Se presentan aquí los criterios de respuesta de valoración respuesta tumoral en oncología basados en los criterios RECIST. También se mencionan los criterios de Lugano (para linfomas) y los criterios de Choi (para tumores estromales gastrointestinales - GISTs). Presentación por la estudiante de medicina de la Universidad CES, Verónica Posada, 28/12/2014.
2014-12-30
Criterios de respuesta tumoral
Se presentan aquí los criterios de respuesta de valoración respuesta tumoral en oncología basados en los criterios RECIST. También se mencionan los criterios de Lugano (para linfomas) y los criterios de Choi (para tumores estromales gastrointestinales - GISTs). Presentación por la estudiante de medicina de la Universidad CES, Verónica Posada, 28/12/2014.
2014-12-22
2014-12-19
2014-12-15
SABCS 2014 - Adjuvant chemotherapy
NSABP-B36: Adjuvant FEC100 x6 vs AC x4 in Node Negative BC
After 82 months, there is no difference in DFS in both arms. Slightly more toxicity with FEC100. Conclusion: No need for 6 cycles of anthracyclines in node-negative disease.
ECOG 1199: How to give adjuvant taxanes in the adjuvant setting (the four arm trial)
Node-positive or high-risk node-negative BC patients received adjuvant AC and were randomized to one of four arms: paclitaxel every three weeks (control), paclitaxel every week, docetaxel every three weeks and docetaxel every week. Several years ago, it was reported that weekly paclitaxel and docetaxel every three weeks had superior DFS compared to the control arm. After 12 years, the results hold. There appear to be some refinements: 1. Obesity and black ethnicity are associated with decreased OS, 2. Weekly paclitaxel is associated with increased DFS and OS in TNBC with a HR of 0.69 (p<0 .05="" a="" i="" in="">post-hoc
analysis (the 10-year DFS went from 59% to 69% and the OS from 66% to 75%). 3. Docetaxel every three weeks appears slightly superior in DFS (but no OS) with a HR of 0.76 in ER+/HER2-/Unknown patients.
ICE: Adjuvant Ibandronate and Capecitabine in 65+ years High-Risk BC and with High Charlson Co-morbidity score
Negative trial.
After 82 months, there is no difference in DFS in both arms. Slightly more toxicity with FEC100. Conclusion: No need for 6 cycles of anthracyclines in node-negative disease.
ECOG 1199: How to give adjuvant taxanes in the adjuvant setting (the four arm trial)
Node-positive or high-risk node-negative BC patients received adjuvant AC and were randomized to one of four arms: paclitaxel every three weeks (control), paclitaxel every week, docetaxel every three weeks and docetaxel every week. Several years ago, it was reported that weekly paclitaxel and docetaxel every three weeks had superior DFS compared to the control arm. After 12 years, the results hold. There appear to be some refinements: 1. Obesity and black ethnicity are associated with decreased OS, 2. Weekly paclitaxel is associated with increased DFS and OS in TNBC with a HR of 0.69 (p<0 .05="" a="" i="" in="">post-hoc
analysis (the 10-year DFS went from 59% to 69% and the OS from 66% to 75%). 3. Docetaxel every three weeks appears slightly superior in DFS (but no OS) with a HR of 0.76 in ER+/HER2-/Unknown patients.
ICE: Adjuvant Ibandronate and Capecitabine in 65+ years High-Risk BC and with High Charlson Co-morbidity score
Negative trial.
SABCS 2014 - Hormone Receptor Positive (HR+) BC
Predicting response to hormone therapy in neoadjuvant BC
JM Dixon et al. developed a binary assay that includes: a baseline assessment of mRNA expression of IL-6 related gene and the apoptotic neutral nerve growth factor receptor asociated protein; and also includes two proliferation markers on day 14 on Letrozole. This assay predicts with 96% accuracy the likelihood of response to hormone therapy. The investigators undertook sequential biopsies and subjected them to in-depth genomic analysis. They found that responding patients were losing mutations over time, and the contrary was true in non-responding patients. In Dr. Dixon's view, lack of early biologic effect has ominous implications to the natural history for the BC patient.
OPPORTUNE trial: Pictilisib + Anastrozole vs Anastrozole alone prior to surgery in HR+ BC
The addition of Pictilisib (formerly known as GDC-0941), a pan-PI3k inhibitor, to Anastrozole showed a marked decrease in the Ki67 proliferative index, restricted to the Luminal B cohort or patients. No apparent benefit was seen in the Luminal A patients. The FERGI trial was performed in with the same agent in the metastatic setting, and no clear benefit - so far.
Clinical benefit with 1st-Line hormonal therapy for metastastic breast cancer no different in visceral metastasis to non-visceral metastasis
Disease control of patients with visceral metastasis was carefully assessed in three large randomized trials in the 1st-line metastatic setting in hormone-sensitive breast cancer (Tamoxifen vs Exemestane; Tamoxifen vs Anastrozol; and Tamoxifen vs Fulvestrant). The investigators found that the clinical benefit in this visceral metastasis group was 58% (not unlike the 66% in the soft-tissue/bone metastasis group). Dr. John Robertson concludes that it is unlikely that any 1st-line chemotherapy will afford superior disease control. But he CONTRADICTS himself by stating that if the patient has life-threatening disease she should undergo chemotherapy. If hormone is as good as chemo, why not give it to the sickest?
FIRST trial: Fulvestrant 500 mg vs Anastrozole in 1st-line HR+ mBC
Again, Dr. Robertson, presents the results of this small (205 patient) phase-2 trial with the newer 500 mg formulation of Fulvestrant (a estrogen receptor (ER) inactivator) vs Anastrozole (as the control arm). Fulvestrant has three mechanisms of actions: 1. Blocks the dimerization of ER, 2. Begrades ER and 3. Impairs ER-related pathway cross-talk. The original primary endpoint was clinical benefit rate and it was previously reported. The investigators found a slightly superior, albeit non-statistically significant, clinical benefit rate in favor of the Fulvestrant arm (76% vs 67%). Overall survival was included in a protocol amendment in 2011, the results of which are presented for the first time at this meeting. And the results are impressive: 30% improvement in OS to 54 months median overall survival. We are waiting the results of the phase-3 FALCON trial in 2-3 years. Just a couple of decades ago, the median survival of this group of patients was 24 months.
JM Dixon et al. developed a binary assay that includes: a baseline assessment of mRNA expression of IL-6 related gene and the apoptotic neutral nerve growth factor receptor asociated protein; and also includes two proliferation markers on day 14 on Letrozole. This assay predicts with 96% accuracy the likelihood of response to hormone therapy. The investigators undertook sequential biopsies and subjected them to in-depth genomic analysis. They found that responding patients were losing mutations over time, and the contrary was true in non-responding patients. In Dr. Dixon's view, lack of early biologic effect has ominous implications to the natural history for the BC patient.
OPPORTUNE trial: Pictilisib + Anastrozole vs Anastrozole alone prior to surgery in HR+ BC
The addition of Pictilisib (formerly known as GDC-0941), a pan-PI3k inhibitor, to Anastrozole showed a marked decrease in the Ki67 proliferative index, restricted to the Luminal B cohort or patients. No apparent benefit was seen in the Luminal A patients. The FERGI trial was performed in with the same agent in the metastatic setting, and no clear benefit - so far.
