Breast Cancer Treatment: A Review
Breast Cancer Treatment: A Review. (2019). Waks A, Wilner E. JAMA.
Overview:
- breast cancer will be diagnosed in 12% of women in the US over their lifetimes
- 3 major subtypes based on molecular markers (ER, PR, and HER2).
- more than 90% of breast cancers not metastatic at time of diagnosis
- if no mets, tx goals is tumor eradication and prevent recurrence
- local therapy for nonmetastatic cancer = surgical resection. mastectomy vs lumpectomy + radiation
- median OS for metastatic triple negative is ~1 yr, vs 5 yrs for other subtypes
Her2 = human epidermal growth factor 2, renamed as ERBB2.
----
Prevelance/Prognosis/Tx For 3 Breast Cancer Subtypes Overview
1. HR+ / ERBB2-
- >1% of tumors stain + or ER or PR proteins. Estrogen receptor A activates oncogenic growth patterns
- 70% of breast cancers. >99% are stage 1 with 5 y breast cancer specific survival
- metastatic median OS = 4-5 yrs
Treatment:
- endocrine therapy (all patients) = tamoxifen, letrozole, anastrozole, or exemestane. PO tx, 5-10 yrs
- chemo (some pts): Adriamycin/Cyclophosphamide (AC); Adriamycin/CYC/paclitaxel (AC-T); Docetaxel/CYC (TC); IV tx. 12-20 weeks
2. ERBB2+ (HR+ or HR-)
- tumor cells stain strongly 3+ for ERBB2 protein, or ERBB 2 gene is amplified in tumor cells. About 50% of these are HR+
- ERBB2 = oncogene; encodes ERBB2-R TK from EGFR family and is overactive
- ~15-20% of all breast cancer cases.
- Stage 1 - 5 yr specific survival >94%. If metastatic, then median OS is 5 yr
Treatment:
- chemo + ERBB2 targeted tx (all patients): paclitaxel/trastuzumab (TH); Adriamycin/CYC/paclitaxel/trastuzumab +/- pertuzumab (AC-TH+/-P); Docetaxel/carboplatin/trastuzumab +/- pertuzumab (TCH =+/-P) = IV tx, 12-20 weeks of chemo and 1 yr of ERBB-2 targeted tx
- endocrine tx (if HR+) = tamox, letrozole, anastrozole, exemestane = PO tx, 5-10 yr
3. Triple negative.
- 15% of breast cancer cases.
- stage 1 = 5 yr specific survival >85%; if metastatic, then median OS is only 10-13 months
Treatment:
- Chemo (all patients): AC, AC-T, TC = IV tx, 12-20 weeks.
Clinical Presentation/ Diagnosis/ Pathophys
- >50% diagnosed by screening mammo, about 1/3 dx by palpable breast mass.
- most common histology is invasive ductal carcinoma (50-75%), then invasive lobar carcinoma.
- ER is expressed in 70% of invasive BC. ER is a steroid hormone recetpro.
- ERBB2 = Her2/new = Her2 = epidermal growth factor 2 = transmembrane receptor tyrosine kinase. Associated with poor prognosis
- triple negative breast cancer is 15% of all rbeast cancers. HIgh risk of relapse in 3-5 yrs after dx. RF of triple neg = younger, black, Hispanic
Principles of Therapy
1. eradicate tumor from breast/lymph nodes and
2. prevent metastatic recurrence
Systemic Tx for Nonmetastatic Breast Cancer
1. HR+/ERBB2-
- PO antiestrogen qd for 5 yrs. Drug depends on menopausal status
- 5 yrs tamoxifen for HR+ breast cancer reduces recurrence by 50% of original 5 yr recurrence risk
- Aromatase inhibitor seems more effective than tamoxifen. Can also try a "switch" strategy of 2-3 yrs of tam then AI after for total 5 yrs = 5 yrs of AI use.
- if premenopausal, 1st decision is ovarian suppresion (gonadotropin releasing hormone agonists like leuprolide or oophorectomy). And 2nd decision, if yes, then tx with tam or AI.
> small but significant improvement in ovarian suppress +tam vs just tam in OS. Suppression + AI NOT associated with better OS compared with suppression + tam, but does improve distant recurrence. So if high risk pt, then ovarian suppression is indicated + tam or AI.
