involvement in upto 60% of their patients at metastatic presentation [Table 3].
Table 3: Question 1 (ii): What fraction of your patients with HR +ve/Her2 −ve breast cancer in the first‑line metastatic setting have visceral involvement?

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The standard adjuvant endocrine therapy in pre-menopausal breast cancer patients is clearly tamoxifen. The consensus was to use it for 5 years. Perception of higher risk (e.g. lymph node positive patients) was associated with longer use of tamoxifen. In fact some patients had a tendency to get attached to their "regular medication" and were not averse to continuing the same. Additional of ovarian suppression for patients who did not have complete suppression during previous therapy (for non-metastatic disease) is accepted as standard of care and that option in fact reflects the current practice in the community. This is particularly for patients who are strong ER-positive or aggressive disease. In case where ovarian suppression is commenced but is not effective, oophorectomy is the next recommendation [Table 4].
Table 4: Question 1 (iii): What is your standard adjuvant endocrine therapy for pre‑menopausal patients?

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Common practice of adjuvant endocrine therapy in post-menopausal hormone-sensitive Her2-negative breast cancer patients is aromatase inhibitors for 5 years, as selected by the majority of oncologists in the poll. Tamoxifen is recommended for older patients and those with poor PS where the risk of skeletal related toxicity of AI is a cause for concern. The expert group agreed that the meta-analysis data showed that the best outcome (balance of efficacy and toxicity) is with a combination of Tamoxifen and AI for 5 years, as selected by 32% in the poll [9] [Table 5].
Table 5: Question 1 (iv): What is your standard adjuvant endocrine therapy for post‑menopausal patients?

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Defining endocrine resistance

Any patient who has received endocrine therapy and then has progressive disease is considered to have endocrine resistance in the broad sense. The group also agreed that there was no standard definition of what constitutes endocrine resistance. However, as the Bolero2 study has shown, several practical considerations have emerged. [10] Their importance relates to the consensus about subsequent management of patients. For patients relapsing while on endocrine therapy there is no debate about defining it as absolute endocrine resistance. However, the oncologists participating in the poll were split about what amounts to a significant off therapy period - upto 6 months or upto 12 months. Voting for secondary endocrine resistance also revealed an identical split [Table 6] and [Table 7].
Table 6: Question 2 (i): How would you define primary endocrine resistance in the adjuvant setting?

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Table 7: Question 2 (ii): How would you define secondary endocrine resistance in the adjuvant setting?

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The expert group agreed that distinction between primary and secondary endocrine resistance was not important for practical management of the patient. Just as a patient who progresses after one line of chemotherapy is still given a second line of chemotherapy, so also should be the approach to the patient with hormone receptor-positive breast cancer. The discussion ended with the consensus that for patients who relapse while on endocrine therapy, the next choice should be everolimus or exemestane. On the other hand for patients who progress while off therapy, it was reasonable to continue with alternate endocrine therapy - irrespective of the off therapy duration.

Significant visceral disease

Various trials have used different definition of impending visceral crisis (e.g. Tamrad v/s Bolero) and these trials also represent different patient populations. [10],[11] Hence, for this practical recommendations expert group, it was decided to explore the meaning of significant visceral disease as opposed to impending visceral crisis. Almost all the oncologists participating in the poll required associated symptoms to define that their patient had significant visceral metastasis. The expert group discussed three hypothetical scenarios to have a clearer understanding. Scenario one represented an asymptomatic patient with liver metastasis in four regions, multiple lung metastasis, and extensive bone involvement. In scenario two, the patient was considered as having 60% of the liver affected by metastasis, multiple lung metastasis, was still asymptomatic and biochemical parameters showed liver and renal profile that was within normal limits. Scenario three envisaged a patient with multiple lung metastases, evidence of lympangitis and being symptomatic with shortness of breath on exertion, though involvement of liver by metastasis was less than 20%. There was unanimous consensus by the expert group for the use of chemotherapy (with endocrine therapy) for scenario one and three. For scenario two while use of endocrine therapy was considered as a reasonable option, the majority still recommended chemotherapy [Table 8],[Table 9] and [Table 10].
Table 8: Question 3 (i): What is the definition of significant visceral disease?