Clinical benefit with 1st-Line hormonal therapy for metastastic breast cancer no different in visceral metastasis to non-visceral metastasis
Disease control of patients with visceral metastasis was carefully assessed in three large randomized trials in the 1st-line metastatic setting in hormone-sensitive breast cancer (Tamoxifen vs Exemestane; Tamoxifen vs Anastrozol; and Tamoxifen vs Fulvestrant). The investigators found that the clinical benefit in this visceral metastasis group was 58% (not unlike the 66% in the soft-tissue/bone metastasis group). Dr. John Robertson concludes that it is unlikely that any 1st-line chemotherapy will afford superior disease control. But he CONTRADICTS himself by stating that if the patient has life-threatening disease she should undergo chemotherapy. If hormone is as good as chemo, why not give it to the sickest?
FIRST trial: Fulvestrant 500 mg vs Anastrozole in 1st-line HR+ mBC
Again, Dr. Robertson, presents the results of this small (205 patient) phase-2 trial with the newer 500 mg formulation of Fulvestrant (a estrogen receptor (ER) inactivator) vs Anastrozole (as the control arm). Fulvestrant has three mechanisms of actions: 1. Blocks the dimerization of ER, 2. Begrades ER and 3. Impairs ER-related pathway cross-talk. The original primary endpoint was clinical benefit rate and it was previously reported. The investigators found a slightly superior, albeit non-statistically significant, clinical benefit rate in favor of the Fulvestrant arm (76% vs 67%). Overall survival was included in a protocol amendment in 2011, the results of which are presented for the first time at this meeting. And the results are impressive: 30% improvement in OS to 54 months median overall survival. We are waiting the results of the phase-3 FALCON trial in 2-3 years. Just a couple of decades ago, the median survival of this group of patients was 24 months.
SABCS 2014 - Triple negative breast cancer (TNBC)
Biomarkers
Myriad-genetics has sponsored two trials on biomarkers in TNBC. The first one in metastatic TNBC comparing Carboplatin to Docetaxel in TNBC (TNT trial). The study showed no difference between Carboplatin and Docetaxel. But, in when the germ-line BRCA+ mTNBC patients were analyzed, the results became quite interesting. The response rate in BRCA+ mTNBC was 68% vs 33% in favor of Carboplatin. The non-basal TNBC (by PAM50) had a remarkable response to Docetaxel (but, it was a small subgroup of patients). The company has also created a genetic test called HRD (Homologous Recombination Deficiency) test to assess the integrity of the DNA repair mechanism in TNBC patients. In a companion trial, patients with early breast cancer had a 52% response rate to platinum if they tested positive to HRD, and only 10% if the results were negative.
Geparsepto: Nab-Paclitaxel in neoadjuvant BC
The germans presented they large Geparsepto trial with about 1200 patients comparing neoadjuvant Paclitaxel followed by EC to nab-Paclitaxel (150 mg/wk) followed by EC. The endpoint was pathologic complete response (pCR). Nab-paclitaxel arm exhibited higher neuropathy and diarrhea. The study met its primary endpoint with an increase in the pCR from 28% to 39% (p=0.001). The results were impressive in the TNBC group with pCR of 48% (25% with the conventional paclitaxel).
Pembrolizumab in TNBC
A phase 1b trial reported by Rita Nanda with Pembrolizumab 10 mg/kg IV q2wk in 32 heavily pretreated PD-L1+ (by IHC) TNBC patients. There were 5 responses in the 27 evaluable patients (ORR: 18.5%), with 1 CR. The median duration of response was >40 weeks (in responding patients), and 1.9 mo (in the others). Treatment was well tolerated, one patient with rapidly progressive metastatic disease died of disseminated intravascular coagulation.
Myriad-genetics has sponsored two trials on biomarkers in TNBC. The first one in metastatic TNBC comparing Carboplatin to Docetaxel in TNBC (TNT trial). The study showed no difference between Carboplatin and Docetaxel. But, in when the germ-line BRCA+ mTNBC patients were analyzed, the results became quite interesting. The response rate in BRCA+ mTNBC was 68% vs 33% in favor of Carboplatin. The non-basal TNBC (by PAM50) had a remarkable response to Docetaxel (but, it was a small subgroup of patients). The company has also created a genetic test called HRD (Homologous Recombination Deficiency) test to assess the integrity of the DNA repair mechanism in TNBC patients. In a companion trial, patients with early breast cancer had a 52% response rate to platinum if they tested positive to HRD, and only 10% if the results were negative.
Geparsepto: Nab-Paclitaxel in neoadjuvant BC
The germans presented they large Geparsepto trial with about 1200 patients comparing neoadjuvant Paclitaxel followed by EC to nab-Paclitaxel (150 mg/wk) followed by EC. The endpoint was pathologic complete response (pCR). Nab-paclitaxel arm exhibited higher neuropathy and diarrhea. The study met its primary endpoint with an increase in the pCR from 28% to 39% (p=0.001). The results were impressive in the TNBC group with pCR of 48% (25% with the conventional paclitaxel).
Pembrolizumab in TNBC
A phase 1b trial reported by Rita Nanda with Pembrolizumab 10 mg/kg IV q2wk in 32 heavily pretreated PD-L1+ (by IHC) TNBC patients. There were 5 responses in the 27 evaluable patients (ORR: 18.5%), with 1 CR. The median duration of response was >40 weeks (in responding patients), and 1.9 mo (in the others). Treatment was well tolerated, one patient with rapidly progressive metastatic disease died of disseminated intravascular coagulation.
2014-12-10
2014-12-09
2014-12-08
ASH 2014 - Lymphoma & Multiple Myeloma
Hodgkin's Lymphoma
Upfront therapy
1. Brentuximab Vedotin instead of Bleomycin in ABVD (both share pulmonary toxicity): 96% 3-yr failure-free survival in advanced-stage Hodgkin's Lymphoma. Phase III studies are under way.
Relapsed / Refractory disease
1. Brentuximab + Bendamustine in preparation to autologous stem-cell transplantation: Small study, outpatient, ORR in the 90% range, and CR in the 80% range.
2. AETHERA trial shows higher 2-yr PFS in patients receiving consolidation with Brentuximab after Stem-Cell Transplantation for Hodgkin's Lymphoma (65% vs 45%), poised to become a new standard-of-care.
3. Nivolumab (anti PD-1 monoclonal antibody) in post-transplant relapse: Hodgkin's lymphoma is an ideal model for immune checkpoint modulation due to high immunocyte infiltration around the tumor cells. There is a Phase 1 study with up to 80% response rate in heavily pretreated patients (including patients previously treated with Brentuximab Vedotin). This is the most exciting result in lymphoma in this ASH 2014 (NEJM On-line first).
Low-grade lymphomas
1. Ibrutinib in follicular lymphoma: Ibrutinib showed only 30% response rate in relapse follicular lymphoma patients (somewhat disappointing). Whereas Idelalisib (PI3k inhibitor) shows 50% response rate with a median PFS of up to a year in chemo & rituximab refractory follicular lymphoma patients (and is FDA approved in that indication).
2. EFS12 as a prognostic marker in follicular lymphoma: A Mayo clinic dataset has shown that patients who have not had an event at 12 months after either initial treatment or observation have a life expectancy similar to age-matched controls. The converse is true, patients that have events within a year will not do well, and require a more aggressive approach.
