HER 2 +++ Need help about post surgery treatment

Hi Johncrow92:

Sorry to hear of your mother's recent diagnosis. I am not sure I understand her actual diagnosis from what you wrote.

Your Mom should obtain complete copies of the pathology reports from all biopsies and surgeries, and any addenda or supplements which may contain results of ER, PR and HER2 testing of the invasive disease. Taken together, certain findings in these reports and test results determine her diagnosis and the recommended treatment plan. Hopefully, she can share the documents with you.

If DCIS and invasive breast cancer are both present, then the relevant features of each should be separateley specified in the pathology report(s). The features of the invasive breast cancer will generally drive systemic drug treatment decisions.

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DCIS Component:

DCIS is typically tested for estrogen receptor ("ER") and progesterone receptor ("PR") status.

DCIS is not routinely tested for HER2 status.

Surgical margins should be separately indicated for the DCIS and for any invasive breast cancer if present.

As far as the ductal carcinoma in situ or "DCIS", note that DCIS is a form of "non-invasive" breast cancer, meaning that it is confined to the inside of the ducts (i.e., has not broken through the wall of the duct to invade the surrounding breast tissue). Because it is considered "non-invasive", DCIS does not generally pose a risk of metastasis. Therefore, the treatment of DCIS focuses on local treatment, most commonly by lumpectomy plus radiation or mastectomy alone.

With mastectomy, if the surgical margins for the DCIS (shortest distance from DCIS to the edge of the surgical sample) are adequate, then mastectomy alone is typically sufficient to treat the DCIS component.

For an explanation of DCIS versus invasive breast cancer, see this page on the Main Site (keep scrolling down and study the illustrations):

>> DCIS: http://www.breastcancer.org/symptoms/types/dcis/diagnosis

For an explanation of surgical margins, see this page on the Main Site:

>> Surgical Margins: http://www.breastcancer.org/symptoms/diagnosis/margins

Those with hormone-receptor positive (ER+ and/or PR+) DCIS may receive a recommendation for endocrine (anti-hormonal) therapy (e.g., Tamoxifen or an Aromatase Inhibitor). With pure DCIS, the primary purpose of endocrine therapy is to reduce same in-breast recurrence or new contralateral (opposite breast) disease, so endocrine therapy may not be warranted with mastectomy for pure DCIS (although there may be appropriate exceptions).

Pure DCIS (with no evidence of invasion) is never treated with chemotherapy or HER2-targeted therapy under clinical consensus guidelines. However, if a person ALSO has some invasive breast cancer present, then the features of the invasive breast cancer will determine the need for chemotherapy and/or HER2-targeted therapy (for HER2-positive invasive breast cancer) per the below.

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Invasive Breast Cancer:

You noted: "Post surgery raport came with HER-2(+++), Ki 67 between 30-40% with cast(relocation?) of the cancer 2,1mm(0,82 inch) to the 1/5 lymph nodes that are already removed."

Lymph Node Metastasis:

"Cast" and "relocation" are not used by our local pathologists. If by the above you mean that an area of breast cancer that is 2.1 mm in size was found in one of the five lymph nodes removed, then in the USA, the pathologist would consider such a nodal deposit to be a "lymph node metastasis." If the cancer deposit in the lymph node is greater than 2.0 mm in size, it would be considered a lymph node "metastasis" (size-wise) and would mean that she has a form of "node-positive" breast cancer.

If the lymph node was not "clinically detected" (within the meaning of the AJCC staging manual), then such a nodal metastasis would be staged as pN1 disease. Look in her pathology report for a designation such a "pN1", "N1" or "N1a", which would be consistent with this understanding.

>> AJCC Staging Summary (7th Edition): https://cancerstaging.org/references-tools/quickreferences/Documents/BreastMedium.pdf

"pN1" Micrometastases; or metastases in 1–3 axillary lymph nodes; and/or in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected***

"pN1a Metastases in 1–3 axillary lymph nodes, at least one metastasis greater than 2.0 mm"

Please note that despite the confusing terminology, a "metastasis" in an axillary lymph node is a type of "regional" spread. That is NOT the same thing as "distant" metastasis (disseminated or "metastatic disease"). However, such nodal involvement is associated with increased risk of distant recurrence, and can impact recommendations for systemic treatments with chemotherapy, HER2-targeted therapy (for HER2-positive disease) and/or endocrine therapy (for ER+ and/or PR+ disease).