- comparison of 5 vs 10 yrs for tam shows small but sig improvement in breast cancer mortality, but higher rate of endometrial cancer and VTE
- comparison of 5 vs 10 yrs of AI shows no diff in OS and worse osteoporosis and fractures.
- chemo in these patients is clinician based and usually looks at 21 gene recurrence and 70 gene assay to guide decision for adjuvant chemo.
Chemo for ERBB2-
- choose a lower toxicity regimen for lower risk pts with smaller chemo benefits.
- AT or AC+T is best choice.
- A is a great choice for high lymph node involvement
2. Triple Negative
- chemo for all if tumor >5 mm
- adding platinum is uncertain at this time, but seems to help with pCR, not disease free survivial
- for neoadjuvant chemo, pCR is highly favorable prognostic biomarker
- only evidence based adjuvant escalation is single agent capecitabine
3. ERBB2+
- 1 yr of trastuzumab is awesome. 1 > 2 yrs
- Adding chemo is either AC-T or docetaxel/carboplatin
- for small node negative ERBB2+, standard of care is single agent taxol + herceptin
- for high risk, can also use pertuzumab and neratinib
Local therapy for nonmetastatic breast cancer
Surgery:
- = total mastectomy or lumpectomy + radiation
- CI to conservative sx = 1. diffuse suspicious microcalcifications, 2. + path margins after lumpectomy, 3. dz that can't be excised in one area, 4. collagen-vascular dz like scleroderma, and 5. prior radiation to the breast
- axillary lymph node dissection is less necessary these days. Seems SLN bx alone is sufficent axillary tx, and may just add axillary radiation in select pts
Radiation:
- to whole or portion of breast, chest wall, and regional lymph nodes
- historic dose is 50 Gy over 25 fractions. But now hypofractionated schedule is just as effective. 42.5 Gy over 16 fractions.
- regional nodal radiation after sx is associated with sig improved DFS, no OS, increased in radiation toxicity. So bc of lack of OS benefit, consider for pts with higher nodal disease burden or high risk biology
Systemic tx for Metastatic Breast Cancer
1. HR+/ ERBB2-
- initial tx: AI + CDK4/6 inhib - MPFS 24.8 mo, overall response rate 53-59%
- later lines tx: hormonal and targeted tx: (fulvestrant + everolimus / exemestane + everolimus / tamoxifen / abemaciclib / olaparib or talazoparib if BRCA)
2. ERBB2+
- initial: taxane + trastuzumab + pertuzumab, can get endocrine tx if HR+, also with ado-trastuzumab emtansine
- later lines: trastuzumab + chemo / trastuzumab + endocrine tx / lapantinib + capectiabine
- note: brain mets are common in ERBB2+
3. triple negative
- initial: single agent chemo (taxane, platinum, anthracycline)
- later lines: single agent chemo (capecitabine, eribulin, vinorebine, gemcitabine, olaparib or talazoparib if BRCA)
general principles:
- single agent in metastatic breast cancer > combination chemo with less toxicity and better QOL
- if HR+, use endocrine tx and CDK4/6 inhib, then move on to chemo
Genomics in breast cancer:
- BRCA1/2 only DNA alterations with associated targeted tx. About 5% of breast cancer have germline mutations here
- PARP inhibitor (olaparib and talazoparib) is FDA approved for refractory metastatic BC with BRCA mutations
- other interesting mutations include some in ERBB2 and ER gene ESR1, but still in clinical trials. ERBB2 mutations has possible sensitivity to neratinib, ESR1 mutations seems to have resistance to aromatase inhibitors.
Disparities
- of note, black Americans have a 41% higher mortality rate than white - seems associated with uninsured, SES, etc.
----
Chemo Notes (with some additional info from outside source)
Hormone therapy:
- SERM: For pre and post menopausal women.
1. tamoxifen. Approved for 5-10 years. Also increases risk for endometrial cancer and VTE. AE: hot flashes,
2. raloxifene: STAR trial (2006). States it has 76% effectiveness as tam, but also 45% less uterine cancer and 25% less blood clots
- Aromatase inhibitors: only for post-menopausal women! unless premenopausal + ovarian suppression. Inhibit conversion of androgen to estrogen. AE: hot flashes, arthralgias/myalgias, osteoporosis bone fx
1. Letrozole (Femara)
2. Anastrozole (Arimidex) - ATAC trial
3. Exemestane (Aromasin). Can be combined with everolimus for HR+/ERBB2-
Chemo
- doxorubicin (adriamycin) - AE: cardiotoxicity with dilated cardiomyopathy -> CHF; it is cumulative dose risk; also SE is typhlitis, palmar plantar erythrodysesthesia (PPE), reactivation of hep B. MOA: inhibits topoisomerase II progression (interferes with DNA transcription).
