Abstract

In the last few decades, research has demonstrated that cancer can be treated and cured if diagnosed at very early stage and a proper therapeutic strategy is adopted. Recent omics-based approaches have unveiled the molecular mechanisms of cancer tumorigenesis and have aided in identifying next-generation molecular markers for early diagnosis, prognosis, and targeted therapy. New tests based on genomic profiling, circulating tumor cells, or mutation profiling are appraised for purpose by Health Technology Assessment. The potential clinical utility of these tests lies on their ability to discriminate between patients who will benefit to a greater or lesser extent from a therapeutic intervention. Assessment of new technologies for the management of cancer could be of interest to other countries given the potentially high impact that they can have on the quality and cost of health care services.

The use of neoadjuvant chemotherapy for the treatment of breast cancer is well established in current clinical practice. The primary objective of neoadjuvant therapy is to improve surgical outcomes in terms of breast conservation with a cosmetic outcome in patients with nonoperable breast cancer (1). However, neoadjuvant treatment has been increasingly employed in operable breast cancer for several reasons: 1) it offers a direct in vivo assessment of tumor response; 2) it allows response monitoring and possible modifications of the treatment plan in the event of poor response; 3) it provides an opportunity to study the impact of systemic therapies on breast cancer biology; 4) it gives researchers the opportunity to obtain tumor specimens (both fresh and formalin-fixed) and blood samples before and during the preoperative treatment enabling research aimed at identifying tumor- or patient-specific biomarkers of response or resistance; and 5) it has also shown great potential as a platform for drug development, which has led the US Food and Drug Administration to recently consider pathologic response to neoadjuvant therapy as an endpoint to support accelerated drug approval in high-risk early-stage breast cancer (2–4).

Monitoring of response to treatment, either in the neoadjuvant or in the metastatic setting, is a key element in the management of breast cancer and it could involve several different viewpoints from surgery, radiology, and medical oncology. Tumor size reduction (locally or metastatic) is positively associated with a favorable patient outcome in terms of increased disease-free, progression-free, or overall survival (5,6). Improvement of the monitoring of breast cancer disease is of paramount importance not only from the clinical point of view but also from the payers involved in health management.

In the neoadjuvant setting, pathological complete response (pCR) has been identified as a possible surrogate marker for long-term survival outcomes. Patients who attain pCR defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival (7). The prognostic value is greatest in aggressive tumor subtypes. However, a recent pooled analysis was unable to validate pCR as a surrogate endpoint for improved event-free survival and overall survival (7). Failure to achieve a pCR is associated with worse long-term outcomes in triple-negative and HER2-positive breast cancer and grade 3 hormone receptor (HR)–positive breast cancers, although this negative prognostic association is not observed for low grade HR–positive breast cancers (8,9). Until now, clinical and radiographic monitoring during neoadjuvant chemotherapy to predict pCR has been notoriously inaccurate (10). However, the exploratory analysis recently performed by von Minckwitz et al. (11) suggests that response-guided neoadjuvant chemotherapy may improve survival among the breast cancer subgroups with a trend of effectiveness, particularly in HR–positive tumors. Although these results will need to be confirmed, it appears that the response-guided approach could provide a clinically meaningful advantage for the neoadjuvant over the adjuvant approach in early breast cancer, supporting the notion that identifying methods monitoring tumor response during treatment will be crucial in patient care.

Yet, monitoring response to treatment for women with metastatic breast cancer is likely to prove challenging. The goal of therapy is to improve quality of life and overall survival, and the challenge has been to find a test for assessing response that is safe, noninvasive, and reliable. Of all the standard monitoring modalities, radiographic examination has been the most readily used to measure treatment response, but we need to also consider patients with nonmeasurable disease as pleural effusions, bone metastatic disease, and other difficult to assess metastatic sites. This has led to the investigation of several circulating and other tissue-based tumor biomarkers (6).

In the neoadjuvant or metastatic settings, as part the emerging clinical or radiological imaging modalities to monitor disease, the use of new RNA- or DNA-based assays or of novel circulating markers, along the ability to obtain tissue/blood from the breast tumor or from the metastasis, will help to evaluate predictive, prognostic, pharmacodynamic, and surrogate markers before and after the administered therapy, which could help determine who may benefit from the treatment and/or from enhanced surveillance. Thus, the primary challenges in the neoadjuvant/metastatic setting include accurate assessment of early response to therapy and noninvasive means of accurately predicting pathologic/radiological complete response to therapy. Both areas are under active investigation from clinicians and from the Health Technology Assessment (HTA) panel, aiming not only to improve outcome in breast cancer but also to address properly the impact of treatment decisions at the social and budgetary levels. HTA programs recently spread across different jurisdictions as a decision-making tool to support sustainable health policy decisions with respect to the introduction and adoption of new technologies (12). In times of resource constraints, HTA is becoming key in identifying subgroups of patients, if any at all, who may benefit the most from the introduction of novel practices and the maintenance of older ones. However, for HTA to be an effective tool, it is important that evidence is gathered and critically appraised, and different perspectives are synthesized (13).