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Table 9: Question 3 (ii): What is the appropriate choice of therapy for HR +ve/ Her2−ve breast cancer in the presence of significant visceral disease in the first‑line metastatic setting

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Table 10: Question 3 (iii): What is the appropriate choice of therapy for HR +ve/Her2 −ve breast cancer in the presence of significant visceral disease in the second‑line metastatic setting

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Hormone Receptor-Positive, Her2-Negative Post-menopausal Breast Cancer Patients

The discussions then shifted to patients without significant visceral disease or visceral crises. For patients with de novo stage IV disease, the polled oncologists and the expert group had no hesitation in recommending AI as the treatment of first choice. The expert groups added that the only reason to use Tamoxifen would be if AI was contraindicated in any particular patient [Table 11].
Table 11: Question 4 (i): What is the most appropriate choice of therapy for HR +ve/ Her2 −ve breast cancer post‑menopausal patients with newly diagnosed stage IV de novo disease and no visceral crisis?

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For a similar patient who has progressed on an AI, the expert group examined three groups of studies. These included results from Bolero (Exemestone 25 and Everolimus 10 + Exemestone 25), Tamrad (Tamoxifen 20 and Everolimus 10 + Tamoxifen 20) and Horizon (Letrozole 2.5 and Letrozole 2.5 + Temsirolimus 30) Studies. In all of them the PFS was about 9 months [10],[11],[12] [Table 12].
Table 12: Question 4 (ii): What is the most appropriate choice of therapy for HR +ve/ Her2 −ve breast cancer post‑menopausal patients who have progressed on previous therapy with an AI and have no visceral crisis?

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The choice of therapy for patients progressing on AI is also quite clear and the voting of the polled oncologists showed their familiarity with the current published literature. The expert group, while taking into consideration that Fulvestrant 500 mg is now shown to be better than 250 mg, still concurred that the strength of the data from BOLERO2 shows that Everolimus is the better option.

To explain further, data from 18 month pre-planned analysis showed a doubling of PFS (Progression Free Survival) in patients receiving Everolimus plus Exemestane compared to Exemestane alone (11 vs 4.1 months; P = 0.0001; HR 0.38; 95% CI 0.31-0.48). [10] Everolimus Plus Exemestane has also demonstrated a beneficial effect on bone marker assessments; C-terminal cross linking telopeptide of type I collagen (CTX), amino terminal propeptide of type 1 collagen (P1NP), and bone-specific alkaline phosphatase (BSAP) all showed reduction at 6 and 12 weeks for patients receiving Everolimus plus Exemestane (irrespective of prior bisphosphonate use), whereas the group on Exemestane alone actually had increase of bone turnover markers. [13] This is evidence of protective effect of Everolimus on bone health, of particular importance in such patients who have high incidence of bony metastasis. Everolimus plus Exemestane was also associated with a longer time to definitive deterioration (TDD) in global HRQOL measured using EORTC QLQ-C30) which strengthens the evidence further. [10],[14],[15]

This, rightly so, also highlights the fact that neither the expert group nor the polled oncologists considered the use of chemotherapy for patients at this stage in their disease [Table 13].
Table 13: Question 4 (iii): In a post‑menopausal patient with HR +ve/Her2 – ve breast cancer who has
progressed on exemestane and who is a candidate for further endocrine therapy what would you consider
as the most appropriate line of therapy?


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For this specific scenario, there is little published evidence. Hence, the expert group decided that there is no single correct answer. The reason for the polled oncologists to select option b was data from the phase 2 TAMRAD study, which is currently the most promising option. The rationale for this is that a key adaptive change leading to endocrine resistance is activation of the mTOR signaling pathway [16],[17],[18] [Table 14].
Table 14: Question 4 (iv): In a patient with no visceral crisis who has progressed on everolimus and exemestane and in whom you are considering next line endocrine therapy, would you continue everolimus beyond progression?