- cyclophosphamide (CP or CYC) - alkylating agent, nitrogen mustard family. SE: bone marrow suppression, hemorrhagic cystitis, n/v. With high doses, SIADH and cardiotoxicity. Teratogenic. MOA: main metabolite is phosphoramide mustard, which interferes with DNA duplication/ creation of RNA by irreversibly crosslinking DNA strands at specific positions.
- paclitaxol (Taxol) - Taxane family. MOA: interferes with microtubule fx during cell division/mitosis. SE: neuropathy, n/v
[NOTE: albumin-bound paclitaxel = Abraxane]
- Docetaxel (Taxotere) - taxane family. Similar to paclitaxol, but maybe slightly more side effects. Main difference is solution that these two are dissolved in (taxol = castor oil and etoh, taxotere = polysorbate and etoh).
- trastuzamab (Herceptin) - monoclonal Ab that binds to HER2-R. Tx for up to 1 year. AE: reversible cardiotoxicity, including CHF. Needs regular echo. HER-R are proteins (HER2 is a tyrosine kinase receptor) in cell membrane and communicate with EGFs to turn cell on/off and assoc with stimulation of cell proliferation. FISH is gold standard to identify pt that benefit from herceptin.
- pertuzumab (Perjeta) - monoclonal Ab used in metastatic Her2+ breast cancer with herceptin and docetaxel. first-in-class "HER dimerization inhibitor". inhibits dimerization of HER2 with other Her-R, prevents normal signaling. AE: neutropenia, diarrhea, loss of RBC. Seems only helpful in node+ and HR- patients, not in node negative and HR+ pts
- neratinib - PO small molecular TK-I of multiple HER family. minor benefit when added to herceptin for ERBB2+ breast cancer. No OS in adjuvant tx. Seems to have disease free survival benefit in HR+ patients
- carboplatin (Paraplatin) - platinum based antineoplastic med - interferes with DNA duplication. Reduced SE compared to cisplatin. AE: myelosuppressive effect and neutropenia
Overview:
- breast cancer will be diagnosed in 12% of women in the US over their lifetimes
- 3 major subtypes based on molecular markers (ER, PR, and HER2).
- more than 90% of breast cancers not metastatic at time of diagnosis
- if no mets, tx goals is tumor eradication and prevent recurrence
- local therapy for nonmetastatic cancer = surgical resection. mastectomy vs lumpectomy + radiation
- median OS for metastatic triple negative is ~1 yr, vs 5 yrs for other subtypes
Her2 = human epidermal growth factor 2, renamed as ERBB2.
----
Prevelance/Prognosis/Tx For 3 Breast Cancer Subtypes Overview
1. HR+ / ERBB2-
- >1% of tumors stain + or ER or PR proteins. Estrogen receptor A activates oncogenic growth patterns
- 70% of breast cancers. >99% are stage 1 with 5 y breast cancer specific survival
- metastatic median OS = 4-5 yrs
Treatment:
- endocrine therapy (all patients) = tamoxifen, letrozole, anastrozole, or exemestane. PO tx, 5-10 yrs
- chemo (some pts): Adriamycin/Cyclophosphamide (AC); Adriamycin/CYC/paclitaxel (AC-T); Docetaxel/CYC (TC); IV tx. 12-20 weeks
2. ERBB2+ (HR+ or HR-)
- tumor cells stain strongly 3+ for ERBB2 protein, or ERBB 2 gene is amplified in tumor cells. About 50% of these are HR+
- ERBB2 = oncogene; encodes ERBB2-R TK from EGFR family and is overactive
- ~15-20% of all breast cancer cases.
- Stage 1 - 5 yr specific survival >94%. If metastatic, then median OS is 5 yr
Treatment:
- chemo + ERBB2 targeted tx (all patients): paclitaxel/trastuzumab (TH); Adriamycin/CYC/paclitaxel/trastuzumab +/- pertuzumab (AC-TH+/-P); Docetaxel/carboplatin/trastuzumab +/- pertuzumab (TCH =+/-P) = IV tx, 12-20 weeks of chemo and 1 yr of ERBB-2 targeted tx
- endocrine tx (if HR+) = tamox, letrozole, anastrozole, exemestane = PO tx, 5-10 yr
3. Triple negative.
- 15% of breast cancer cases.