Diffuse Large B-cell lymphoma (DLBCL)
1. Double-hit DLBCL: Abnormalities in both c-Myc and bcl-2 genes should be looked in high Ki67/proliferative DLCL. Some studies show that DA-EPOCH is effective with PFS in the 60% at 1-year.
2. Selenexor (a nuclear trafficking inhibitor): some 40% response rate in relapsed DLBCL, with some CRs, in phase-I trials.
Mantle-Cell lymphoma (MCL)
1. Intensive therapy is still disappointing in MCL: The current theme in MCL is highly aggressive upfront chemotherapy (R-CHOP alternating with DHAP, followed by transplant; R-CHOP followed by Bortezomib; Bortezomib + Rituximab + Bendamustine). All these trials are showing some relapses at the 3-year mark.
2. Chemo-free for MCL with Lenalidomide + Rituximab in 1-st line: Small study (38 patients) with median age of 65: 88% went into remission and 2-yr EFS in 80%.
Multiple Myeloma
Upfront therapy
1. Carfilzomib in 1st-line multiple myeloma patients: An italian trial showed very high response rate in the order of >75% in patients receiving high-dose weekly Carfilzomib + Cyclophosphamide + Dexamethasone.
2. Ixazomib, an oral proteasome inhibitor, + Lenalidomide + Dexamethasone: The all oral combination chemotherapy was well tolerated and exhibited high response rate.
Relapsed / Refractory disease
1. ASPIRE trial (Carfilzomib + Lenalidomide + Dexamethasone): Possibly the most outstanding result of the ASH 2014 (NEJM On-line first). Carfilzomib + Lenalidomide + Dexamethasone increases the PFS by 9 months over Lenalidomide + Dexamethasona in relapsed multiple myeloma patiens (26 months vs 17 months). The benefit was also seen in patients with high-risk cytogenetics. Quality-of-life was also superior in the Carfilzomib-based arm.
2. Oral proteasome inhibitors: Several presentations showed that both Ixazomib and Oprozomib are active in heavily-treated myeloma patients. Specifically, Oprozomib showed a single-agent activity with 30% response-rate in Carfilzomib-refractory patients. A change in formulation to tablet, and the use of antiemetic agents decreased its chemotherapy-induced nausea and vomiting. Still, not ready for prime time.
3. Anti CD38 monoclonal antibodies (MoAbs): CD38 is a surface marker in plasmocytes (and other blood cells). Daratumumab and SAR650984 are MoAbs that have shown activity in myeloma patients. In this ASH it was presented a combination of Daratumumab + Lenalidomide + Dexamethasone in relapsed myeloma patients. No added toxicity was found beyond a few infusion reactions.
4. Histone Deacetylase (HDAC) inhibitors (Panobinostat): Some interesting results with Panobinostat in relapsed/refractory myeloma. Further studies are required, especially to deal with its gastrointestinal toxicity.
5. Ibrutinib: The Bruton Tyrosine Kinase inhibitor, Ibrutinib has exhibited high clinical benefit rate of 50% with a median PFS of 6 months in heavily pre-treated myeloma patients. Another interesting agent that merits further investigation in this condition.
Maintenance
The longer exposure to anti-myeloma agents, the better. Post transplant lenalidomide maintenance is highly effective with responses that occur over several months. Some other trials have shown that Bortezomib maintenance is also highly effective.
Pomalidomide
1. Single-agent pomalidomide in heavily pre-treated myeloma: The newer imid Pomalidomide has shown to be effective as a single-agent, with a response rate of about 35%.
2. Pomalidomide in combination with other agents: In this ASH there are reports that show that Pomalidomide can be safely combined with Bortezomib + Dexamethasone, with Cyclophosphamide + Dexamethasone, also with Liposomal Doxorubicine + Dexamethasone with very good safety profile, and response rate in the range of 60-70%.
3. Safety of Pomalidomide in renal insufficiency: Some data were presented that show that Pomalidomide can be safely administered in pretty much any patient with any degree of renal dysfunction, provided they are not in dialysis.
Upfront therapy
1. Brentuximab Vedotin instead of Bleomycin in ABVD (both share pulmonary toxicity): 96% 3-yr failure-free survival in advanced-stage Hodgkin's Lymphoma. Phase III studies are under way.
Relapsed / Refractory disease
1. Brentuximab + Bendamustine in preparation to autologous stem-cell transplantation: Small study, outpatient, ORR in the 90% range, and CR in the 80% range.
2. AETHERA trial shows higher 2-yr PFS in patients receiving consolidation with Brentuximab after Stem-Cell Transplantation for Hodgkin's Lymphoma (65% vs 45%), poised to become a new standard-of-care.
3. Nivolumab (anti PD-1 monoclonal antibody) in post-transplant relapse: Hodgkin's lymphoma is an ideal model for immune checkpoint modulation due to high immunocyte infiltration around the tumor cells. There is a Phase 1 study with up to 80% response rate in heavily pretreated patients (including patients previously treated with Brentuximab Vedotin). This is the most exciting result in lymphoma in this ASH 2014 (NEJM On-line first).
Low-grade lymphomas
1. Ibrutinib in follicular lymphoma: Ibrutinib showed only 30% response rate in relapse follicular lymphoma patients (somewhat disappointing). Whereas Idelalisib (PI3k inhibitor) shows 50% response rate with a median PFS of up to a year in chemo & rituximab refractory follicular lymphoma patients (and is FDA approved in that indication).
2. EFS12 as a prognostic marker in follicular lymphoma: A Mayo clinic dataset has shown that patients who have not had an event at 12 months after either initial treatment or observation have a life expectancy similar to age-matched controls. The converse is true, patients that have events within a year will not do well, and require a more aggressive approach.
Diffuse Large B-cell lymphoma (DLBCL)
1. Double-hit DLBCL: Abnormalities in both c-Myc and bcl-2 genes should be looked in high Ki67/proliferative DLCL. Some studies show that DA-EPOCH is effective with PFS in the 60% at 1-year.
2. Selenexor (a nuclear trafficking inhibitor): some 40% response rate in relapsed DLBCL, with some CRs, in phase-I trials.
Mantle-Cell lymphoma (MCL)
1. Intensive therapy is still disappointing in MCL: The current theme in MCL is highly aggressive upfront chemotherapy (R-CHOP alternating with DHAP, followed by transplant; R-CHOP followed by Bortezomib; Bortezomib + Rituximab + Bendamustine). All these trials are showing some relapses at the 3-year mark.
2. Chemo-free for MCL with Lenalidomide + Rituximab in 1-st line: Small study (38 patients) with median age of 65: 88% went into remission and 2-yr EFS in 80%.
Multiple Myeloma
Upfront therapy
1. Carfilzomib in 1st-line multiple myeloma patients: An italian trial showed very high response rate in the order of >75% in patients receiving high-dose weekly Carfilzomib + Cyclophosphamide + Dexamethasone.
2. Ixazomib, an oral proteasome inhibitor, + Lenalidomide + Dexamethasone: The all oral combination chemotherapy was well tolerated and exhibited high response rate.