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A clear majority of the polled oncologists and the entire expert group were of the opinion that, at present, there is no data to support continuation of everolimus beyond progression [Table 15].
Table 15: Question 4 (v): Would you consider the combination of everolimus and exemestane among post‑menopausal patients with HR +ve/Her2 – ve breast cancer who have >3 visceral organs involved by metastatic disease?

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The expert group discussed and agreed that number or type of visceral organs involved by metastatic disease did not prevent the use of everolimus and exemestane in this group of patients. Even among patients with metastasis involving more than three visceral organs, there was no hesitation in recommending this combination [Table 16].
Table 16: Question 4 (vi) Given the BOLERO‑ 2 trial data, can the combination of everolimus and exemestane be considered as standard treatment option in patients with HR +ve/Her2 – ve breast cancer that has progressed on a previous AI in the post‑menopausal setting?

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The expert group was unanimous in voting yes. While the updated investigator assessment of the progression-free survival (PFS) rate for patients treated with exemestane and everolimus was 7.8 months, independent reviewers assessed PFS at 11.0 months - strengthening the confidence and statistics. [19] When this data represents 724 post-menopausal women with hormone receptor-positive metastatic breast cancer who had progressed on a nonsteroidal aromatase inhibitor (AI), it clearly affirms the superior value of the exemestane and everolimus combination.

The benefit is in terms of PFS was also associated with better bone health and QoL. The risk reduction is identical for patients with visceral metastasis (53%) and those without visceral metastasis (59%). In fact, the 61% risk reduction in patients who had progressed after adjuvant therapy also suggests that this combination is likely to be of greater benefit in the first-line setting. [10],[19]

Treatment approach [Table 17]

In the poll of oncologists, 85% selected Tamoxifen as the best option in this situation, with or without ovarian suppression. The expert group agreed that both of these are valid options. Without compelling evidence, the rationale for combining tamoxifen with ovarian suppression was considered as the better practical recommendation [Table 18].
Table 17: Question 5 (i): Assuming absence of visceral crisis, what is the most appropriate choice of therapy
for pre‑menopausal patients with newly diagnosed stage IV de novo HR +ve/Her2 – ve breast cancer?


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Table 18: Question 5 (ii): Assuming absence of visceral crisis, what is the most appropriate choice of therapy for pre‑menopausal patients who have progressed on Tamoxifen?

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The expert group agreed that there is no strong evidence for selecting any one of the choices. The poll results reflect the current practice of using AI for such patients. The expert consensus was that chemotherapy is also an option, even in the absence of visceral crisis. For instance when patients having speedy progress of the disease or significant symptoms.

Role of everolimus refined [Table 19]

There were arguments on both sides for the approach to appropriate use of everolimus. Based on the evidence from pivotal data the consensus was to start with the labeled dose of 10 mg and de-escalate if necessary. [20] This is supported by the study in metastatic renal cell carcinoma that predicted median change in single largest diameter (SLD) of the disease will be increase of 22.4 ± 17.2% with 5 mg of Everolimus and reduction of 15.7 ± 11.5% with 10 mg. [21] For frail patients a fraction of oncologists may still continue to start with a lower dose and escalate if no toxicity, but this is without evidence and not recommended. [22]
Table 19: Question 6: What is the appropriate way of using everolimus for advanced breast cancer in your practice?

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Measures to prevent and minimize toxicity used in clinical trials are often neglected in routine clinical practice. Application of such measures will ensure that toxicity remains manageable in most patients. [23] Hence the following are recommended for all patients receiving Everolimus: Proper counseling and patient information, prophylactic measures for maintaining oral hygiene, more frequent follow up in the first few weeks (when toxicity are most likely to develop) and communicating early onset of specific symptoms to the healthcare team (to allow appropriate intervention that can prevent the toxicity from worsening). Interventions for common clinically relevant toxicities include use of non-alcohol containing mouth wash, topical corticosteriods and anti-fungal agents (for stomatitis), routine anti-diabetic agents (for hyperglycemia), statins (for hyperlipidemia) and correction of anemia, optimized hydration and restricted physical activity (for fatigue). It is also important to check for and correct hypophosphatemia (which can lead to muscle weakness and is often mistaken for fatigue). [23]