- stage 1 = 5 yr specific survival >85%; if metastatic, then median OS is only 10-13 months
Treatment:
- Chemo (all patients): AC, AC-T, TC = IV tx, 12-20 weeks.
Clinical Presentation/ Diagnosis/ Pathophys
- >50% diagnosed by screening mammo, about 1/3 dx by palpable breast mass.
- most common histology is invasive ductal carcinoma (50-75%), then invasive lobar carcinoma.
- ER is expressed in 70% of invasive BC. ER is a steroid hormone recetpro.
- ERBB2 = Her2/new = Her2 = epidermal growth factor 2 = transmembrane receptor tyrosine kinase. Associated with poor prognosis
- triple negative breast cancer is 15% of all rbeast cancers. HIgh risk of relapse in 3-5 yrs after dx. RF of triple neg = younger, black, Hispanic
Principles of Therapy
1. eradicate tumor from breast/lymph nodes and
2. prevent metastatic recurrence
Systemic Tx for Nonmetastatic Breast Cancer
1. HR+/ERBB2-
- PO antiestrogen qd for 5 yrs. Drug depends on menopausal status
- 5 yrs tamoxifen for HR+ breast cancer reduces recurrence by 50% of original 5 yr recurrence risk
- Aromatase inhibitor seems more effective than tamoxifen. Can also try a "switch" strategy of 2-3 yrs of tam then AI after for total 5 yrs = 5 yrs of AI use.
- if premenopausal, 1st decision is ovarian suppresion (gonadotropin releasing hormone agonists like leuprolide or oophorectomy). And 2nd decision, if yes, then tx with tam or AI.
> small but significant improvement in ovarian suppress +tam vs just tam in OS. Suppression + AI NOT associated with better OS compared with suppression + tam, but does improve distant recurrence. So if high risk pt, then ovarian suppression is indicated + tam or AI.
- comparison of 5 vs 10 yrs for tam shows small but sig improvement in breast cancer mortality, but higher rate of endometrial cancer and VTE
- comparison of 5 vs 10 yrs of AI shows no diff in OS and worse osteoporosis and fractures.
- chemo in these patients is clinician based and usually looks at 21 gene recurrence and 70 gene assay to guide decision for adjuvant chemo.
Chemo for ERBB2-
- choose a lower toxicity regimen for lower risk pts with smaller chemo benefits.
- AT or AC+T is best choice.
- A is a great choice for high lymph node involvement
2. Triple Negative
- chemo for all if tumor >5 mm
- adding platinum is uncertain at this time, but seems to help with pCR, not disease free survivial
- for neoadjuvant chemo, pCR is highly favorable prognostic biomarker
- only evidence based adjuvant escalation is single agent capecitabine
3. ERBB2+
- 1 yr of trastuzumab is awesome. 1 > 2 yrs
- Adding chemo is either AC-T or docetaxel/carboplatin
- for small node negative ERBB2+, standard of care is single agent taxol + herceptin
- for high risk, can also use pertuzumab and neratinib
Local therapy for nonmetastatic breast cancer
Surgery:
- = total mastectomy or lumpectomy + radiation
- CI to conservative sx = 1. diffuse suspicious microcalcifications, 2. + path margins after lumpectomy, 3. dz that can't be excised in one area, 4. collagen-vascular dz like scleroderma, and 5. prior radiation to the breast
- axillary lymph node dissection is less necessary these days. Seems SLN bx alone is sufficent axillary tx, and may just add axillary radiation in select pts
Radiation:
- to whole or portion of breast, chest wall, and regional lymph nodes
- historic dose is 50 Gy over 25 fractions. But now hypofractionated schedule is just as effective. 42.5 Gy over 16 fractions.