Relapsed / Refractory disease
1. ASPIRE trial (Carfilzomib + Lenalidomide + Dexamethasone): Possibly the most outstanding result of the ASH 2014 (NEJM On-line first). Carfilzomib + Lenalidomide + Dexamethasone increases the PFS by 9 months over Lenalidomide + Dexamethasona in relapsed multiple myeloma patiens (26 months vs 17 months). The benefit was also seen in patients with high-risk cytogenetics. Quality-of-life was also superior in the Carfilzomib-based arm.
2. Oral proteasome inhibitors: Several presentations showed that both Ixazomib and Oprozomib are active in heavily-treated myeloma patients. Specifically, Oprozomib showed a single-agent activity with 30% response-rate in Carfilzomib-refractory patients. A change in formulation to tablet, and the use of antiemetic agents decreased its chemotherapy-induced nausea and vomiting. Still, not ready for prime time.
3. Anti CD38 monoclonal antibodies (MoAbs): CD38 is a surface marker in plasmocytes (and other blood cells). Daratumumab and SAR650984 are MoAbs that have shown activity in myeloma patients. In this ASH it was presented a combination of Daratumumab + Lenalidomide + Dexamethasone in relapsed myeloma patients. No added toxicity was found beyond a few infusion reactions.
4. Histone Deacetylase (HDAC) inhibitors (Panobinostat): Some interesting results with Panobinostat in relapsed/refractory myeloma. Further studies are required, especially to deal with its gastrointestinal toxicity.
5. Ibrutinib: The Bruton Tyrosine Kinase inhibitor, Ibrutinib has exhibited high clinical benefit rate of 50% with a median PFS of 6 months in heavily pre-treated myeloma patients. Another interesting agent that merits further investigation in this condition.
Maintenance
The longer exposure to anti-myeloma agents, the better. Post transplant lenalidomide maintenance is highly effective with responses that occur over several months. Some other trials have shown that Bortezomib maintenance is also highly effective.
Pomalidomide
1. Single-agent pomalidomide in heavily pre-treated myeloma: The newer imid Pomalidomide has shown to be effective as a single-agent, with a response rate of about 35%.
2. Pomalidomide in combination with other agents: In this ASH there are reports that show that Pomalidomide can be safely combined with Bortezomib + Dexamethasone, with Cyclophosphamide + Dexamethasone, also with Liposomal Doxorubicine + Dexamethasone with very good safety profile, and response rate in the range of 60-70%.
3. Safety of Pomalidomide in renal insufficiency: Some data were presented that show that Pomalidomide can be safely administered in pretty much any patient with any degree of renal dysfunction, provided they are not in dialysis.
ASH 2014 - Myeloproliferative neoplasms, Myelodysplasia, Acute lymphocytic leukemia and Acute Myeloid Leukemia
Myelofibrosis
1. From the mutational perspective there are three driver mutations in myelofibrosis: JAK2, MPL and CALR. Nevertheless, there are about 10% of patients that are triple-negative, with worse prognosis. All three mutations activate the JAK2 pathway and respond to JAK2 inhibitors. But, some patients deemed Low-Risk by clinical criteria can move up to High-Risk based on the mutational pattern, therefore transplantations should be offered sooner to them. Several additional passenger mutations have been discovered that reflect clonal evolution and deal mainly with epigenetic phenomena.
2. Currently, there are three new research avenues in myelofibrosis: 1. Addition of another agent to the JAK2 inhibitor: JAK2 inhibitors are good at decreasing inflammation and spleen, but they are not good at improving blood counts. There are studies combining JAK2 inhibitors with PI3k inhibitors, Hedgehog inhibitors, HiDAC inhibitors, Antifibrotic agents. 2. Exploring selective JAK1 inhibitor: it appears that JAK1 inhibitor may provide anti-inflammatory effects, but it is less effective on the splenomegaly. 3. A promising anti-Telomerase agent is under study with some patients achieving complete remission. Will have to see the actual results in this meeting.
Polycythemia vera (PV)
Just 3 days ago, Ruxolitinib was approved by the FDA for 2nd-line therapy in PV in patients resistant or intolerant to Hydrea. (The presenter summarizes what the standard of care of PV is: you treat with phlebotomy, aspirin and probably Hydrea the majority of PV patiens. The goal is to keep the hematocrit below 45% in order to decrease the risk of thrombosis. The actual indication for Hydrea is patient older than 60 or a history of thrombosis). About 25% of patients do not tolerate Hydrea, and they don't do well. Ruxolitinib becomes an option for these patients (it is estimated that about 25.000 patients are going to need it in the US alone). In this ASH there will be a presentation on QoL with Ruxoilitinib, showing a marked improvement in several aspects with Ruxolitinib.
Essential thrombocythemia (ET)
1. ET is the most benign of the myeloproliferative neoplasms, with nearly normal life-expectancy. It can be treated with aspirin, Hydrea or Anagrelide. Ruxolitinib is not as good in ET compared to its results in Myelofibrosis and PV. It affords adequate response in 70-80% High-Risk ET patients; but may cause significant anemia.
2. Pegylated-Interferon (Pegassys) has shown activity in both PV and ET, and appears quite effective in both. In this ASH there is going to be a presentation on the impact of the mutation status and response to pegylated interferon in MPN.
Myelodysplasia (MDS)
1. MDS - Negative results of S117 (Azacytidine vs Azacytidine + Vorinostat vs Azacytidine + Lenalidomide)
Enrolled about 280 patients, no difference in response in the three arms, combination therapy more toxic, more patients came out of the study due to toxicity, some evidence of longer PFS with combination, not powered to detect OS benefit. Does not change practice.
2. Rigosertib not effective in 2nd-Line MDS after hypomethylating agents in a Phase 3 trial
OS increased from 5 to about 8 months, not reaching statistical significance. An oral formulation is still being developed with some encouraging results, but it is not ready for prime-time.
3. New treatment options for Low-Risk (LR) MDS
LR-MDS patients are treated with EPO or Lenalidomide (indicated in del-5q MDS, buy often used "off-label" in other settings). But some patients are refractory to these agents (or have high EPO blood levels predicting a poor response to a pharmacologic EPO formulation).
There are two promising agents in this particular setting, and both share the same mechanism of action as ligand traps to the TGF-Beta receptor superfamily (Sotatercept: an activin type IIA receptor-fusion protein, and ACE-536: a modified activin type IIB receptor-fusion protein). It is known that TGF-Beta mediates anemia and chronic inflammation. Some preliminary results show up to 40% response rate (including transfusion-independence) to Sotatercept, and further results are going to be presented at this ASH with both agents. It is interesting to know that these agents are bone-morphogenetic factors that show promise in osteoporosis, multiple myeloma, thalassemia, and Castleman disease.
Newer agents in Acute Lymphoblastic Leukemia (ALL)
The FDA approved Blinatumumab (CD19-CD3 bi-specific antibody) for refractory and relapsed B-Cell ALL. There are other agents under investigation: a CD-19 conjugated to a toxin, Inotuzumab (CD22 conjugated to ozogamycin), CAR-T-Cells. Inotuzumab also appears very promising and it is now on a Phase III trial.