Value and need for rebiopsy [Table 20]

Among the polled oncologists, 15% were reluctant to do a rebiopsy for any patient. On the other hand 60% would biopsy in all patients. Neither of these extreme positions was recommended by the expert group. A rebiopsy is recommended in specific circumstances. One is to confirm that the patient actually has a relapse rather than a lesion due to other causes, like infections. The other is when the clinical picture or behavior of the patient is not in tune with what is expected from a hormone-sensitive Her2-negative disease. An example of this would be development of liver metastasis within 3 months of starting tamoxifen. This was particularly important since the earlier laboratory methodology or tumor block processing may have been using techniques that have undergone significant improvement over time. The group also understood that a patient with recurrences in an easily accessible location is more likely to agree to undergo a rebiopsy. Hence counseling skills are vital for such a discussion with patients and family members [Table 21].
Table 20: Question 7 (i): Do you routinely rebiopsy a breast cancer patient with recurrence?

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Table 21: Question 7 (ii): Among patient with Her2‑negative and HR‑ positive breast cancer patients, changes of concern that will significantly impact treatment decision making will include?

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There is evidence about change in receptor status either way. [24],[25] While the question pertained to changes that would indicate the need to use chemotherapy, the expert group was of the opinion that the reverse is equally important.


 » Conclusions Top


The ICON 2013 expert group hormone receptor-positive Her2-negative advanced or metastatic breast cancer had the specific mandate to develop practical consensus recommendations for easy application by the community oncologist. It took into consideration data as well as the current practices in India, in addition to international data that conventional panels look at, making it the perfect blend of evidence, clinical expertise, and real life preference.

The options for treatment of such patients include tamoxifen, aromatase inhibitors, exemestane, everolimus, fulvestrant, chemotherapy, and ovarian suppression.

Common factors to be considered while selecting therapy in individual patients include previous therapy, disease-free interval, tumor biology, underlying medical and social issues (age, PS and co-morbidities), patient preferences (convenience vs compliance), risk of toxicities and their implications, menopausal status and presence/absence of visceral crisis or significant visceral metastasis.

This practical consensus recommendation allows for optimal sequencing if the effective therapeutic interventions available today. While both Everolimus Exemestane combination as well as Fulvestrant 500 mg result in better outcome as compared to their control arms, the magnitude of clinical benefit as well as the robustness of currently available data favors the use of the Everolimus Exemestane combination. Benefit to individual patients can be optimized (response as well as quality of life) by paying adequate attention to proactively minimizing toxicity.

Unresolved issues of importance include value of ovarian suppression, systematic segregation of visceral organ involvement (nature, speed, number), identification of co-morbidities of significance.

 
 » References Top

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2.Badwe RA, Gangawal S, Mitra I, Desai PB. Clinico-pathological features and prognosis of breast cancer in different religious communities in India. Indian J Cancer 1990;27:220-8.  Back to cited text no. 2
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8.Ghosh J, Gupta S, Desai S, Shet T, Radhakrishnan S, Suryavanshi P, et al. Estrogen, progesterone and HER2 receptor expression in breast tumors of patients, and their usage of HER2-targeted therapy, in a tertiary care centre in India. Indian J Cancer 2011;48:391-6.  Back to cited text no. 8
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10.Piccart M, Baselga J, Noguchi S, Burris H, Gnant M, Hortobagyi G, et al. Final progression free survival analysis of BOLERO-2: A phase III trial of everolimus for postmenopausal women with advance breast cancer. JCO 2012;30.  Back to cited text no. 10
    
11.Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Greyer G, et al. Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormore receptor positive human epidermal growth factor receptor 2 negative metastatic breast cancer with prior exposure to aromatase inhibitors: A GINECO study. JCO 2012;30:2718-24.  Back to cited text no. 11
    