In October 2013, within an opening satellite of the sixth Symposium on Primary Chemotherapy in Breast Cancer held in Cremona, Italy, a round table was organized by A.O. Istituti Ospedalieri. Experts in medical oncology, pathologists, and scientists with expertise in the field of next-generation testing in breast cancer and representatives of the HTA program of Regione Lombardia were involved. Presenting panel members were charged with reviewing all available data on noninvasive means of assessing response to therapy from published studies (published reports indexed on Medline). A consideration of budget impact analysis was also included. This initiative provided rigorous evidence-based criteria for evaluating new tests for clinical and public health practice. The working group adopted a modified Delphi process (14), which was coordinated by an external coordinating person. The process was structured as joining together an expert panel to answer to specific questions. The experts completed the questionnaires blinded to the responses provided by other members of the group. Each panel member was asked to evaluate the quality of evidence of new tests in the four parameters [analytical validity, clinical validity, clinical utility, and cost effectiveness, see definitions by Simon et al. (15)] as convincing, adequate, or inadequate based on sources find in the published reports. Evaluation was carried out independently. Each panel member provided his/her review to the working group coordinator. After completing the evaluation process, a summary of all evaluations was shared with all the working group members for discussion to reach a final consensus (Table 1). The majority of the panel agreed that circulating tumor cells are strong markers, which might be helpful in clinical practice. From a recent meta-analysis, circulating tumor cells are superior to routine markers such as CEA and CA 15-3 in being both prognostic and predictive in the metastatic setting (16). Although economic data are not available, the experts in the field of the panel believe that the magnitude of the benefit in term of clinical impact was considered so strong that their use should be supported in monitoring the treatment efficacy and outcome. The majority of panel also agreed with the use of high-throughput and parallel mutation analysis by next-generation sequencing/mass spectroscopy on tumor samples for selecting the proper drug. In some cancer, the use it is already an evidence-based consideration as it occurs for gefitinib, cetuximab, or vemurafenib in lung cancer or colon cancer or melanoma (17–19); in others, it is confined to an expert opinion in relation to the information these new techniques provide in understanding the biology of the cancer and/or the possible effect of the administered treatment as in breast cancer. With respect to the genomic tests, some can identify a group of node negative, hormone receptor–positive patients treated with endocrine treatment in which the risk of relapse is low enough to be safely spared from additional chemotherapy. Because they are not designed to be a “predictive” marker for chemotherapy benefit, the data from prospective trials such as Microarray In Node Negative Disease May Avoid Chemotherapy (MINDACT) or Trial Assigning Individualized Options for Treatment (Rx) (TAILORx) are needed to provide evidence for patient survival benefit from altered chemotherapy decision making due to the use of these tests. Oncotype Dx is the only test that received approval from the UK National Institute for Health and Care Excellence (NICE) and was incorporated into the American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), St Gallen, and German Gynecological Oncology Group (AGO) guidelines (20). However, a majority of panel consider that additional information on the budget impact analysis (considering direct and indirect costs) is needed before consideration to be incorporated into the Italian national health system. The use of other tests such as RNA Disruption Index in clinical practice also needs to be assessed in standardized clinical trials to provide the necessary evidence for clinical benefit.

Table 1.

Recommendations from the opening satellite of sixth Symposium on Primary Chemotherapy in Breast Cancer, Cremona, Italy 2013 (based on the agreement of the majority of the panel members)*

Molecular test Analytical validity Clinical validity Clinical utility Cost-benefit 
 Circulating markers 
 Circulating tumor cell YES YES YES NE 
 Circulating free DNA YES YES NE NE 
Genomic profile 
 Oncotype Dx YES YES NE NE 
 Mammaprint YES YES NE NE 
 EndoPredict YES YES NE NE 
 PAM50 YES YES NE NE 
RNA profile 
 RNA Disruption Index YES NE NE NE 
Mutation analysis profile 
 Mass Spect YES YES YES YES 
 NGS YES YES YES YES 
Molecular test Analytical validity Clinical validity Clinical utility Cost-benefit 
 Circulating markers 
 Circulating tumor cell YES YES YES NE 
 Circulating free DNA YES YES NE NE 
Genomic profile 
 Oncotype Dx YES YES NE NE 
 Mammaprint YES YES NE NE 
 EndoPredict YES YES NE NE 
 PAM50 YES YES NE NE 
RNA profile 
 RNA Disruption Index YES NE NE NE 
Mutation analysis profile 
 Mass Spect YES YES YES YES 
 NGS YES YES YES YES 

*Mass Spect = mass spectrometry; NE = not evaluable; NGS = next-generation sequencing; PAM50 = Prosigna Breast Cancer Prognostic Gene Signature Assay.

Conclusion

Determining which cancer patients are at higher risk of relapse or progression during and after treatment remains a main challenge. With the use of “omics tools” such as the microarray- and DNA-based assays, the ability to obtain tumor tissue to assess predictive and prognostic markers before, during, and after therapy may help the clinicians to determine which patients may benefit from the administered treatment or from an enhanced surveillance. The real challenge in the management of neoadjuvant and metastatic disease is to provide safe, inexpensive, and accurate tumor marker assessment for our patients. The introduction of mutation analysis in clinical practice is already well established in some solid tumors and the optimization of the use of circulating tumor cells might improve the management of cancer patients in routine clinical practice.

With regard to the genomic tests, although HTA committees may accept for assessment well designed indirect evidence of clinical utility, such as using a genomic test in clinical practice while additional evidence is being collected or even simply allowing physicians and patients to determine when to use the test on a case-by-case basis, these authorities mostly rely on systematic revisions of clinical trials in their assessment of the appropriateness of genomic tests for clinical integration (see report at http://vts-hta.asl.pavia.it). However, there is a nuanced interpretation of the adequacy of the evidence base among the panelists. In addition, the data quality from the current evidence varies greatly across various sources, which is not unique to genomic tests. Clearly, there is a need to develop a better understanding of the “feedback” coming from the post-regulatory decision makers such as clinicians, patients, and payers to design useful studies with regard to their impact on direct and indirect costs in Italian national health system in the future.

Dedicated studies will help the clinicians in validating or discovering novel markers or techniques that will help in moving forward into the cancer treatment or even average-risk screening population to find new ways to improve cancer-specific mortality.

The authors declare that they have no competing interests. There are no financial or other interests with regard to the submitted manuscript that might be construed as a conflict of interest.

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