Primary Tumor in the Breast:

The presence of a lymph node metastasis suggests the presence of invasive breast cancer in the breast. However, the info in your post is not clear about whether a primary invasive breast cancer was found or not (no histology or primary tumor size).

Does her pathology report mention finding a primary tumor in the breast? Check the pathology report for mention of "Invasive Ductal Carcinoma" (also referred to as "Infiltrating Ductal Carcinoma" or "IDC", the most common type) or "Invasive Lobular Carcinoma" ("ILC'), or invasive breast cancer with some other type of histology (e.g., Mucinous, Tubular, other).

{{SKIP THIS PARAGRAPH if an invasive tumor was found in the breast. In the relatively rare case that no primary invasive breast tumor can be found in the breast, then that would be "occult" breast cancer (where no primary invasive cancer can be located in the breast)). This may be indicated in a pathology report by the designation "pT0" or "T0"). There is a thread for such relatively rare occult primary tumors with lymph node metastasis here: https://community.breastcancer.org/forum/137/topics/799403?page=4#idx_113). Different guidelines apply for radiation therapy and systemic drug treatment of occult breast cancer.}}

If a primary invasive breast tumor was found in the breast (look for invasive tumor size and a tumor size designation such as "pT1", "pT2" or "pT3"), then the pathology report (or related test reports) should also separately indicate key features of the primary invasive breast cancer:

>> Tumor Histology (e.g., ductal, lobular, etc.)

>> Lymph node status

>> Tumor Size

>> Hormone receptor status (Estrogen Receptor ("ER") status and Progesterone Receptor ("PR") status)

>> HER2 status

The above are key pathologic features that affect recurrence risk, including the risk of distant (metastatic) recurrence. With HER2-positive invasive breast cancer, recommendations for systemic drug treatment(s) depend largely on the factors listed above and the individual's estimated distant recurrence risk.

In addition, the pathology report should include Grade of invasive disease and may note the presence or absence of "lymphovascular invasion" (sometimes referred to as angiolymphatic invasion). Optionally, other markers (e.g., Ki-67 (a marker of proliferation) may be mentioned. The surgical margins with respect to any invasive disease should be noted.

You mentioned HER-2(+++). HER2 status can be determined by immunohistochemistry ("IHC"). Assuming validated IHC methods were used, an IHC HER2 test result of 3+ (+++) is considered HER2 "positive." (Be sure to confirm that it is the invasive breast cancer that is HER2-positive.)

HER2-positive invasive breast cancer is a relatively aggressive form of breast cancer. Node-positive, HER2-positive invasive breast cancer generally warrants chemotherapy plus HERCEPTIN to reduce the risk of suffering distant metastatic recurrence.

Thus, under our local guidelines applicable to early stage breast cancer, invasive breast cancer of ductal, lobular, metaplastic or mixed histology, that is node-positive (one or more metastases >2 mm to one or more ipsilateral axillary lymph nodes), hormone receptor positive (ER+ and/or PR+) and HER2-positive is typically treated with:

>> "Adjuvant chemotherapy [z,aa,dd] with trastuzumab [bb] followed by endocrine therapy [x,y] (category 1)"

(trastuzumab = HERCEPTIN)

The selection of a particular chemotherapy regimen is within the area of expertise of medical oncologists, may be influenced by clinical factors (e.g., age, co-morbidities), and there is some variation between countries. Your Mom should request the names of the actual drugs, regimen details (e.g., dose-dense, number of cycles), and information regarding their side effect profiles.

In the USA, common HERCEPTIN-containing regimens for HER2-positive, node-positive early stage invasive breast cancer include the following (although other regimens are also used):

>> AC followed by T: Doxorubicin ("A") / Cyclophosphamide ("C") followed by paclitaxel ("P") plus trastuzumab (HERCEPTIN) (various schedules)

OR

>> TCH: Docetaxel ("T") / Carboplatin "C") / trastuzumab (HERCEPTIN)

In other countries, FEC-based regimens may be more common (FEC = Fluorouracil/epirubicin/cyclophosphamide), such as FEC plus paclitaxel plus trastuzumab.