Acute Myeloid Leukemia (AML)
1. Sorafenib + Anthracycline + Cytarabine in AML: Not quite there.
In the SORAML trial Sorafenib was added to standard induction chemotherapy in AML and was found to increase event-free survival (3-yr EFS 56% vs 38%, with PFS of 21 vs 9 months, in favor of the Sorafenib arm) and relapse-free survival was also superior in the Sorafenib. But no OS advantage was detected (but the study was underpowered to detect it, with only 276 patients). The speaker points out that Sorafenib is used off-label in relapsed FLT3 mutated patients (sometimes in combination with hypomethylating agents) with very good results. Interestingly, the response to sorafenib in the german trial was not restricted to FLT3 mutation+ AML.
2. DH2 inhibitors are promising in IDH2 mutated AML
Isocytrate dehydrogenase-2 (IDH2) is mutated in about 20% of AML. Anti IDH2 agents are clearly EFFECTIVE in this group of patients achieving significant cytoreduction allowing some highly refractory patients to bridge to allo-transplantation.
1. From the mutational perspective there are three driver mutations in myelofibrosis: JAK2, MPL and CALR. Nevertheless, there are about 10% of patients that are triple-negative, with worse prognosis. All three mutations activate the JAK2 pathway and respond to JAK2 inhibitors. But, some patients deemed Low-Risk by clinical criteria can move up to High-Risk based on the mutational pattern, therefore transplantations should be offered sooner to them. Several additional passenger mutations have been discovered that reflect clonal evolution and deal mainly with epigenetic phenomena.
2. Currently, there are three new research avenues in myelofibrosis: 1. Addition of another agent to the JAK2 inhibitor: JAK2 inhibitors are good at decreasing inflammation and spleen, but they are not good at improving blood counts. There are studies combining JAK2 inhibitors with PI3k inhibitors, Hedgehog inhibitors, HiDAC inhibitors, Antifibrotic agents. 2. Exploring selective JAK1 inhibitor: it appears that JAK1 inhibitor may provide anti-inflammatory effects, but it is less effective on the splenomegaly. 3. A promising anti-Telomerase agent is under study with some patients achieving complete remission. Will have to see the actual results in this meeting.
Polycythemia vera (PV)
Just 3 days ago, Ruxolitinib was approved by the FDA for 2nd-line therapy in PV in patients resistant or intolerant to Hydrea. (The presenter summarizes what the standard of care of PV is: you treat with phlebotomy, aspirin and probably Hydrea the majority of PV patiens. The goal is to keep the hematocrit below 45% in order to decrease the risk of thrombosis. The actual indication for Hydrea is patient older than 60 or a history of thrombosis). About 25% of patients do not tolerate Hydrea, and they don't do well. Ruxolitinib becomes an option for these patients (it is estimated that about 25.000 patients are going to need it in the US alone). In this ASH there will be a presentation on QoL with Ruxoilitinib, showing a marked improvement in several aspects with Ruxolitinib.
Essential thrombocythemia (ET)
1. ET is the most benign of the myeloproliferative neoplasms, with nearly normal life-expectancy. It can be treated with aspirin, Hydrea or Anagrelide. Ruxolitinib is not as good in ET compared to its results in Myelofibrosis and PV. It affords adequate response in 70-80% High-Risk ET patients; but may cause significant anemia.
2. Pegylated-Interferon (Pegassys) has shown activity in both PV and ET, and appears quite effective in both. In this ASH there is going to be a presentation on the impact of the mutation status and response to pegylated interferon in MPN.
Myelodysplasia (MDS)
1. MDS - Negative results of S117 (Azacytidine vs Azacytidine + Vorinostat vs Azacytidine + Lenalidomide)
Enrolled about 280 patients, no difference in response in the three arms, combination therapy more toxic, more patients came out of the study due to toxicity, some evidence of longer PFS with combination, not powered to detect OS benefit. Does not change practice.
2. Rigosertib not effective in 2nd-Line MDS after hypomethylating agents in a Phase 3 trial
OS increased from 5 to about 8 months, not reaching statistical significance. An oral formulation is still being developed with some encouraging results, but it is not ready for prime-time.
3. New treatment options for Low-Risk (LR) MDS
LR-MDS patients are treated with EPO or Lenalidomide (indicated in del-5q MDS, buy often used "off-label" in other settings). But some patients are refractory to these agents (or have high EPO blood levels predicting a poor response to a pharmacologic EPO formulation).
There are two promising agents in this particular setting, and both share the same mechanism of action as ligand traps to the TGF-Beta receptor superfamily (Sotatercept: an activin type IIA receptor-fusion protein, and ACE-536: a modified activin type IIB receptor-fusion protein). It is known that TGF-Beta mediates anemia and chronic inflammation. Some preliminary results show up to 40% response rate (including transfusion-independence) to Sotatercept, and further results are going to be presented at this ASH with both agents. It is interesting to know that these agents are bone-morphogenetic factors that show promise in osteoporosis, multiple myeloma, thalassemia, and Castleman disease.
Newer agents in Acute Lymphoblastic Leukemia (ALL)
The FDA approved Blinatumumab (CD19-CD3 bi-specific antibody) for refractory and relapsed B-Cell ALL. There are other agents under investigation: a CD-19 conjugated to a toxin, Inotuzumab (CD22 conjugated to ozogamycin), CAR-T-Cells. Inotuzumab also appears very promising and it is now on a Phase III trial.
Acute Myeloid Leukemia (AML)
1. Sorafenib + Anthracycline + Cytarabine in AML: Not quite there.
In the SORAML trial Sorafenib was added to standard induction chemotherapy in AML and was found to increase event-free survival (3-yr EFS 56% vs 38%, with PFS of 21 vs 9 months, in favor of the Sorafenib arm) and relapse-free survival was also superior in the Sorafenib. But no OS advantage was detected (but the study was underpowered to detect it, with only 276 patients). The speaker points out that Sorafenib is used off-label in relapsed FLT3 mutated patients (sometimes in combination with hypomethylating agents) with very good results. Interestingly, the response to sorafenib in the german trial was not restricted to FLT3 mutation+ AML.
2. DH2 inhibitors are promising in IDH2 mutated AML
Isocytrate dehydrogenase-2 (IDH2) is mutated in about 20% of AML. Anti IDH2 agents are clearly EFFECTIVE in this group of patients achieving significant cytoreduction allowing some highly refractory patients to bridge to allo-transplantation.
2014-12-05
2014-12-04
Avances en Oncología y Hematología oncológica
Podcasts sobre los estudios, avances, descubrimientos y otros aspectos interesantes de la actualidad en hematología oncológica, oncología clínica y biología molecular del cáncer.
2014-12-03
Lecciones de oncología - Día 1
Esta serie de Podcasts son las lecciones impartidas durante la rotación de la Dra. Verónica Posada en el servicio de oncología de la clínica SOMA, en Medellín. Buscan ilustrar la forma como se enfocan los pacientes ya en un entorno asistencial.
Día 1.
Día 1.