12.Delea TE, Amdahl J, Chit A, Amonkar MM. Cost-effectiveness of lapatinib plus letrozole in her2-positive, hormone receptor-positive metastatic breast cancer in Canada. Curr Oncol 2013;20:e371-87.  Back to cited text no. 12
    
13.Gnant M, Baselga J, Rugo HS, Noguchi S, Burris HA, Piccart M, et al. Effect of everolimus on bone marker levels and progressive disease in bone in BOLERO-2. J Natl Cancer Inst 2013;105:654-63.  Back to cited text no. 13
    
14.Burris HA 3 rd , Lebrun F, Rugo HS, Beck JT, Piccart M, Neven P, et al. Health-related quality of life of patients with advanced breast cancer treated with everolimus plus exemestane versus placebo plus exemestane in the phase 3, randomized, controlled, BOLERO-2 trial. Cancer 2013;119:1908-15.  Back to cited text no. 14
    
15.CroleyJJ, Black EP, Romond E, Chambers M, Waynick S, Sloan S, et al. A phase II study of combined fulvestrant and RAD001 (everolimus) in metastatic estrogen receptor (ER) positive breast cancer after aromatase inhibitor (AI) failure. Cancer Res 2012;72 (24 Suppl).  Back to cited text no. 15
    
16.Everolimus plus Letrozol-Safra Abstr P5-20-06 of SABCS 2012. RAD001 (Everolimus) in combination with letrozole in the treatment of postmenopausal women with estrogen receptor-positive metastatic breast cancer after failure of hormonal therapy-A Phase II Study. Abstract P5-20-06.  Back to cited text no. 16
    
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19.Hope S, Rugo J, Thaddeus B, Baselga J, Shinzaburo N, Michael G, et al. BOLERO-2: Health-related quality-of-life (HRQoL) in metastatic breast cancer patients treated with everolimus and exemestane versus exemestane. Adv Dis 2012;125.  Back to cited text no. 19
    
20.Besse B, Heist RS, Papadmitrakopoulos VA, Camidge DR, Beck JT, Schmid P, et al. A phase Ib dose-escalation study of everolimus combined with cisplatin and etoposide as first-line therapy in patients with extensive-stage small-cell lung cancer. Ann Oncol 2014;25:505-11.  Back to cited text no. 20
    
21.Stein A, Wang W, Carter AA, Chiparus O, Hollaender H, Kim H, et al. Dynamic tumor modeling of the dose response relationship for everolimus in metastatic renal cell carcinoma using data from the phase 3 RECORD-1 trial BMC. Cancer 2012;12:311-20.  Back to cited text no. 21
    
22.Inamoto T, Azuma H, Nonomura N, Nakatani T, Matsuda T, Nozawa M, et al. Favorable outcome in elderly asian patients with metastatic renal cell carcinoma treated with everolimus: The Osaka Urologic Oncology Group. Asian Pac J Cancer Prev 2014;15:1811-5.  Back to cited text no. 22
    
23.Rodrigues-Pascual J, Cheng E, Maroto P, Duran I. Emergent toxicities associated with the use of mTOR inhibitors in patients with advanced renal carcinoma. Anticancer Drugs 2010;21:478-86.  Back to cited text no. 23
    
24.Arihiro K, Oda M, Ogawa K, Tominaga K, Kaneko Y, Shimizu T, et al. Biopsy changes either way Discordant HER2 status between primary breast carcinoma and recurrent/metastatic tumors using fluorescence in situ hybridization on cytological samples. Jpn J Clin Oncol 2013;43:55-62.  Back to cited text no. 24
    
25.Macfarlane R, Seal M, Speers C, Woods R, Masoudi H, Aparicio S, et al. Molecular alterations between the primary breast cancer and the subsequent locoregional/metastatic tumor. Oncologist 2012;17:172-8.  Back to cited text no. 25
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12], [Table 13], [Table 14], [Table 15], [Table 16], [Table 17], [Table 18], [Table 19], [Table 20], [Table 21]



 

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