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Post-mastectomy radiation is a question for a trained Radiation Oncologist familiar with the relevant details of her diagnosis and treatment plan. If recommended, she should request details regarding the fields of radiation, and the basis for radiation therapy in her particular case (request the specific factors that warrant the recommendation).

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Regarding the sequence of treatments, per our local guidelines, "It is common for radiation therapy to follow chemotherapy when chemotherapy is indicated." And, "Chemotherapy and endocrine therapy used as adjuvant therapy should be given sequentially with endocrine therapy following chemotherapy. Available data suggest that sequential or concurrent endocrine therapy with radiation therapy is acceptable."

If you or you Mom have any concerns about any aspect of her treatment plan (systemic drug treatments or radiation) or the particular regimen, the best ways to probe medical advice are to seek review by a "Tumor Board" (multidisciplinary panel) at her current institution and/or to seek a second opinion at an independent institution. A second opinion may include a review of the actual pathology slides (sent overnight) by a Pathologist, as well as all related reports and test results, plus consultations with additional relevant experts, such as a Medical Oncologist and Radiation Oncologist.

Re timing of a second opinion, she can inquire with her current Radiation Oncologist and Medical Oncologist re by when each treatment (Chemo plus Herceptin; Radiation Therapy; Hormonal therapy) should be initiated and prioritize consultations accordingly. She should inform the independent institution of her date of diagnosis and date of surgery to ensure timely consultation and minimize or avoid delay in treatment. The second opinion place can advise what materials are needed and how and where to send them. Some lead time is needed to collect and send materials and obtain appointments.

If your mom has a primary tumor that is ER+ PR+ HER2+, this active "triple-positive" thread may be of interest, where many have received chemotherapy plus Herceptin and anti-hormonal therapy:

"Triple-positive Group": https://community.breastcancer.org/forum/80/topics/764183?page=1021#idx_30601

I am a layperson with no medical training, so be sure to confirm all outside information (including the above) with her treatment team to ensure receipt of current, accurate, case-specific expert professional medical advice.

BarredOwl

Hi Johncrow92:

It looks like she was diagnosed with invasive breast cancer, and it was accompanied by some DCIS. The Paget's disease of the nipple can be associated with invasive breast cancer and/or DCIS.

I had to look up "Invasive Cancer NST". This patient-oriented UK web site indicates that "NST" means "No Special Type" and corresponds to a "ductal" histology, which is the most common histology ("Invasive ductal carcinoma" or "IDC"). Please confirm it with her team.

>> http://www.cancerresearchuk.org/about-cancer/breast-cancer/stages-types-grades/types/invasive-breast-cancer

>> "NST stands for No Special Type. . . Most invasive breast cancers have no special features and so are classed as No Special Type. NST is also sometimes called NOS (not otherwise specified). It used to be called ductal carcinoma."

Re: "Advancement of cancer pT2 N1a(sn)"

This information is pertinent to stage. Staging has three main components:

>> T (tumor size), N (lymph node status), and M (evidence of distant metastases)

The surgical pathology of breast and lymph node tissues does not assess the question of distant metastasis (M status), so often the pathologist only includes The "T" and "N" status.

Please confirm it with her team, but under our local AJCC criteria:

AJCC Staging Summary: https://cancerstaging.org/references-tools/quickreferences/Documents/BreastMedium.pdf

p means "pathologic" (determined after surgical pathology)

T2 is a size-designation for invasive breast cancer where the tumor is " > 20 mm but ≤ 50 mm in greatest dimension"

This "T2" designation is consistent with the notation "Invasive cancer of the size: 3x1.3 cm, was removed", which would be a tumor that is 3 cm in or 30 mm in greatest dimension.

N1a applies when there are "Metastases in 1–3 axillary lymph nodes, at least one metastasis greater than 2.0 mm"

This is consistent with the notation that a "Cancer metastasis of diameter 2,1 mm found in 1/5 lymph nodes."