2014-11-26
Mire cómo se baila bien un BOLERO
Contexto
Se considera que el 75% de las mujeres con cáncer de mama exhiben receptores hormonales de estrógeno y o progesterona, y en este subgrupo de pacientes la manipulación hormonal ha demostrado ser eficaz tanto en enfermedad temprana como en la avanzada. Estas pacientes se denominan hormonosensibles, pues frecuentemente lo son en los inicios de su enfermedad. La mayoría de las pacientes pierden, sin embargo, esta sensibilidad hormonal con el paso del tiempo. En los esquemas de manejo anteriores se ha seguido una secuencia de varios agentes antihormonales hasta que se establecía que ninguno funcionaba más y se cambiaba a quimioterapia citotóxica. Una de las secuencias más utilizadas en mujeres postmenopáusicas es el inicio de terapia hormonal con un inhibidor de aromatasa no esteroideo (Anastrozol/Letrozol), posteriormente administrar bien sea un inactivador de receptor de estrógeno (Fulvestrant) o un inhibidor de aromatasa esteroideo (Exemestano), seguido por el agente que no se usó en segunda línea al progresar. Los más avezados oncólogos son capaces de encontrar líneas hormonales adicionales como acetato de megestrol, DES, andrógenos, tamoxifén, efectos de retiro, etc. Sin embargo, la mayoría de nosotros encontramos que cuando estamos considerando alguna de estas últimas maniobras mencionadas realmente estamos en apuros. Entre otras cosas, porque casi nunca funcionan. Y es que la probabilidad de control de la enfermedad disminuye en forma sustancial con cada línea, así: la probabilidad de beneficio clínico (respuesta completa + respuesta parcial + enfermedad estable por 6 meses) en primera línea es de aproximadamente 60-80%, baja a 30% en segunda línea, baja a 15% en tercera línea, y es anecdótica de allí en adelante. Este escenario de retornos cada vez menores a terapias hormonales subsecuentes es la manifestación clínica del desarrollo de resistencia hormonal. Desde el punto de vista biológico, la resistencia hormonal puede explicarse por la activación de mecanismos de escape de las células tumorales por las que estas células contrarrestan los estímulos antiproliferativos de los tratamientos hormonales. La activación de la vía de la PI3k en pacientes con deprivación prolongada de estrógenos es el mecanismo de escape más bien caracterizado en estudios preclínicos. Como conclusión inmediata se propuso la investigación de terapia anti PI3k como estrategia de resensibilización hormonal. De nuevo, los estudios preclínicos mostraron resultados alentadores. Vamos, brevemente, a exponer la lógica y los resultados de los estudios que nos permiten explotar este conocimiento.
Hormonoterapia en cáncer de mama metastásico, en dos minutos
Durante las últimas décadas hemos aprendido lo siguiente en cáncer de mama metastásico en mujeres postmenopáusicas que se pueden resumir así: 1. Tanto los inhibidores de aromatasa no esteroideos como los esteroideos son mejores que el tamoxifén, haciendo de éste último un medicamento de interés histórico en primera línea metastásica. 2. Cualquier secuencia de inhibidores de aromatasa no esteroideos seguido por esteroideos, o viceversa, es esencialmente igual desde el punto de vista de los desenlaces relavante. Por razones no claras, casi todos los oncólogos iniciamos con inhibidores de aromatasa no esteroideos. 3. No hay diferencia entre utilizar Exemestano (inhibidor de aromatasa esteroideo) o Fulvestrant (un inactivador de receptor de estrógeno) en pacientes que progresaron a inhibidores de aromatasa no esteroideos. 4. Existe evidencia de que la combinación de Fulvestrant con Anastrozol en primera línea mejora los desenlaces relevantes en pacientes que no habían recibido inhibidores de aromatasa previamente (ie, cáncer de mama metastásica de-novo), esta combinación se ha convertido en una de las opciones preferidas para este grupo de pacientes.
Resensibilización hormonal con inhibidores de mTOR
Pese al beneficio clínico observado con las terapias hormonales secuenciales, podemos decir que todas las pacientes van a progresar por el desarrollo de resistencia. La manifestación más palpable de esta resistencia es la duración del control de la enfermedad cada vez más corto con las líneas subsecuentes. Una forma de contrarrestar esta resistencia hormonal es la inhibición de la vía de la PI3k, que es la vía de escape usual en pacientes. La inhibición de la mTOR que es un componente de la cascada de la PI3k es una diana lógica pues es modulable con los rapálogos como se describe en este mismo blog y que culminan con el BOLERO-2, un importante estudio que demostró que la combinación de Exemestano + Everolimus (un inhibidor del mTOR) incrementaba la supervivencia libre de progresión en pacientes con cáncer de mama previamente tratadas con inhibidores de aromatasa no esteroideos. Se convierte así en un avance clínico notable, así como una corroboración de los principios biológicos en juego para esta neoplasia (resensitización hormonal con inhibición del mTOR - Bolero 2).
Y, cómo se baila bien un BOLERO?
Empecemos respondiendo las siguientes preguntas:
1. Quiénes fueron candidatos a la combinación de Exemestano + Everolimus en el BOLERO-2?
En el BOLERO-2 se incluyeron mujeres con cáncer de mama postmenopáusicas, con positividad para receptores hormonales, y que habían progresado a tratamiento en el que tenían que haber recibido previamente inhibidores de aromatasa no esteroideos. Se incluyeron pacientes con desempeño ECOG 0, 1 o 2.
2. Quiénes fueron excluidos del BOLERO-2?
Pacientes con desempeño ECOG 3 y 4; pacientes con metástasis cerebrales; disfunción de órganos o hematológica; pacientes que recibieron inhibidores de aromatasa no esteroideos adyuvantes y con progresión después de un año de terminados; así como pacientes que habían recibido Exemestano o inhibidores de mTOR. También se excluyeron pacientes Her2+, o que habían recibido más de una línea de tratamiento con quimioterapia para enfermedad metastásica.
3. Después de los resultados del BOLERO-2 hay algún subgrupo adicional que debería ser excluido de la combinación Exemestano + Everolimus?
Considero, y es tan sólo mi opinión, que aquellas pacientes que tienen una crisis visceral grave que requieran de una disminución sustancial y rápida de la carga tumoral no son las mejores candidatas para la combinación Everolimus + Exemestano pues la tasa de respuesta fue de aproximadamente 10%. Otro grupo al que le tengo respeto con el uso del Everolimus es pacientes con disfunción pulmonar (fibrosis pulmonar o EPOC dependientes de oxígeno) puesto que una de las toxicidades de este agente (y otros inhibidores del mTOR) son pneumonitis.
4. Por qué no utilizar la combinación de inhibidor de mTOR y agentes hormonales en primera línea?
Se hicieron estudios iniciales combinando Letrozol con Temsirolimus en primera línea, incluyendo un estudio grande que fue suspendido por futilidad. No debería sorprender este resultado si la activación de la vía PI3k es la resultante de un estado de deprivación hormonal prolongado que no se da cuando se utiliza en primera línea.
6. Si ya la paciente recibió Exemestano (ie, en adyuvancia), se puede utilizar otro agente hormonal como Tamoxifén o Fulvestrant?
Ya no es BOLERO, es salsa. María Elvira nos va a responder eso.