- regional nodal radiation after sx is associated with sig improved DFS, no OS, increased in radiation toxicity. So bc of lack of OS benefit, consider for pts with higher nodal disease burden or high risk biology
Systemic tx for Metastatic Breast Cancer
1. HR+/ ERBB2-
- initial tx: AI + CDK4/6 inhib - MPFS 24.8 mo, overall response rate 53-59%
- later lines tx: hormonal and targeted tx: (fulvestrant + everolimus / exemestane + everolimus / tamoxifen / abemaciclib / olaparib or talazoparib if BRCA)
2. ERBB2+
- initial: taxane + trastuzumab + pertuzumab, can get endocrine tx if HR+, also with ado-trastuzumab emtansine
- later lines: trastuzumab + chemo / trastuzumab + endocrine tx / lapantinib + capectiabine
- note: brain mets are common in ERBB2+
3. triple negative
- initial: single agent chemo (taxane, platinum, anthracycline)
- later lines: single agent chemo (capecitabine, eribulin, vinorebine, gemcitabine, olaparib or talazoparib if BRCA)
general principles:
- single agent in metastatic breast cancer > combination chemo with less toxicity and better QOL
- if HR+, use endocrine tx and CDK4/6 inhib, then move on to chemo
Genomics in breast cancer:
- BRCA1/2 only DNA alterations with associated targeted tx. About 5% of breast cancer have germline mutations here
- PARP inhibitor (olaparib and talazoparib) is FDA approved for refractory metastatic BC with BRCA mutations
- other interesting mutations include some in ERBB2 and ER gene ESR1, but still in clinical trials. ERBB2 mutations has possible sensitivity to neratinib, ESR1 mutations seems to have resistance to aromatase inhibitors.
Disparities
- of note, black Americans have a 41% higher mortality rate than white - seems associated with uninsured, SES, etc.
----
Chemo Notes (with some additional info from outside source)
Hormone therapy:
- SERM: For pre and post menopausal women.
1. tamoxifen. Approved for 5-10 years. Also increases risk for endometrial cancer and VTE. AE: hot flashes,
2. raloxifene: STAR trial (2006). States it has 76% effectiveness as tam, but also 45% less uterine cancer and 25% less blood clots
- Aromatase inhibitors: only for post-menopausal women! unless premenopausal + ovarian suppression. Inhibit conversion of androgen to estrogen. AE: hot flashes, arthralgias/myalgias, osteoporosis bone fx
1. Letrozole (Femara)
2. Anastrozole (Arimidex) - ATAC trial
3. Exemestane (Aromasin). Can be combined with everolimus for HR+/ERBB2-
Chemo
- doxorubicin (adriamycin) - AE: cardiotoxicity with dilated cardiomyopathy -> CHF; it is cumulative dose risk; also SE is typhlitis, palmar plantar erythrodysesthesia (PPE), reactivation of hep B. MOA: inhibits topoisomerase II progression (interferes with DNA transcription).
- cyclophosphamide (CP or CYC) - alkylating agent, nitrogen mustard family. SE: bone marrow suppression, hemorrhagic cystitis, n/v. With high doses, SIADH and cardiotoxicity. Teratogenic. MOA: main metabolite is phosphoramide mustard, which interferes with DNA duplication/ creation of RNA by irreversibly crosslinking DNA strands at specific positions.
- paclitaxol (Taxol) - Taxane family. MOA: interferes with microtubule fx during cell division/mitosis. SE: neuropathy, n/v
[NOTE: albumin-bound paclitaxel = Abraxane]
- Docetaxel (Taxotere) - taxane family. Similar to paclitaxol, but maybe slightly more side effects. Main difference is solution that these two are dissolved in (taxol = castor oil and etoh, taxotere = polysorbate and etoh).
- trastuzamab (Herceptin) - monoclonal Ab that binds to HER2-R. Tx for up to 1 year. AE: reversible cardiotoxicity, including CHF. Needs regular echo. HER-R are proteins (HER2 is a tyrosine kinase receptor) in cell membrane and communicate with EGFs to turn cell on/off and assoc with stimulation of cell proliferation. FISH is gold standard to identify pt that benefit from herceptin.
- pertuzumab (Perjeta) - monoclonal Ab used in metastatic Her2+ breast cancer with herceptin and docetaxel. first-in-class "HER dimerization inhibitor". inhibits dimerization of HER2 with other Her-R, prevents normal signaling. AE: neutropenia, diarrhea, loss of RBC. Seems only helpful in node+ and HR- patients, not in node negative and HR+ pts
- neratinib - PO small molecular TK-I of multiple HER family. minor benefit when added to herceptin for ERBB2+ breast cancer. No OS in adjuvant tx. Seems to have disease free survival benefit in HR+ patients
- carboplatin (Paraplatin) - platinum based antineoplastic med - interferes with DNA duplication. Reduced SE compared to cisplatin. AE: myelosuppressive effect and neutropenia
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