(sn) is a notation that stands for "sentinel node" and indicates that lymph node status ("N1a") was determined "solely on sentinel lymph node biopsy without subsequent axillary lymph node dissection."

In the absence of clinical symptoms and evidence of distant metastasis (e.g., from scans), "pT2 N1a" disease would be considered Stage IIB disease per the Anatomic Stage/ Prognostic Group chart in the AJCC summary chart on page 1 (please confirm it with her team):

Based on her treatment plan, I would infer that the immunohistochemistry (IHC) information regarding ER, PR and HER2 status is probably for the Invasive Cancer NST. Please confirm it with her team. If so, it indicates ER+ PR- HER2+ invasive disease. The invasive disease is grade 3 (highest grade), which is common with faster-growing HER2-positive disease. The Ki-67 is another marker of cell growth/proliferation, and is consistent with the high grade and HER2-positive status.

After proper local treatment for the Paget's, systemic treatment follows the usual guidelines. Anti-hormonal therapy is recommended for ER+ and/or PR+ pT2N1 disease. ER+ (20%) is sufficiently positive to support the recommendation (threshold is 1%).

Per my first post, under our local NCCN guidelines (Version 2.2017) applicable to early stage breast cancer, for invasive ductal carcinoma, that is node-positive (one or more metastases >2 mm to one or more ipsilateral axillary lymph nodes), hormone receptor positive (ER+ in her case) and HER2-positive is typically treated by the following systemic drug treatments:

>> Adjuvant chemotherapy + trastuzumab, followed by endocrine therapy (category 1)

(trastuzumab = HERCEPTIN)

Thus, the recommendation for systemic treatments that she received appears to be consistent with our local NCCN guidelines, and is within the standard of care in the USA.

(Note: In the USA, some patients with HER2-positive disease, particularly those with larger, node-positive, hormone receptor-negative (ER- PR-) tumors, may also receive a recommendation for a second HER2-targeted agent (pertuzumab (PERJETA) in addition to Herceptin). However, a recent trial showed relatively modest benefit in the adjuvant setting.)

You asked if they are "using same letters where my mom is living." Please check, but I do not think so. The notations "z,aa,dd" , "bb" and "x,y" were footnote references from the guideline document I cited.

I am not sure what initial regimen is being recommended to her. Does it contain four drugs or three drugs?

Is it "T plus trastuzumab"?

In this regard, one of the two "preferred" regimens under our local NCCN guidelines is:

• AC followed by T + trastuzumab (4 different drugs) (± pertuzumab (5 drugs))

(1) A = Doxorubicin (also known as "Adriamycin" or "A")

(2) C = Cyclophosphamide

(3) T = Paclitaxel (which is in the class of "Taxanes" or "T")

(4) trastuzumab (HERCEPTIN)

(5) (optionally plus pertuzumab)

AC followed by T + trastuzumab is a common regimen in her situation.

TCH (docetaxel/carboplatin/trastuzumab) (or TCHP (if pertuzumab is included)) is the second "preferred" option under NCCN guidelines.

The use of trastuzumab (HERCEPTIN) is critical for HER2-positive disease. It is a "targeted agent" meaning it is specific for HER2-positive cells, so it does not have the same side effect profile as chemotherapy.

The "AC" part of the regimen contains an "anthracycline" and sometimes impacts the heart. Typically, the AC is given for only four cycles (Cycled every 21 days for 4 cycles). Please confirm it with her team. After AC, an additional 12 weeks of paclitaxel and trastuzumab is given, with trastuzumab continuing to complete one year.

Selection of the particular chemotherapy regimen requires the expertise, training, and clinical judgment of a medical oncologist familiar with her diagnosis and presentation (age, co-morbidities), which none of us have. Your mom should discuss any heart conditions/concerns she may have with her Medical Oncologist and confirm that she is a suitable candidate for AC. In addition, to better understand the basis for the recommendation she can ask questions such as (you may think of more):

- What particular clinical and pathologic features in her case support the use of an anthracycline-containing regimen in her particular case?

- Are there any other suitable regimens for her particular case? What is known about comparable effectiveness of each? How do they compare in side effect profiles?

- What type of heart monitoring before or during treatment is recommended?