Se considera que el 75% de las mujeres con cáncer de mama exhiben receptores hormonales de estrógeno y o progesterona, y en este subgrupo de pacientes la manipulación hormonal ha demostrado ser eficaz tanto en enfermedad temprana como en la avanzada. Estas pacientes se denominan hormonosensibles, pues frecuentemente lo son en los inicios de su enfermedad. La mayoría de las pacientes pierden, sin embargo, esta sensibilidad hormonal con el paso del tiempo. En los esquemas de manejo anteriores se ha seguido una secuencia de varios agentes antihormonales hasta que se establecía que ninguno funcionaba más y se cambiaba a quimioterapia citotóxica. Una de las secuencias más utilizadas en mujeres postmenopáusicas es el inicio de terapia hormonal con un inhibidor de aromatasa no esteroideo (Anastrozol/Letrozol), posteriormente administrar bien sea un inactivador de receptor de estrógeno (Fulvestrant) o un inhibidor de aromatasa esteroideo (Exemestano), seguido por el agente que no se usó en segunda línea al progresar. Los más avezados oncólogos son capaces de encontrar líneas hormonales adicionales como acetato de megestrol, DES, andrógenos, tamoxifén, efectos de retiro, etc. Sin embargo, la mayoría de nosotros encontramos que cuando estamos considerando alguna de estas últimas maniobras mencionadas realmente estamos en apuros. Entre otras cosas, porque casi nunca funcionan. Y es que la probabilidad de control de la enfermedad disminuye en forma sustancial con cada línea, así: la probabilidad de beneficio clínico (respuesta completa + respuesta parcial + enfermedad estable por 6 meses) en primera línea es de aproximadamente 60-80%, baja a 30% en segunda línea, baja a 15% en tercera línea, y es anecdótica de allí en adelante. Este escenario de retornos cada vez menores a terapias hormonales subsecuentes es la manifestación clínica del desarrollo de resistencia hormonal. Desde el punto de vista biológico, la resistencia hormonal puede explicarse por la activación de mecanismos de escape de las células tumorales por las que estas células contrarrestan los estímulos antiproliferativos de los tratamientos hormonales. La activación de la vía de la PI3k en pacientes con deprivación prolongada de estrógenos es el mecanismo de escape más bien caracterizado en estudios preclínicos. Como conclusión inmediata se propuso la investigación de terapia anti PI3k como estrategia de resensibilización hormonal. De nuevo, los estudios preclínicos mostraron resultados alentadores. Vamos, brevemente, a exponer la lógica y los resultados de los estudios que nos permiten explotar este conocimiento.
Hormonoterapia en cáncer de mama metastásico, en dos minutos
Durante las últimas décadas hemos aprendido lo siguiente en cáncer de mama metastásico en mujeres postmenopáusicas que se pueden resumir así: 1. Tanto los inhibidores de aromatasa no esteroideos como los esteroideos son mejores que el tamoxifén, haciendo de éste último un medicamento de interés histórico en primera línea metastásica. 2. Cualquier secuencia de inhibidores de aromatasa no esteroideos seguido por esteroideos, o viceversa, es esencialmente igual desde el punto de vista de los desenlaces relavante. Por razones no claras, casi todos los oncólogos iniciamos con inhibidores de aromatasa no esteroideos. 3. No hay diferencia entre utilizar Exemestano (inhibidor de aromatasa esteroideo) o Fulvestrant (un inactivador de receptor de estrógeno) en pacientes que progresaron a inhibidores de aromatasa no esteroideos. 4. Existe evidencia de que la combinación de Fulvestrant con Anastrozol en primera línea mejora los desenlaces relevantes en pacientes que no habían recibido inhibidores de aromatasa previamente (ie, cáncer de mama metastásica de-novo), esta combinación se ha convertido en una de las opciones preferidas para este grupo de pacientes.
Resensibilización hormonal con inhibidores de mTOR
Pese al beneficio clínico observado con las terapias hormonales secuenciales, podemos decir que todas las pacientes van a progresar por el desarrollo de resistencia. La manifestación más palpable de esta resistencia es la duración del control de la enfermedad cada vez más corto con las líneas subsecuentes. Una forma de contrarrestar esta resistencia hormonal es la inhibición de la vía de la PI3k, que es la vía de escape usual en pacientes. La inhibición de la mTOR que es un componente de la cascada de la PI3k es una diana lógica pues es modulable con los rapálogos como se describe en este mismo blog y que culminan con el BOLERO-2, un importante estudio que demostró que la combinación de Exemestano + Everolimus (un inhibidor del mTOR) incrementaba la supervivencia libre de progresión en pacientes con cáncer de mama previamente tratadas con inhibidores de aromatasa no esteroideos. Se convierte así en un avance clínico notable, así como una corroboración de los principios biológicos en juego para esta neoplasia (resensitización hormonal con inhibición del mTOR - Bolero 2).
Y, cómo se baila bien un BOLERO?
Empecemos respondiendo las siguientes preguntas:
1. Quiénes fueron candidatos a la combinación de Exemestano + Everolimus en el BOLERO-2?
En el BOLERO-2 se incluyeron mujeres con cáncer de mama postmenopáusicas, con positividad para receptores hormonales, y que habían progresado a tratamiento en el que tenían que haber recibido previamente inhibidores de aromatasa no esteroideos. Se incluyeron pacientes con desempeño ECOG 0, 1 o 2.
2. Quiénes fueron excluidos del BOLERO-2?
Pacientes con desempeño ECOG 3 y 4; pacientes con metástasis cerebrales; disfunción de órganos o hematológica; pacientes que recibieron inhibidores de aromatasa no esteroideos adyuvantes y con progresión después de un año de terminados; así como pacientes que habían recibido Exemestano o inhibidores de mTOR. También se excluyeron pacientes Her2+, o que habían recibido más de una línea de tratamiento con quimioterapia para enfermedad metastásica.
3. Después de los resultados del BOLERO-2 hay algún subgrupo adicional que debería ser excluido de la combinación Exemestano + Everolimus?
Considero, y es tan sólo mi opinión, que aquellas pacientes que tienen una crisis visceral grave que requieran de una disminución sustancial y rápida de la carga tumoral no son las mejores candidatas para la combinación Everolimus + Exemestano pues la tasa de respuesta fue de aproximadamente 10%. Otro grupo al que le tengo respeto con el uso del Everolimus es pacientes con disfunción pulmonar (fibrosis pulmonar o EPOC dependientes de oxígeno) puesto que una de las toxicidades de este agente (y otros inhibidores del mTOR) son pneumonitis.
4. Por qué no utilizar la combinación de inhibidor de mTOR y agentes hormonales en primera línea?
Se hicieron estudios iniciales combinando Letrozol con Temsirolimus en primera línea, incluyendo un estudio grande que fue suspendido por futilidad. No debería sorprender este resultado si la activación de la vía PI3k es la resultante de un estado de deprivación hormonal prolongado que no se da cuando se utiliza en primera línea.
6. Si ya la paciente recibió Exemestano (ie, en adyuvancia), se puede utilizar otro agente hormonal como Tamoxifén o Fulvestrant?
Ya no es BOLERO, es salsa. María Elvira nos va a responder eso.
Interpretando la biología tumoral a través de la IHQ en cáncer de mama: contras
El cáncer de mama es un grupo de enfermedades que se parecen entre sí morfológicamente pero tienen marcadas diferencias en su biología, factores pronósticos, predictivos, así como en su tratamiento. Brevemente, se reconocen por su expresión de perfiles de transcripción los subtipos Luminal A, Luminal B, Her2, Basal-like, Claudin-Low, y Normal-Like (31%, 20%, 17%, 15%, 10% y 7%, respectivamente)(1). Infortunadamente, la clasificación molecular del cáncer de mama no ha sido adoptada en la práctica diaria. Como sucedáneo usamos la inmunohistoquímica (IHQ).