- Would TCH (docetaxel/carboplatin/trastuzumab) (which I believe does not contain an anthracycline, please confirm it) be a reasonable option for her or not? If not, why not? Any other suitable options?

Because selection of particular regimen requires some clinical judgment, a second opinion can be helpful (if she has time to do before she needs to start treatment).

Radiation Therapy: When the sentinel node biopsy is positive, sometimes further axillary surgery (completion axillary lymph node dissection "ALND") is performed in case there may additional involved nodes. However, ALND can substantially increase the risk of lymphedema, and more recently, some patients will receive a recommendation for Radiation Therapy instead of ALND.

As far as her prognosis, this is a question for her medical oncologist, in light of all relevant clinical and pathologic findings in her case.

Each treatment (chemotherapy plus trastuzumab; radiation; endocrine therapy) entails a risk / benefit analysis. In general, with higher risk disease, the risk reduction benefit of systemic drug treatments (which are proportional to risk) outweigh the risks of severe adverse effects on a statistical basis.

Again, please confirm all information with her team.

Best,

BarredOwl

[Edited a few tiimes]

BarredOwl - after lots of reading here for some weeks, I finally decided to post to ask specifically you a question. I really don't intend to hijack this thread from the original poster, but my question fits so well in here and you seem so knowable concerning therapy-recommendations.

I am German, ER-/PR-/HER2 +++ , and here my planned neoadjuvant therapy is:

4x DD EC (equals AC) + 12x weekly Paclitaxel + Herceptin + Perjata

BUT: They plan to add the Heceptin + Perjeta only every 3rd week to the Paclitaxel, meaning, I would only get it 4 times.

After surgery Herceptin would be given for another year or so.

I am wondering now, if I just misread other statements here on this website OR if in US and UK Herceptin + Perjeta is really administered with each of the 12x Paclitaxel. My tumor is at least 3cm, with lymph node involvement + LVI. Thus, my doctors wouldn't have a reason to "soften" anything - in the contrary rather.

Sorry for any language flaws. I'm trying hard. ;-)

Btw, had first dose of EC (AC) on June 29th and doing really well. Hardly any SE so far.

Hi Enia:

As you may know, I am a layperson with no medical training, and I did not receive a recommendation for either chemotherapy or HER2-targeted therapy. Although it is often possible to determine the HER2 status of very small invasive tumors (including microinvasive tumors ≤ 1 mm), the HER2 status of my small T1a-size IDC (1.5 millimeters) and additional microinvasion could not be determined (insufficient tissue remaining after other stains). Therefore, my own HER2 status is unknown.

The selection of a particular chemotherapy regimen requires the expertise, training, and clinical judgment of a medical oncologist familiar with your diagnosis and presentation (age, co-morbidities). Also, there are differences in practice between countries. I do not have any information about what local guidelines or the drug labels may provide in either the UK or Germany.

You noted: "BUT: They plan to add the Heceptin + Perjeta only every 3rd week to the Paclitaxel, meaning, I would only get it 4 times".

You asked whether in the USA "Herceptin + Perjeta is really administered with each of the 12x Paclitaxel".

I do not have knowledge of all possible regimens in use, but I can provide the following general background information:

United States FDA Label for pertuzumab (PERJETA) (March 2016):

https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125409s109lbl.pdf

Regarding dosage, the current FDA label in the USA provides for dosing every three weeks: "The initial dose of PERJETA is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks by a dose of 420 mg administered as an intravenous infusion over 30 to 60 minutes."

For the "Neoadjuvant Treatment of Breast Cancer" in particular, the FDA Label includes a section with specific regimens. It provides that "PERJETA should be administered every 3 weeks for 3 to 6 cycles as part of one of the following [regimens]."

The three specific Neoadjuvant (pre-operative) regimens set forth in the FDA Label are based on specific regimens used in some early trials that supported FDA approval, and variously include three (3), four (4) or six (6) cycles of Perjeta. (Based on clinical consensus guidelines, it appears that there are additional regimens in clinical use today.)

Thus, for neoadjuvant therapy, the FDA approved labeling in the USA provides for dosing every three weeks, for three, four or six cycles, depending on the underlying regimen.