Clasificación por inmunohistoquímica del cáncer de mama
Por IHQ podemos evaluar los receptores hormonales de estrógeno (ER), progesterona (PR), Her2 y Ki 67. En algunos lugares miden también CK5/6 y Her1. Basados en IHQ llamamos tumores luminales A a aquellos que tienen receptores hormonales positivos (ER+ o PR+, en cualquier combinación), Her2- y baja proliferación. Empezamos a tener problemas con la definición de Luminales B, pues algunos autores incluyen en este grupo pacientes con RH+ y Her2+ (1), otras autoridades incluyen además los ER+/Her2- con PR- (o pobre)(2); otros incluyen sólo a los RH+/Her2- y Ki67 >14%. Desde el punto de vista de la IHQ, los Her2+ pueden ser Luminales B, como ya vimos, o Her2 propiamente (si tienen son RH-). Se denominan triple negativos cuando tanto ER, PR y Her2 son negativos
Limitaciones de la IHQ para la clasificación del cáncer de mama
1. Pobre correspondencia entre la clasificación molecular y la obtenida por inmunohistoquímica (figura 1).
Clasificación por inmunohistoquímica del cáncer de mama
Por IHQ podemos evaluar los receptores hormonales de estrógeno (ER), progesterona (PR), Her2 y Ki 67. En algunos lugares miden también CK5/6 y Her1. Basados en IHQ llamamos tumores luminales A a aquellos que tienen receptores hormonales positivos (ER+ o PR+, en cualquier combinación), Her2- y baja proliferación. Empezamos a tener problemas con la definición de Luminales B, pues algunos autores incluyen en este grupo pacientes con RH+ y Her2+ (1), otras autoridades incluyen además los ER+/Her2- con PR- (o pobre)(2); otros incluyen sólo a los RH+/Her2- y Ki67 >14%. Desde el punto de vista de la IHQ, los Her2+ pueden ser Luminales B, como ya vimos, o Her2 propiamente (si tienen son RH-). Se denominan triple negativos cuando tanto ER, PR y Her2 son negativos
Limitaciones de la IHQ para la clasificación del cáncer de mama
1. Pobre correspondencia entre la clasificación molecular y la obtenida por inmunohistoquímica (figura 1).
Figura 1. Correspondencia entre la clasificación molecular y por inmunohistoquímica en cáncer de mama (tomado de 1).
2. Imposibilidad por IHQ para caracterizar confiablemente los tumores triple negativos. Creemos saber que en ese subgrupo están los Basal-like, los Claudin-Low y los Normal-Like. Los Basal-like exhiben marcadores de citokeratinas 5 y 6, así como EGFR que pueden ser evaluados por IHQ, pero ello no se hace rutinariamente. No hay manera de establecer por IHQ si un cáncer de mama triple negativo es Claudin-low o Normal-like.
3. No uniformidad en la definición de qué es POSITIVO y NEGATIVO para marcadores fundamentales como ER o PR. Por ejemplo, en los Estados Unidos se considera que 1% de marcación para ER es positivo (3). En Francia, el punto de corte es 10% (Fabrice André, comunicación personal). Otro ejemplo, es la definición de PR pobre como por debajo de 20% por Prat, et al, que sirvió como base para una redefinición de Luminal B utilizando este criterio.
4. Cómo interpretar la combinación ER+/PR- o PR-/ER+. Existen dudas de cómo interpretar las discordancias que se suscitan cuando uno de los receptores hormonales es positivo y el otro es negativo. La mayoría de los autores consideran que se trata de un problema de tipo técnico y que si uno es positivo, el otro lo es también (1).
5. Discordancia entre el estado del receptor de progesterona por IHQ y por RT-qPCR. De hasta 14.7% (5)
6. Inhabilidad de la IHQ para establecer el estado Her2 en el grupo indeterminado (2+). Tanto es así, que se requiere de FISH para adjudicar si hay amplificación, o no del Her2. De pronto, sería mejor hacerle FISH a todos de una vez, y no perder el tiempo con la IHQ.
7. Extrema variabilidad inter-observador para establecer el Ki 67. El índice de proliferación Ki 67 es utilizado para clasificar los pacientes en los diferentes subtipos de cáncer de mama. En particular, las pacientes con tumores RH+. Sin embargo, no hay concordancia entre varios observadores, ni en lo observado en distintas áreas del mismo tumor. Por tal razón, se ha llegado a concluir que este marcador no tiene la suficiente robustez para ser incorporado en forma confiable dentro de la clasificación de los cánceres de mama (3).
8. Inhabilidad para establecer cánceres de mama causados por deficiencia de BRCA1 / BRCA2. Sabemos que los cánceres de mama por mutaciones de los genes BRCA1 y BRCA2 están típicamente en el grupo triple negativo, pero no todos los triple negativos son deficientes en BRCA1/2 (ni siquiera la mayoría). La exquisita sensibilidad a la letalidad sintética con inhibidores de la PARP1 o derivados de platino hacen deseable la identificación de este subgrupo de pacientes (además de otras consideraciones como mastectomía y ooforectomía profilácticas). Sólo la detección de las mutaciones BRCA1/2 por secuenciación de la línea germinal permiten establecer, hoy en día, qué pacientes tienen esta condición. La inmunohistoquímica NO ofrece ninguna clave para la detección de este subgrupo de pacientes. Esto ha tenido impacto nefasto en la investigación clínica pues grandes estudios se han visto malogrados porque se utilizó el estado triple negativo para definir tratamiento, cuando la eficacia del mismo se circunscribía tan sólo a los deficientes de BRCA1/2.
Conclusión
La inmunohistoquímica como estrategia para interpretar la biología tumoral del cáncer de mama es imprecisa y errática. Sus limitaciones propician un número desafortunadamente alto de errores con impacto clínico potencial. Su única cualidad es que es barata, definida esta desde una perspectiva bastante miope.
Referencias
1. Rivenbark AG1, O'Connor SM, Coleman WB. Molecular and
cellular heterogeneity in breast cancer: challenges for personalized medicine. Am
J Pathol. 2013 Oct;183(4):1113-24.
2. Goldhirsch A1, Winer EP, Coates AS, Gelber RD,
Piccart-Gebhart M, Thürlimann B, Senn HJ; Panel members. Personalizing the
treatment of women with early breast cancer: highlights of the St Gallen
International Expert Consensus on the Primary Therapy of Early Breast Cancer
2013. Ann Oncol. 2013 Sep;24(9):2206-23.
3. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25(33):5287–5312.
3. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25(33):5287–5312.
4. Prat A, Cheang MC, Martín M, Parker JS, Carrasco E,
Caballero R, Tyldesley S, Gelmon K, Bernard PS, Nielsen TO, Perou CM. Prognostic
significance of progesterone receptor-positive tumor cells within
immunohistochemically defined luminal A breast cancer. J Clin Oncol. 2013 Jan
10;31(2):203-9.
5. Khoury T, Yan L, Liu S, Bshara W. Oncotype DX RT-qPCR Assay
for ER and PR Correlation With IHC: A Study of 3 Different Clones. Appl
Immunohistochem Mol Morphol. 2014 Jul 2. [Epub ahead of print]
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