NCCN Guidelines for Breast Cancer (Version 2.2017):

Our local NCCN guidelines (Version 2.2017) do not seem to include the exact "dose dense EC" regimen recommended to you, which may reflect regional differences in practice and health systems. However, the NCCN guidelines include various possible regimens for HER2-positive early stage breast cancer. One of our local preferred regimens was discussed above, and is noted as being suitable for neoadjuvant therapy:

• AC followed by T + trastuzumab ± pertuzumab

One example of the above regimen is:

AC followed by T chemotherapy with trastuzumab + pertuzumab

- Doxorubicin 60 mg/m2 IV day 1

- Cyclophosphamide 600 mg/m2 IV day 1

>>> Cycled every 21 days for 4 cycles.

Followed by:

- Pertuzumab 840 mg IV day 1 (first cycle) followed by 420 mg IV (subsequent cycles)

- Trastuzumab 8 mg/kg IV day 1 (first cycle) followed by 6 mg/kg IV (subsequent cycles)

- Paclitaxel 80 mg/m2 IV days 1, 8, and 15

>>> Cycled every 21 days for 4 cycles

- Trastuzumab 6 mg/kg IV day 1

>>> Cycled every 21 days to complete 1 y of trastuzumab therapy.

COMMENT: As you can see in the above example, in the second phase of weekly Paclitaxel, the trastuzumab + pertuzumab (Herceptin + Perjeta) is given on Day 1 of a 21-day cycle (every three weeks), while the paclitaxel is given on Days 1, 8 and 15 of the 21-day cycle (weekly), for a total of 4 cycles.

The above general information does not directly address your exact regimen. If you have any concerns about it, do not hesitate to ask your Medical Oncologist whether your particular regimen is featured in a clinical trial publication and/or is exemplified in local treatment guidelines. You can ask for a copy or a link.

I am glad to hear you are tolerating treatment well!

Best,

BarredOwl

SpecialK - thanks so much for answering. You exactly sensed my concerns about under-treatment. Yes, your AC-THP regimen seems pretty much the same as our "EC". The "E" is also an anthracycline, and the "C" is the same substance as yours. Generally, over here doctors are a little bit more cautious, though. Thus, they wouldn't turn regimen around to "THP - AC" because of the heart issues Herceptin might cause before anthracycline is given. There are also slight differences in the administration of Carboplatin. It's not part of "ordinary" Her2-positive treatment. It's advised for triple negative and/or proven genetic BC. Other than that, everything seems pretty much the same. Thank God for globalism & St. Antonio when it comes to this disease !!!

SpecialK - you gave me the right hint I overlooked so easily. The dosing is the key, of course. I wasn't aware of the different doses - rather didn't think of it. Thank you so much!

Just noting that my reply to Enia above focused on NEOADJUVANT pertuzumab (given before surgery), because Enia mentioned "my planned neoadjuvant therapy" in her post.

For those with a surgery-first treatment plan (who receive a recommendation for "adjuvant" therapy for HER2-positive disease): As SpecialK noted, the situation with respect to ADJUVANT pertuzumab (Perjeta) therapy in the USA differs somewhat. For example, adjuvant pertuzumab is not yet FDA approved; however, NCCN guidelines do include "off-label" use of adjuvant pertuzumab in certain specified cases. ASCO took a different view. Both NCCN guidelines re breast cancer (Version 2.2017, dated April 2017) and the ASCO guideline re adjuvant treatments (2016) do NOT reflect the most recent clinical trial of ADJUVANT pertuzumab (i.e, the APHINITY trial), because the results were only just published in June, 2017:

>> von Minckwitz (2017)(APHINITY): "Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer"

>> http://www.nejm.org/doi/full/10.1056/NEJMoa1703643?query=featured_home

>> "Patients with nonmetastatic, adequately excised, histologically confirmed invasive HER2-positive breast cancer were eligible for participation in the trial."

>> Miller Editorial (2017)(re APHINITY):http://www.nejm.org/doi/full/10.1056/NEJMe1706150

Those who receive a recommendation for adjuvant pertuzumab should be sure to discuss the APHINITY trial results with their medical oncologist.

BarredOwl